+1 (208) 254-6996 [email protected]
  

Is there gender bias in HIV cure research? A case study of female representation at the 2015 HIV Persistence Workshop

Rowena Johnston1*, Suteeraporn Pinyakorn2,3 and Jintanat Ananworanich2,3

Don't use plagiarized sources. Get Your Custom Essay on
Women, Gender, And Science
Just from $13/Page
Order Essay

1 amfAR, New York, USA 2 U.S. Military HIV Research Program, Walter Reed Army Institute of Research, Silver Spring, MD, USA

3 Henry M Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA

Introduction

According to the United States National Science Foundation 2015 report on women, minorities and persons with disabilities in science and engineering [1], 56.5% of college enrollees are women. Of the roughly 2.3 million freshmen who intend to major in biological and agricultural science, 63.2% are female. About 48% of people employed in life sciences are female. Of these 53.1% have doctoral degrees and 63% are technologists and technicians. Fewer than 25% of full professors are female. Of academic institution faculty, 47% of males have federal support, while 40% of women receive such support. The gender gap in science, technology, engineering and maths (STEM) participation is wider in almost every other region of the world [2]..

Several factors have been proposed to contribute to the progressively smaller female representation in positions of increasing seniority and success in STEM disciplines. Both male and female scientists cite historical bias in training of, and degrees awarded to, male scientists as explanations for the unequal participation of women in physics and biology, but men almost never cite present-day discrimination as a contributory factor [3]. Indeed, only in the last decade or so have doctoral degrees awarded to women reached parity with those awarded to men [4].

Yet, female scientists continue to encounter manifestations of sexism, defined by the online Merriam-Webster dictionary as: ‘1: prejudice or discrimination based on sex; especially: discrimination against women, 2: behavior, conditions, or attitudes that foster stereotypes of social roles based on sex’ [5], at all stages of their careers. A recent study [6] analysed the performance, outspokenness, and perceived subject mastery of undergraduates in an introductory biology course. Teachers rated the males as more outspoken. When students were asked to nominate which of their peers seemed to have mastered the subject matter best, males received more nominations than females, independent of their actual performance on exams. The bias was stronger among males – for a male to nominate a female versus a male, her grade point average (GPA) needed to be 0.765 higher than the male nominee‘s. Females nominated females and males at the same rate per GPA. The three to four most-nominated students in each of the three classes that were studied were male, despite the most-nominated females having better grades than some of the most-nominated males.

Across 18 academic fields, the terms ‘brilliant’ and ‘genius’ were disproportionately used by students to describe male rather than female instructors [7]. Faculty also rate male students more favourably than female students. Identical science laboratory manager job application materials were sent to biology, chemistry and physics professors. Materials were assigned either a male or female applicant name. Male and female faculty, regardless of their field, age or tenure status, viewed the female applicant as less competent than the (identical) male applicant, and offered her a significantly lower salary and less career mentoring [8].

Despite an increase in the proportion of biology or life sciences degrees awarded to women [1,4], proportionately fewer academic positions are held by or offered to women. An older study indicated a bias by both male and female faculty to hire a male job applicant into an academic department over an identical female, and to judge the male applicant‘s job experience as more satisfactory [9]. By contrast, a more recent study found evidence of bias towards women, where male and female biology faculty voted about 2:1 in favour of hiring a female over an identical male applicant [10]. A recent news feature article in Nature cites data that although 45% of PhDs in biology were earned by women between 1999 and 2003, only 26% of applicants for academic jobs were female. Those who did apply, however, were more likely to receive interviews and to be the first to be offered the job than men, and were more successful in tenure applications than men [11].

Although the pay gap between men and women is closing, female biologist salaries were only 77% of those of male biologists in 2008. In 2012, only 30% of NIH grants went to women, and the size of each grant was only 83% of those of men [11]. One important potential boost to early science careers, the NIH Director‘s Early Independence Award, for which host institutions nominate applicants, was awarded to proportionally (relative to applicants) twice as many males as females in 2015 [12]. Women publish fewer papers than men, and are under-represented in the prestige positions of first and last author. A recent analysis of scholarly articles spanning the sciences and humanities revealed that only one-in-five authors is female. Women represent almost 30% of authors in molecular and cell biology but are under- represented in the last author position, at approximately 15% [13]. Start-up support is significantly lower for female than male PhD basic scientists, where males received more than twice the funding for salary and other support, research technicians, equipment and supplies – a disparity not explained by years of experience or level of NIH support to the host institution [14]. Female physicians with faculty appointments also experience unequal career advancement: when adjusted for years since residency, scientific authorship, NIH funding and clinical trial participation, women are less likely to be full professors [15]. Perhaps not surprisingly, women are less satisfied with their careers as scientists than are men [16].

By analysing attendance at the most recent HIV cure-specific conference (the Seventh International Workshop on HIV Persistence During Therapy) and authorship of presented abstracts, we sought to determine whether there was evidence of gender bias in the selection, and type, of abstracts accepted by the conference.

Methods

HIV Persistence During Therapy conference

The Seventh International Workshop on HIV Persistence During Therapy took place in Miami December 8–11, 2015. According to the workshop‘s website [17], it was designed to interest physicians, clinicians, scientists and clinical researchers in the HIV persistence and latency arena. All attendees, whether submitting an abstract or not, were required to submit an application for

*Corresponding author: Rowena Johnston, amfAR 120 Wall Street, 13th Floor, New York, NY 10005-3908, USA

Email: [email protected]

Journal of Virus Eradication 2016; 2: 117–120 VIEWPOINT

© 2016 The Authors. Journal of Virus Eradication published by Mediscript Ltd This is an open access article published under the terms of a Creative Commons License. 117

review and approval by abstract reviewers and/or the conference steering committee. More than 140 abstracts were submitted and reviewed by 25 reviewers, with at least four reviewers per abstract. Selected abstracts were published as a supplement to the Journal of Virus Eradication issue 1.4 (www.viruseradication.com). Presentations at the conference were in the form of general overview of a topic (invited oral presentation), oral presentations and poster presentations.

Information concerning the number of attendees and fraction of whom were women was obtained from the conference organisers. Details of overview, oral and poster presentations, authors, and affiliations were extracted from the published abstracts. Information concerning abstracts that were submitted but not selected, or for attendance applications that were not accepted, was not available. Sex and country of affiliation was noted for each author, and the sex of the first author of each abstract was noted.

Sex and country affiliation determinations

Perceived sex, referred to here as variable ‘sex’, was noted for each abstract author as either male or female. Sex determinations were made on the basis of study authors’ familiarity with the abstract author or by internet search. In internet searches, photos of the abstract author were sought, where possible confirmed by mention of affiliation or co-authors, and a sex determination was made visually; or biographical documents were searched and scanned for mentions of ‘he’ or ‘she’, again where possible confirmed by mention of affiliation or co-authors. We are aware that potential errors inherent in this methodology may have led to misattribution of sex in some cases. In cases where sex appeared unclear, two or more study authors reached consensus or sex was marked as unknown and that abstract author was omitted from analyses, as noted below. Country affiliation was attributed as noted in the published abstract. In some cases the abstract noted only one affiliation for all authors, in which case that country was attributed to all authors on the abstract.

Descriptive and statistical analyses

Analyses of the sex and country affiliation of the steering committee, scientific committee, attendees and authors were conducted. Authorship analyses included: any-authorship; first- authorship of overview, oral and poster abstracts; any-authorship

of oral versus poster abstracts; authorship of multiple abstracts; authorship of multiple oral versus poster abstracts; and authorship when only one abstract was selected. We assumed the number of abstracts for each author follows the Poisson distribution. Rate ratios and 95% confidence intervals (CI) were obtained by Poisson regression model to compare first authorship rates among female versus male for each type of abstract. Chi-squared test for trend was used to assess whether the proportion of female authorship decreased with more prestigious presentations (where invited overview presentations were considered more prestigious than an oral presentation, which in turn were more prestigious than a poster presentation). We tested whether the proportion of female authorship deviated from 0.5, indicating equality between male and female, by binomial probability test. All analyses were performed using Stata Statistical Software Release 13 (StataCorp, College Station, TX, USA). Significance was set at alpha equal to 0.05 and all P values are two-sided.

Results

Overview

The workshop steering and scientific committees (‘conference directorship’) consisted of 36 males and seven females. There were 259 workshop attendees, of whom 152 (59%) were male and 107 (41%) were female (P=0.006). Of 720 unique abstract authors, 701 were of known sex, of whom 294 (42%) were female. The conference directorship had significantly lower female representation than either attendees (P=0.005) or abstract authors (P=0.003). The 407 male authors had 554 abstracts, averaging 1.36 each, whereas the 294 female authors had 380 abstracts, averaging 1.29 each (P=0.42). Abstract authors noted affiliations in 21 countries, with 56.3% of all authors from the US. Female representation from each country ranged from 0 to 67% (Figure 1).

Authorship of overview vs oral vs poster presentations

The conference consisted of three types of presentations: overview presentations to orient the audience to a session theme, oral presentations and poster presentations. There were nine overview presentations, of which two (22.2%) were delivered by females. Of 53 oral presentations, 21 (39.6%) were first-authored by females. Of 75 poster presentations, 73 were first-authored by

Figure 1. Percentage of male and female authors from each of 21 countries represented at the workshop. Numbers in parentheses indicate total number of authors from each country

VIEWPOINT Journal of Virus Eradication 2016; 2: 117–120

118 R Johnston et al.

authors of known sex, of whom 41 (56.2%) were female (Figure 2). A chi-squared test for trend indicated that higher-prestige presentations were less likely to be presented by females (P=0.02).

Each overview presentation had one author. There were 416 oral abstract authors of known sex, and each oral abstract averaged 8 authors, of whom 153 (36.8%) were female. There were 508 poster abstract authors of known sex, and each poster abstract averaged 6.9 authors, of whom 220 (43.3%) were female. A significantly greater proportion of poster compared to oral presentation authors were female (P=0.003, Figure 3).

Six hundred and twenty-two authors of known sex had only one type (either oral or poster) of abstract accepted. Two hundred and seventy-one authors had only oral abstracts (one or more) accepted, of whom 103 (38%) were female, while 351 authors had only poster abstracts (one or more) accepted, of whom 163 (46.4%) were female (P=0.002, Figure 4).

One oral and one poster abstract were withdrawn and no data were available on these.

Authors with more than one abstract

One hundred and forty authors of known sex had more than one accepted abstract. Of the twelve authors with five or more abstracts, none were female (P≤0.001, Figure 5).

Considering authors with multiple oral abstracts, five authors had four or more oral abstracts, of whom none were female, although

this difference did not quite reach statistical significance (P=0.06, Figure 6).

Authors with one abstract

Five hundred and sixty-one authors of known sex had one abstract, of whom 235 (41.9%) were female. Of the 239 authors whose single abstract was oral, 90 (37.7%) were female, whereas for the 322 authors whose single abstract was poster, 145 (45%) were female, a difference that did not quite reach statistical significance (P=0.08).

Figure 2. The percentage of male vs female first-author presenters of each of the three types of presentations

Figure 3. Percentage of total oral and poster authors who were male vs female

Figure 4. Of authors whose only accepted abstracts were oral or poster, percentage who were female vs male

Figure 5. The percentage of authors with two or more, three or more, four or more, or five or more total abstracts who were male vs female. Note: Authors in higher categories (e.g. 5+) are also represented in lower categories (e.g. 4+ etc.)

Figure 6. The percentage of authors with two or more, three or more, or four or more oral abstracts who were male vs female. Note: Authors in higher categories (e.g. 4+) are also represented in lower categories (e.g. 3+ etc.)

Is there gender bias in HIV cure research? 119

Journal of Virus Eradication 2016; 2: 117–120 VIEWPOINT

Discussion We observed that female authors were proportionately less likely to hold more prestigious roles (e.g. presenting author) at the conference. The directorship of the conference had a significantly lower female representation than among attendees or authors. Females were less likely to give oral or overview presentations. Although we have no privileged insight into the thinking behind the conference planning, it seems possible that the directorship made a proactive effort to ensure higher representation of females than among their own ranks. The authors also represented a wide range of countries, again suggesting that the directorship was interested in promoting diversity. These findings suggest that sexism was none the less apparent.

According to the authors of a recent study, male scientists may be less likely than female scientists to perceive sexism or to value efforts to change it [18]. In a series of three experiments, researchers asked the general public, and faculty from non-STEM or STEM fields, to read an academic abstract describing sexism in STEM research. The research was evaluated less favourably by male than female participants from the general population. However, while there was no sex difference in evaluations by non-STEM male and female faculty, male STEM faculty evaluated the research more negatively than female STEM faculty, and the effect size was larger than among the general population. To evaluate whether male STEM faculty were antipathic towards gender bias research in general, the abstract was altered slightly to report no gender bias. Under these conditions, male STEM faculty evaluated the research more positively than did female STEM faculty. The study authors suggest that because STEM fields are male-dominated, broadening female participation will be especially challenging.

It is important to distinguish between the impact of sexism versus intent. Although we do not have access to data to support our view, we do not believe that the conference planners intended to have fewer females in prestigious presentation roles. There is ample recent research demonstrating that men and women can be exposed to beliefs throughout their lifetime that are internalised and that manifest later as poorer performance by women in traditionally male-dominated fields, or the expectation that women will perform more poorly [19,20]. Alternatively, there may be no bias against women if other factors are controlled for. Ceci and Williams [21] suggest that when resources are comparable between men and women, there is no sex discrimination in publishing, but they acknowledge that resources are not in fact comparable between the sexes.

The female participation and authorship at this conference were both around 42%. It is difficult to know how this rate compares to the HIV field in general, but at the opening session of the 2016 Conference on Retroviruses and Opportunistic Infections, it was announced that 47% of attendees were female [22], suggesting that the cure field, at least as represented at this persistence conference, may be slightly more male-dominated than HIV in general. We also had no access to data concerning rejected abstract submissions and thus cannot draw conclusions in terms of potential gender biases regarding rejections. We analysed data from only one conference that was held in the USA and female representation in other meetings, particularly those held elsewhere, may be different.

Although there may have been conscious or unconscious bias at the abstract review level, it appears more likely that some constellation of the factors discussed here – an early internalisation

of stereotyped gender roles by both sexes, the preferential encouragement of males in STEM fields by male and female peers and teachers, the disproportionate hiring and early career support of males, the higher level of grant support awarded to males resulting in the potential for higher impact research, and the historical bias towards males in STEM fields resulting in males holding more senior positions – contributed to the sex differences in authorship prestige observed in this study. We encourage conference organisers of HIV cure-related conferences to be cognisant of the broader influence their decisions may have regarding the allocation of higher prestige oral presentation slots.

Acknowledgements

We thank Ms Oratai Butterworth for her help in preparing this manuscript.

Disclaimer

The views expressed are those of the authors and should not be construed to represent the positions of the US Army or the Department of Defense

References 1. National Science Foundation. Women, minorities and person with disabilities in

science and engineering. 2015. Available at: www.nsf.gov/statistics/2015/ nsf15311/start.cfm (accessed February 2016).

2. Andres JTH. Overcoming gender barriers in science: facts and figures. 2011. Available at: http://www.scidev.net/global/education/feature/overcoming-gender- barriers-in-science-facts-and-figures-1.html (accessed March 2016).

3. Ecklund HE, Lincoln EA, Tansey C. Gender segregation in elite academic science. Gender & Society 2012; 26: 693–717.

4. Burrelli J. Thirty-three years of women in S&E faculty positions. 2008. Available at: www.nsf.gov/statistics/infbrief/nsf08308/ (accessed February 2016).

5. Merriam-webster. Definition of sexism. Available at: www.merriam-webster.com/ dictionary/sexism (accessed February 2016).

6. Grunspan DZ, Eddy SL, Brownell SE et al. Males under-estimate academic performance of their female peers in undergraduate biology classrooms. PLoS One 2016; 11: e0148405.

7. Storage D, Horne Z, Cimpian A, Leslie SJ. The frequency of “Brilliant” and “Genius” in teaching evaluations predicts the representation of women and African Americans across fields. PLoS ONE 2016; 11: e0150194.

8. Moss-Racusin CA, Dovidio JF, Brescoll VL et al. Science faculty‘s subtle gender biases favor male students. Proc Natl Acad Sci U S A 2012; 109: 16474–16479.

9. Steinpreis ER, Anders AK, Ritzke D. The impact of gender on the review of the curricula vitae of job applicants and tenure candidates: a national empirical study. Sex Roles 1999; 41: 509–528.

10. Williams WM, Ceci SJ. National hiring experiments reveal 2:1 faculty preference for women on STEM tenure track. Proc Natl Acad Sci U S A 2015; 112: 5360–5365.

11. Shen H. Inequality quantified: mind the gender gap. Nature 2013; 495: 22–24.

12. Nature.com. Funding: gender grant disparity. 2016. Available at: www.nature.com/ naturejobs/science/articles/10.1038/nj7590–373c (accessed February 2016).

13. West JD, Jacquet J, King MM et al. The role of gender in scholarly authorship. PLoS One 2013; 8: e66212.

14. Sege R, Nykiel-Bub L, Selk S. Sex Differences in Institutional Support for Junior Biomedical Researchers. JAMA 2015; 314: 1175–1177.

15. Jena AB, Khullar D, Ho O et al. Sex differences in academic rank in US medical schools in 2014. JAMA 2015; 314: 1149–1158.

16. Holden C. General contentment masks gender gap in first AAAS salary and job survey. Science 2001; 294: 396–411.

17. hiv-persistence.com. 8th Edition HIV Persistence During Therapy, Reservoirs & Eradication Strategies Workshop. Available at: www.hiv-persistence.com/ (accessed February 2016).

18. Handley IM, Brown ER, Moss-Racusin CA, Smith JL. Quality of evidence revealing subtle gender biases in science is in the eye of the beholder. Proc Natl Acad Sci U S A 2015; 112: 13201–13206.

19. Tiedemann J. Gender-related beliefs of teachers in elementary school mathematics. 2005. Available at: http://link.springer.com/article/10.1023/A:1003953801526 (accessed February 2016).

20. Dar-Nimrod I, Heine SJ. Exposure to scientific theories affects women‘s math performance. Science 2006; 314: 435.

21. Ceci SJ, Williams WM. Understanding current causes of women‘s underrepresentation in science. Proc Natl Acad Sci U S A 2011; 108: 3157–3162.

22. Conference on Retroviruses and Opportunistic Infections. Webcasts 2016. Available at: http://www.croiwebcasts.org/ (accessed February 2016).

VIEWPOINT Journal of Virus Eradication 2016; 2: 117–120

120 R Johnston et al.

HIV PATHOGENESIS AND TREATMENT (AL LANDAY AND N UTAY, SECTION EDITORS)

Sex Differences in HIV Infection

Eileen P. Scully1

Published online: 5 March 2018 # The Author(s) 2018. This article is an open access publication

Abstract Purpose of Review This review will outline the multilevel effects of biological sex on HIVacquisition, pathogenesis, treatment response, and prospects for cure. Potential mechanisms will be discussed along with future research directions. Recent Findings HIV acquisition risk is modified by sex hormones and the vaginal microbiome, with the latter acting through both inflammation and local metabolism of pre-exposure prophylaxis drugs. Female sex associates with enhanced risk for non- AIDS morbidities including cardiovascular and cerebrovascular disease, suggesting different inflammatory profiles in men and women. Data from research on HIV cure points to sex differences in viral reservoir dynamics and a direct role for sex hormones in latency maintenance. Summary Biological sex remains an important variable in determining the risk of HIV infection and subsequent viral pathogen- esis, and emerging data suggest sex differences relevant to curative interventions. Recruitment of women in HIV clinical research is a pathway to both optimize care for women and to identify novel therapeutics for use in both men and women.

Keywords HIV . Sex . Inflammation . Prevention . Pathogenesis . Cure

Introduction

A combination of environmental factors, host genetics, and viral features determines the acquisition and pathogenesis of HIV infection. Some of these features, such as host HLA genotype, have been delineated, but the diversity of clinical manifestations of HIV suggests multiple sources of variation that are, as yet, undefined. Biological sex, with a distinct ge- netic complement, hormonal environment, and behavioral and social context, is a substantial contributor to heterogeneity in host responses. Research defining sex differences serves a dual purpose: first, defining sex-specific responses will insure that interventions have efficacy in both men and women, and second, differences may highlight pathways that can be mod- ulated in both sexes to optimize treatment and prevention and curative interventions.

Clinical studies to isolate the effects of biological sex are challenging, but work to date has yielded important insights. This review will address sex-specific features of HIV preven- tion, pathogenesis, and cure research, and then outline poten- tial biological mechanisms for these differences. Finally, bar- riers to research on sex differences and to enrolling women in clinical trials are discussed, along with the opportunities to circumvent these obstacles.

Prevention

Sex-Specific Acquisition Risks

The risk of HIV seroconversion per heterosexual act is esti- mated to be approximately twofold higher for the female com- pared to male partner [1], with multiple contributing factors. The unique characteristics of the female genital tract as com- pared with rectal and penile mucosal surfaces confer differ- ences in transmission risk. Inflammation at the cervicovaginal mucosa lowers the barrier to HIVinfection [2–5], and both the vaginal microbiome itself [6] and sexually transmitted infec- tions [7–11] are important determinants of the levels of local inflammation. The association of depot medroxyprogesterone (DMPA) hormonal contraception with enhanced risk of

This article is part of the Topical Collection on HIV Pathogenesis and Treatment

1 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Pre-Clinical Teaching Building, Suite 211, 725 N Wolfe Street, Baltimore, MD 21205, USA

Current HIV/AIDS Reports (2018) 15:136–146 https://doi.org/10.1007/s11904-018-0383-2

http://crossmark.crossref.org/dialog/?doi=10.1007/s11904-018-0383-2&domain=pdf
mailto:[email protected]
infection (hazard ratio of 1.4) [12–14] underlines the sex- specific risk associated with hormone exposure, which also impacts the vaginal microbiome. Clearly, these factors have distinct manifestations in the male and female genital tracts and these basic differences have important implications for prevention interventions discussed below.

Vaccine Responses

Sex differences in both adverse effects and the efficacy of protective responses to vaccination are well described [15]. These differences are of clinical significance as seen in the higher rates of vaccine-associated severe viscerotropic yellow fever disease in women [16, 17] and the HSV glycoprotein vaccine that was protective only in women [18]. The mecha- nisms driving these differences are not totally clear; no specif- ic immunologic correlate was reported for the sex differences in the HSV vaccine trial [18] although subsequent work sug- gested that specific epitopes may be preferentially recognized in women [19]. Systems biology analysis of gene expression profiles after yellow fever vaccine identified sex-specific pro- grams of gene induction [20], highlighting the potential for studies of sex differences to identify correlates of successful protection. In HIV vaccine trials, there has not been clear evidence of sex differential effects. In the RV144 study, pro- tective efficacy was estimated 25.8% in men (n = 4875) and 38.6% in women (n = 3085), with no statistical difference as- sociated with sex [21]. In terms of immune correlates of pro- tection, differences in humoral and cell-mediated immune re- sponses have been seen in multiple vaccines [20]. Mechanistically, there is evidence for more potent induction of inflammatory pathways in cytotoxic T cells from women [22]; sex comparison of the magnitude and breadth of T cell responses induced by vaccines would be of interest. Likewise, there is data to suggest that somatic hypermutation is en- hanced by estrogen [23] and that antibody glycosylation pat- terns are influenced by sex [24] suggesting that biological sex may influence both antibody affinity and non-neutralizing functions.

Moving forward, sex-specific analyses of both efficacy and immune correlates of protection should be leveraged to en- hance responses. For example, sex-specific induction of type 1 interferons or the inflammasome might indicate a role for specific adjuvanting strategies in men versus women. Given the challenges of vaccine development, all avenues for opti- mization bear consideration.

Pre-Exposure Prophylaxis

In the absence of an effective vaccine, pharmacologic strate- gies have become a critical adjunct to the prevention of trans- mission. Notably, despite initial studies showing high levels of efficacy for PrEP in men who have sex with men [25] and in

serodiscordant couples [26], studies of PrEP exclusively in women showed no efficacy, results that were attributed to very low adherence to study drug [27, 28]. Clinical pharmacology studies have highlighted differences in drug concentration at the rectal mucosal and cervicovaginal tissues [29] that may obligate different levels of adherence in women versus men to maximize effectiveness. To circumvent this, topical delivery designed for the vaginal microenvironment is another poten- tial route to modulate risk of infection in women; the CAPRISA 004 study reported a 39% risk reduction with tenofovir gel [30], although the VOICE study, which was limited by low adherence, did not show efficacy in the vaginal gel arm [27]. The topical approach using a vaginal ring prep- aration of the novel antiretroviral dapivirine has recently dem- onstrated a significant but modest reduction in the risk of HIV acquisition (27–31%) [31, 32]. Importantly, recent work has shown that adherence is not the only challenge to the topical approach. Local metabolism of tenofovir itself by components of the vaginal microbiome is associated with reduced efficacy of protection [33]. As studies defining the effects of topical exposure at the rectal mucosa have suggested that tenofovir may increase certain inflammatory mediators [34], specific assessment of the in vivo cervicovaginal effects is also war- ranted. Further studies are necessary to define the optimal approach to risk reduction in both men and women; advan- tages of topical preparations must be considered in light of adherence challenges, and careful studies are necessary to fully define sex-specific modulators of efficacy at the sites of acquisition. Taken together, the data suggest that there are sex-specific features of risk perception and medication adher- ence, along with critical differences in pharmacologic proper- ties and the microenvironment at sites of acquisition in men and women. Considering these differences will be critical in the design and implementation of chemoprophylaxis strategies.

Pathogenesis

Disease Progression

Sex is a clear contributor to disease pathogenesis in multiple infectious diseases [35], and HIV follows this paradigm. Across most studies, women have lower HIV viral loads early during infection but despite this difference, disease progres- sion is comparable between the sexes [36–46]. Substantial differences in immune activation may underlie this apparent paradox; women have higher CD8+ Tcell activation at a given level of HIV viremia, corresponding to activation seen in men at one log10 higher viral load [47]. Similarly, the expression of interferon-stimulated genes was higher in women when con- trolling for HIV viral load [48]. Given the role of immune activation in driving HIV disease progression [49, 50] and in

Curr HIV/AIDS Rep (2018) 15:136–146 137

comorbidities that emerge during effective ART [51, 52], the sex difference in immune setpoint likely has clinical consequences.

In selected individuals, HIV disease progression is attenu- ated, with either spontaneous control of viral replication in the absence of drug therapy [53–55] or sustained viral suppres- sion after interruption of ART (post-treatment controllers; PTCs) [56]. The factors that allow natural control of HIV are not fully defined but include host genetics, highly efficient immune responses, and in select cases, viral fitness [53–55]. Cohort studies have reported that women are more likely to be categorized as spontaneous controllers of HIV [57, 58] al- though the determinants of this advantage have not been elu- cidated. Similarly, women are overrepresented in cohorts of post-treatment control: women were 36% of PTCs, 43% of low viremia patients (viral load between 50 and 500), and only 14% of post-treatment non-controllers in one study [59]. Again, sex-specific mechanisms of protection have not been defined within this group, and it should be noted that the total numbers evaluated are very low. Thus, although limited by biases in case finding, women more frequently demonstrate phenotypes of viral control. This suggests that identifying sex determinants of immune response and viral setpoint may shed light onto features of a successful host response.

Response to Treatment

Consistent with sex differences in pharmacokinetics/pharma- codynamics, drug metabolism, body composition, and drug distribution, the rates of adverse reactions with the early gen- eration of antiretroviral therapies showed sex variation [60, 61]. Efforts to analyze these differences are hampered by the limited enrollment of women in trials of new therapeutics [62]. In response to this challenge, the GRACE (Gender, Race And Clinical Experience) trial specifically enrolled women to determine the sex-specific efficacy of a darunavir- based ART regimen [63] and yielded critical insights into the barriers to participation by women (discussed further below) [64]. Recent subgroup analyses of therapeutic trials have largely demonstrated similar efficacy in men and women, con- sistent with the improved therapeutic index of modern antiretrovirals [65–67]. However, unanticipated effects of antiretrovirals, such as the recently reported weight gain asso- ciated with integrase inhibitor regimens in a predominantly male cohort (14% women in integrase inhibitor subgroup) [68], should be carefully evaluated for sex effects. In addition, the response to treatment as measured by CD4+ T cell recov- ery has been reported to favor women, although with unclear implications for immune competence [69]. Complications of immune reconstitution such as the immune reconstitution in- flammatory syndrome (IRIS) have not been reported to have a particular sex predilection. However, this is difficult to clearly establish given the heterogeneity in case definitions of IRIS,

bias for women to be enrolled in resource-limited settings, and lack of disaggregation of data by sex in some larger studies.

Treatment-induced changes in biomarkers of inflammation also show discordance; in one cohort, women had higher baseline high-sensitivity C reactive protein (hsCRP) levels and less change with therapy, along with higher levels of sol- uble CD163, a marker of monocyte activation [70]. Other cohorts have reported similar differences in response to treat- ment, although inconsistent differences in baseline levels [71]. Further work will be necessary to dissect the direct contribu- tion of HIVand ART as compared with concurrent inflamma- tory stimulators such as coinfections and smoking, and modulators such as sex hormones given the potential for direct effects of estrogen on some markers such as CRP [72]. Overall, women and men can both achieve viral suppression with ART but differences in residual immune activation and reconstitution may remain, with consequences for comorbid conditions.

Non-AIDS Morbidity and Mortality

With the advent of effective ART, morbidity and mortality among people living with HIV has shifted to non-AIDS events including cardiovascular disease, cancer, and neurocognitive dysfunction, many of which are driven by inflammatory con- sequences of HIV infection. Biological sex is one contributor to the multifactorial determinants of these comorbidities [52]. The excess risk of cardiovascular events in people living with HIV [73] is amplified in women [74] and linked to higher levels of circulating markers of monocyte activation [75]. Likewise, the increased risk of cerebrovascular events in HIV-infected individuals [76, 77] is exaggerated in women [78]. Of note, the epidemiology of these comorbid conditions varies significantly across different social and geographic con- texts obligating thoughtful design of trials to assess for the contribution of sex [79]. The differences in risk profile be- tween men and women highlight the potential for studies of sex differences to identify causal pathways or biomarkers of disease pathogenesis.

HIV Eradication and Functional Cure

The goal of HIV eradication or functional cure has become a focal point for HIV research. It is not known whether sex differences in viral and inflammatory set points in untreated infection translate into differences in ART-treated disease that have implications for HIV cure efforts. As women bear half the burden of the HIV epidemic, any intervention that will have a meaningful impact will need to be effective for both men and women. Importantly, several of the interventions in development for HIV cure are immunomodulatory [80]; this is an important divergence from the direct antiviral agents used

138 Curr HIV/AIDS Rep (2018) 15:136–146

in suppressive ART. Subtle immunologic differences between men and women may play a critical role in determining the safety and efficacy of curative interventions.

There are limited data defining sex differences in viral res- ervoir size and dynamics. Two cross-sectional studies with approximately 30% enrollment of women reported lower levels of HIV DNA in women [81, 82]. However, data from a prospectively enrolled cohort of ART-treated men and wom- en did not show any significant difference in HIV DNA levels, but rather showed lower levels of residual viremia by single copy assay and lower levels of multiply-spliced cell associated HIV RNA from women (Scully et al., Abstract 281, CROI 2017). In general, conclusions are limited by the underrepre- sentation of women in studies relevant to cure [83]. Specifically, in seminal work comparing different methods of reservoir quantitation, there were no XX participants and only 2 of 30 are identified as transgender (male to female) without data about exogenous hormone exposure [84]. In studies assessing the role of HIV DNA in predicting viral rebound, cohorts have been 82–100% male [85–87]. Of par- ticipants in trials of the histone deacetylase (HDAC) inhibitor class of latency reversal agents, only 2 of 50 participants were women [88–91]. As mentioned above, curative interventions such as TLR agonists and exhaustion reversal with immune checkpoint inhibitors are primarily targeting host and not viral factors. Both the TLR7 agonist pathway [47] and the immune checkpoint inhibitor pathways [92, 93] have shown sex- specificity in other contexts that should be considered careful- ly in the development of clinical trials.

Potential Mechanisms

Outlined above are multiple features of HIV acquisition, pre- vention, pathogenesis, and persistence that show sex varia- tion. Behavioral and social characteristics differ between men and women, and these factors play an important role in sexual agency, reproductive health, and access to education and medical care. Indeed, sex-specific behaviors around ad- herence to interventions proved to be critical modifiers of the efficacy of PrEP [94]. Aside from these factors, there are a few domains of biological sex-specificity that are likely contribut- ing to differences and can be exploited to therapeutic benefit (Fig. 1).

Sex Hormone Effects

As noted above, there is an association with DMPA contra- ceptive use and enhanced rates of infection. The precise mech- anisms are unclear, as the progestin-associated thinning of the vaginal mucosal observed in non-human primate models [95–97] has not been seen in women [98–102]. Recent data identified endogenous and exogenously administered

progesterone-induced variations in the frequency of cervical HIV-susceptible target cells [103]. There are additional inter- sections between sex hormone levels and inflammation in- duced by microbiome composition and concurrent infections [104]. Given the global need for effective family planning methods and widespread use of hormonal contraception, de- termining the mechanisms of hormonal contribution to risk of infection and potential pathways for modification is of critical importance.

Outside of acquisition, estrogen is also a direct modifier of HIV transcription. Previous work has demonstrated that the estrogen receptor can be indirectly recruited to the HIV-1 long terminal repeat (LTR) and act to repress transcriptional activ- ity [105]. More recently, using an unbiased small hairpin RNA screening strategy, the estrogen receptor was identified as a potent inhibitor of HIV transcription in latency models and primary cells (Karn et al., IAS, 2015; Das et al., submitted). Ex vivo studies using primary cells from both men and wom- en confirmed that estrogen is repressive to latency reversal, and that blockade of the estrogen receptor can enhance reac- tivation (Karn et al., IAS 2015; Das et al., submitted).

Sex hormones have also been reported to have a variety of direct effects on immune cell function. Both estrogen and progesterone have been reported to modulate plasmacytoid dendritic cell IFNα secretion [47, 106–109]. Cytotoxic Tcells from women have higher expression of inflammatory/ cytotoxic pathways after ex vivo restimulation, and multiple genes in these pathways have estrogen responsive elements in their promoters [22]. Of note, the presence of estrogenic com- pounds in standard cell culture media components [110, 111] and the difficulty in replicating the in vivo balance of hor- mones with in vitro studies obligates careful interpretation of these studies. However, hormonal pathways can be safely modulated in vivo and offer a potential adjunctive therapeutic pathway that may be of use in studies of HIV cure.

Microbiome

Sex-specificity of the microbiome composition in the genital tracts is one determinant of the local immune environment. Further, recent work identified novel features of this relation- ship, with specific microbiome components associated with alterations in wound healing [112] and direct microbial me- tabolism of tenofovir associated with reduced efficacy of PrEP in the female genital tract [33]. Aside from this direct role, animal studies have demonstrated that sex hormones impact microbiome composition in the gut, with implications for sex- specific susceptibility to autoimmunity [113, 114]. Studies have confirmed sex variation in gut microbial contents in humans [115–117] and further work will be necessary to de- termine if these differences have consequences for inflamma- tion in HIV disease. Interventions to reshape the microbiome (e.g., with probiotics) may offer therapeutic benefits.

Curr HIV/AIDS Rep (2018) 15:136–146 139

Genetic Differences

The sex-specific chromosomal complement is an additional pathway to biological differences. The X chromosome carries critical immune genes including TLR7, which encodes a path- ogen sensor, FOXP3, a transcription factor critical for regula- tory immune responses, and 10% of all microRNAs which have pleiotropic regulatory roles [118].

As some sex differences including lower viral loads in fe- males are present prior to the onset of puberty, non-hormonal mechanisms including genetics are likely to play a role [119]. Gene dosage effects are attenuated by X chromosome inacti- vation, but the enhanced risk of female predominant diseases such as systemic lupus erythematosus in phenotypic males with XXY karyotype suggests that this is incomplete [120]. Growing evidence demonstrates that up to 20% of X

chromosome genes escape inactivation [121]; this has clinical implications, with recent work suggesting that these genes may determine a portion of sex-specific susceptibility to can- cer [122]. The role of sex chromosome-encoded genes in dif- ferential vaccine responses, HIV pathogenesis, and cure ef- forts is undefined; it is notable that the HIV controllers genome-wide association study to assess for genetic determi- nants of spontaneous control was restricted to autosomes [123]. Studies to identify polymorphisms in sex chromosomal genes should be pursued.

Of note, research has also demonstrated sex-specific tran- scriptional programs related to both chromosomal determi- nants and ongoing hormonal programming [124]. Analysis of the methylation patterns and transcriptome of immune cell subsets identifies differences between men and women, supporting a potential role for epigenetic regulation in sex

Fig. 1 Summary of five critical domains of sex differences with relevance for HIV infection and potential or demonstrated mechanisms for their effects

140 Curr HIV/AIDS Rep (2018) 15:136–146

differences in immune responses [125]. Given the potential use of epigenetic modifiers in latency reversal, sex-specific patterns of epigenetic regulation should be explored.

Immunological Differences

The combined effects of sex hormones, microbiome, and chromosomal complement contribute to distinct immune pro- files. Preliminary work suggests that the relationship between residual virus activity and T cell activation and exhaustion phenotypes may be different between men and women, with men showing more activation and exhaustion and more cor- relations with measures of viral reservoir (Scully et al., Abstract 281,CROI 2017). Previous work has also demon- strated sex differences, partially mediated by estrogen, in an- tibody features including subclass, levels of hypermutation, and Fc glycan modifications [23, 24]. Sex-stratified compari- sons of the humoral responses to vaccines may provide insight into the critical features of a successful response.

Also notable is the role of sex hormones in lipid metabo- lism that is in turn linked to innate cellular activation and risk of non-AIDS morbidity and mortality in HIV infection [126, 127]. Of note, recent data suggests that there may be sex- specific responses to lipid-lowering therapy, with women showing qualitatively greater reductions in sCD163 after treat- ment with pitavastatin [128]. In studies of soluble markers of inflammation, sex differences in baseline levels and in the changes after ART initiation have been reported; neopterin (marker of cellular activation associated with HIV-related neurocognitive disease) was higher in women with impaired cognition, a finding not observed in men alone, and TNF-RII was similarly elevated in cognitively impaired women but not in men [129]. In a heterogenous cohort of men and women from multiple global sites, women were reported to have low- er baseline levels of CRP, lipopolysaccharide, and soluble CD14 (sCD14) but less decrease in CRP and sCD14 and more increase in TNFα after ART [71]. In contrast, in a more ho- mogenous cohort comparison, women had lower CRP than men did at baseline but again showed limited change after initiation of ART [70]. In total, the data are far from definitive and the multiple determinants of inflammatory outcomes in- cluding coinfections, microbiome differences, sex hormones, and immune setpoints will need to be carefully parsed to guide interventions. What is clear is that sex is a modifier of immune responses and may also dictate which biomarkers are predic- tive of risk for a particular population.

Gaps in Knowledge and Opportunities

Historically, there has been limited enrollment of women in clinical trials of HIV therapy in the developed world, a prob- lem that has extended to the field of cure research [62, 83,

130]. Given the multiple lines of evidence for sex-based dif- ferences in immune responses [131], HIV disease pathogene- sis [132], and pharmacokinetics/pharmacodynamics [133], it is imperative that biological sex is considered in the develop- ment and implementation of new clinical interventions; suc- cessful innovations will need to have efficacy in both men and women. Further, as discussed above, sex differences offer a comparator point that may elucidate pathways critical for ro- bust immune responses or curative strategies that can be lev- eraged to therapeutic success in both sexes.

Although not the focus of this review, the intersection be- tween genetic complement and sex hormone exposure is par- ticularly highlighted in transgender individuals. Given the burden of HIV in transgender individuals [134] and growing evidence for the feasibility of high-quality studies in this pop- ulation [135], HIV cure research needs to include transgender participants. Thoughtful comparative analysis may point to mechanistic links between the genetic complement and hor- monal exposure and virologic and immunologic outcomes and will be critical to verify the safety and efficacy of pro- posed interventions.

Given the importance of analyzing the role of sex [136], what are the barriers to implementation? From the perspective of the investigator, the cyclic variation in hormone levels and/ or exogenous hormone administration and potential for preg- nancy introduce variables and safety concerns that can require larger sample sizes and more intensive monitoring of interven- tions. These concerns notwithstanding, the global burden of HIV infection in women and the population of women and girls at risk obligates that research specifically address the optimal treatment, prevention, and curative interventions for women [137]. From the view of the potential study partici- pants, engagement with research, education about risks and benefits, and addressing logistical challenges to enrollment are all feasible [138]. Prior work has established that women can be successfully recruited and retained in HIV research [139, 140], and these experiences should be used to guide recruitment efforts. In addition, exploratory basic and clinical studies should report data by sex; while not always sufficient for a powered analysis, this data can be helpful in aggregate to determine when sex differences bear more focused investigation.

Conclusion

Sex differences in HIVarise from the combinatorial effects of sex hormones, genetic differences, and sociobehavioral and environmental influences. These differences are clinically rel- evant, translating into enhanced risk for acquisition and non- AIDS morbidity in women, but also potentially for more effi- cacious immune responses to vaccination. The role of sex differences in cure interventions remains to be defined.

Curr HIV/AIDS Rep (2018) 15:136–146 141

Robust sex comparisons must be carefully controlled as en- rollment of women tends to be preferentially in resource- limited settings introducing potentially confounding genetic and environmental differences when compared to predomi- nantly male cohorts from the developed world. Despite these challenges, focused investigation of sex differences has un- covered important features of disease, highlighting pathogenic inflammatory pathways. The direct role of sex hormones in modulating immune subset distribution and HIV transcription exemplifies how this research can lead to therapeutic interven- tions with hormone receptor antagonists or specific selection of contraceptive preparations. Likewise, highlighting the im- mune pathways that differ between men and women may indicate mechanisms to optimize treatment responses with adjuvant or immunomodulatory interventions that target these pathways in the “weaker” sex, whichever that may be.

Acknowledgments The author would like to thank Avery Normandin for expert assistance in figure design.

Funding Information Dr. Scully is supported by K08AI116344.

Compliance with Ethical Standards

Conflict of Interest The author declares that she has no competing interests.

Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http:// creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appro- priate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

References

  1. Patel P, Borkowf CB, Brooks JT, Lasry A, Lansky A, Mermin J. Estimating per-act HIV transmission risk: a systematic review. AIDS. 2014;28(10):1509–19. https://doi.org/10.1097/QAD. 0000000000000298.
  2. Arnold KB, Burgener A, Birse K, Romas L, Dunphy LJ, Shahabi K, et al. Increased levels of inflammatory cytokines in the female reproductive tract are associated with altered expression of prote- ases, mucosal barrier proteins, and an influx of HIV-susceptible target cells. Mucosal Immunol. 2016;9(1):194–205. https://doi. org/10.1038/mi.2015.51.
  3. Masson L, Passmore JA, Liebenberg LJ, Werner L, Baxter C, Arnold KB, et al. Genital inflammation and the risk of HIVacqui- sition in women. Clin Infect Dis. 2015;61(2):260–9. https://doi. org/10.1093/cid/civ298.
  4. Naranbhai V, Abdool Karim SS, Altfeld M, Samsunder N, Durgiah R, Sibeko S, et al. Innate immune activation enhances hiv acquisition in women, diminishing the effectiveness of

tenofovir microbicide gel. J Infect Dis. 2012;206(7):993–1001. https://doi.org/10.1093/infdis/jis465.

  1. Selhorst P, Masson L, Ismail SD, Samsunder N, Garrett N, Mansoor LE, et al. Cervicovaginal inflammation facilitates acqui- sition of less infectious HIV variants. Clin Infect Dis. 2016;64:79– 82. https://doi.org/10.1093/cid/ciw663.
  2. Anahtar MN, Byrne EH, Doherty KE, Bowman BA, Yamamoto HS, Soumillon M, et al. Cervicovaginal bacteria are a major mod- ulator of host inflammatory responses in the female genital tract. Immunity. 2015;42(5):965–76. https://doi.org/10.1016/j.immuni. 2015.04.019.
  3. Brown JM, Wald A, Hubbard A, Rungruengthanakit K, Chipato T, Rugpao S, et al. Incident and prevalent herpes simplex virus type 2 infection increases risk of HIVacquisition among women in Uganda and Zimbabwe. AIDS. 2007;21(12):1515–23. https://doi. org/10.1097/QAD.0b013e3282004929.
  4. Freeman EE, Weiss HA, Glynn JR, Cross PL, Whitworth JA, Hayes RJ. Herpes simplex virus 2 infection increases HIV acqui- sition in men and women: systematic review and meta-analysis of longitudinal studies. AIDS. 2006;20(1):73–83.
  5. Masson L, Arnold KB, Little F, Mlisana K, Lewis DA, Mkhize N, et al. Inflammatory cytokine biomarkers to identify women with asymptomatic sexually transmitted infections and bacterial vagi- nosis who are at high risk of HIV infection. Sex Transm Infect. 2016;92(3):186–93. https://doi.org/10.1136/sextrans-2015- 052072.
  6. Masson L, Mlisana K, Little F, Werner L, Mkhize NN, Ronacher K, et al. Defining genital tract cytokine signatures of sexually transmitted infections and bacterial vaginosis in women at high risk of HIV infection: a cross-sectional study. Sex Transm Infect. 2014;90(8):580–7. https://doi.org/10.1136/sextrans-2014- 051601.
  7. van de Wijgert JH, Morrison CS, Brown J, Kwok C, Van Der Pol B, Chipato T, et al. Disentangling contributions of reproductive tract infections to HIVacquisition in African women. Sex Transm Dis. 2009;36(6):357–64. https://doi.org/10.1097/OLQ. 0b013e3181a4f695.
  8. Morrison CS, Chen PL, Kwok C, Baeten JM, Brown J, Crook AM, et al. Hormonal contraception and the risk of HIV acquisi- tion: an individual participant data meta-analysis. PLoS Med. 2015;12(1):e1001778. https://doi.org/10.1371/journal.pmed. 1001778.
  9. Polis CB, Curtis KM, Hannaford PC, Phillips SJ, Chipato T, Kiarie JN, et al. Update on hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epide- miological evidence, 2016. AIDS. 2016;30:2665–83. https://doi. org/10.1097/QAD.0000000000001228.
  10. Ralph LJ, McCoy SI, Shiu K, Padian NS. Hormonal contraceptive use and women’s risk of HIV acquisition: a meta-analysis of ob- servational studies. Lancet Infect Dis. 2015;15(2):181–9. https:// doi.org/10.1016/S1473-3099(14)71052-7.
  11. Cook IF. Sexual dimorphism of humoral immunity with human vaccines. Vaccine. 2008;26(29–30):3551–5. https://doi.org/10. 1016/j.vaccine.2008.04.054.
  12. Seligman SJ. Yellow fever virus vaccine-associated deaths in young women. Emerg Infect Dis. 2011;17(10):1891–3. https:// doi.org/10.3201/eid1710.101789.
  13. Seligman SJ. Risk groups for yellow fever vaccine-associated viscerotropic disease (YEL-AVD). Vaccine. 2014;32(44):5769– 75. https://doi.org/10.1016/j.vaccine.2014.08.051.
  14. Stanberry LR, Spruance SL, Cunningham AL, Bernstein DI, Mindel A, Sacks S, et al. Glycoprotein-D-adjuvant vaccine to prevent genital herpes. N Engl J Med. 2002;347(21):1652–61. https://doi.org/10.1056/NEJMoa011915.
  15. Zhang X, Castelli FA, Zhu X, Wu M, Maillere B, BenMohamed L. Gender-dependent HLA-DR-restricted epitopes identified from

142 Curr HIV/AIDS Rep (2018) 15:136–146

https://doi.org/10.1097/QAD.0000000000000298
https://doi.org/10.1097/QAD.0000000000000298
https://doi.org/10.1038/mi.2015.51
https://doi.org/10.1038/mi.2015.51
https://doi.org/10.1093/cid/civ298
https://doi.org/10.1093/cid/civ298
https://doi.org/10.1093/infdis/jis465
https://doi.org/10.1093/cid/ciw663
https://doi.org/10.1016/j.immuni.2015.04.019
https://doi.org/10.1016/j.immuni.2015.04.019
https://doi.org/10.1097/QAD.0b013e3282004929
https://doi.org/10.1097/QAD.0b013e3282004929
https://doi.org/10.1136/sextrans-2015-052072
https://doi.org/10.1136/sextrans-2015-052072
https://doi.org/10.1136/sextrans-2014-051601
https://doi.org/10.1136/sextrans-2014-051601
https://doi.org/10.1097/OLQ.0b013e3181a4f695
https://doi.org/10.1097/OLQ.0b013e3181a4f695
https://doi.org/10.1371/journal.pmed.1001778
https://doi.org/10.1371/journal.pmed.1001778
https://doi.org/10.1097/QAD.0000000000001228
https://doi.org/10.1097/QAD.0000000000001228
https://doi.org/10.1016/S1473-3099(14)71052-7
https://doi.org/10.1016/S1473-3099(14)71052-7
https://doi.org/10.1016/j.vaccine.2008.04.054
https://doi.org/10.1016/j.vaccine.2008.04.054
https://doi.org/10.3201/eid1710.101789
https://doi.org/10.3201/eid1710.101789
https://doi.org/10.1016/j.vaccine.2014.08.051
https://doi.org/10.1056/NEJMoa011915
herpes simplex virus type 1 glycoprotein D. Clin Vaccine Immunol. 2008;15(9):1436–49. https://doi.org/10.1128/CVI. 00123-08.

  1. Klein SL, Jedlicka A, Pekosz A. The Xs and Y of immune re- sponses to viral vaccines. Lancet Infect Dis. 2010;10(5):338–49. https://doi.org/10.1016/S1473-3099(10)70049-9.
  2. Rerks-Ngarm S, Pitisuttithum P, Nitayaphan S, Kaewkungwal J, Chiu J, Paris R, et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. New Engl J Med. 2009;361(23):2209–20. https://doi.org/10.1056/ NEJMoa0908492.
  3. Hewagama A, Patel D, Yarlagadda S, Strickland FM, Richardson BC. Stronger inflammatory/cytotoxic T-cell response in women identified by microarray analysis. Genes Immun. 2009;10(5): 509–16. https://doi.org/10.1038/gene.2009.12.
  4. Sakiani S, Olsen NJ, Kovacs WJ. Gonadal steroids and humoral immunity. Nat Rev Endocrinol. 2013;9(1):56–62. https://doi.org/ 10.1038/nrendo.2012.206.
  5. Chen G, Wang Y, Qiu L, Qin X, Liu H, Wang X, et al. Human IgG Fc-glycosylation profiling reveals associations with age, sex, fe- male sex hormones and thyroid cancer. J Proteome. 2012;75(10): 2824–34. https://doi.org/10.1016/j.jprot.2012.02.001.
  6. Grant RM, Lama JR, Anderson PL, McMahan V, Liu AY, Vargas L, et al. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N Engl J Med. 2010;363(27): 2587–99. https://doi.org/10.1056/NEJMoa1011205.
  7. Baeten JM, Donnell D, Ndase P, Mugo NR, Campbell JD, Wangisi J, et al. Antiretroviral prophylaxis for HIV prevention in heterosexual men and women. N Engl J Med. 2012;367(5): 399–410. https://doi.org/10.1056/NEJMoa1108524.
  8. Marrazzo JM, Ramjee G, Richardson BA, Gomez K, Mgodi N, Nair G, et al. Tenofovir-based preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2015;372(6): 509–18. https://doi.org/10.1056/NEJMoa1402269.
  9. Van Damme L, Corneli A, Ahmed K, Agot K, Lombaard J, Kapiga S, et al. Preexposure prophylaxis for HIV infection among African women. N Engl J Med. 2012;367(5):411–22. https://doi. org/10.1056/NEJMoa1202614.
  10. Hendrix CW. The clinical pharmacology of antiretrovirals for HIV prevention. Curr Opin HIVAIDS. 2012;7(6):498–504. https://doi. org/10.1097/COH.0b013e32835847ae.
  11. Abdool Karim Q, Sibeko S, Baxter C. Preventing HIVinfection in women: a global health imperative. Clin Infect Dis. 2010;50(Suppl 3):S122–9. https://doi.org/10.1086/651483.
  12. Baeten JM, Palanee-Phillips T, Brown ER, Schwartz K, Soto-Torres LE, Govender V, et al. Use of a vaginal ring containing dapivirine for HIV-1 prevention in women. N Engl J Med. 2016;375(22): 2121–32. https://doi.org/10.1056/NEJMoa1506110.
  13. Nel A, van Niekerk N, Kapiga S, Bekker LG, Gama C, Gill K, et al. Safety and efficacy of a dapivirine vaginal ring for HIV prevention in women. N Engl J Med. 2016;375(22):2133–43. https://doi.org/10.1056/NEJMoa1602046.
  14. Klatt NR, Cheu R, Birse K, Zevin AS, Perner M, Noel-Romas L, et al. Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women. Science. 2017;356(6341):938–45. https://doi. org/10.1126/science.aai9383.
  15. Hladik F, Burgener A, Ballweber L, Gottardo R, Vojtech L, Fourati S, et al. Mucosal effects of tenofovir 1% gel. elife. 2015;4 https://doi.org/10.7554/eLife.04525.
  16. vom Steeg LG, Klein SL. SeXX matters in infectious disease pathogenesis. PLoS Pathog. 2016;12(2):e1005374. https://doi. org/10.1371/journal.ppat.1005374.
  17. Anastos K, Gange SJ, Lau B, Weiser B, Detels R, Giorgi JV, et al. Association of race and gender with HIV-1 RNA levels and im- munologic progression. J Acquir Immune Defic Syndr. 2000;24(3):218–26.
  18. Bush CE, Donovan RM, Markowitz N, Baxa D, Kvale P, Saravolatz LD. Gender is not a factor in serum human immuno- deficiency virus type 1 RNA levels in patients with viremia. J Clin Microbiol. 1996;34(4):970–2.
  19. Evans JS, Nims T, Cooley J, Bradley W, Jagodzinski L, Zhou S, et al. Serum levels of virus burden in early-stage human immuno- deficiency virus type 1 disease in women. J Infect Dis. 1997;175(4):795–800.
  20. Farzadegan H, Hoover DR, Astemborski J, Lyles CM, Margolick JB, Markham RB, et al. Sex differences in HIV-1 viral load and progression to AIDS. Lancet. 1998;352(9139):1510–4. https:// doi.org/10.1016/S0140-6736(98)02372-1.
  21. Gandhi M, Bacchetti P, Miotti P, Quinn TC, Veronese F, Greenblatt RM. Does patient sex affect human immunodeficiency virus levels? Clin Infect Dis. 2002;35(3):313–22. https://doi.org/ 10.1086/341249.
  22. Katzenstein DA, Hammer SM, Hughes MD, Gundacker H, Jackson JB, Fiscus S, et al. The relation of virologic and immu- nologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millime- ter. AIDS Clinical Trials Group study 175 virology study team. N Engl J Med. 1996;335(15):1091–8. https://doi.org/10.1056/ NEJM199610103351502.
  23. Lyles CM, Dorrucci M, Vlahov D, Pezzotti P, Angarano G, Sinicco A, et al. Longitudinal human immunodeficiency virus type 1 load in the italian seroconversion study: correlates and temporal trends of virus load. J Infect Dis. 1999;180(4):1018– 24. https://doi.org/10.1086/314980.
  24. Moore RD, Cheever L, Keruly JC, Chaisson RE. Lack of sex difference in CD4 to HIV-1 RNA viral load ratio. Lancet. 1999;353(9151):463–4. https://doi.org/10.1016/S0140-6736(98) 05379-3.
  25. Napravnik S, Poole C, Thomas JC, Eron JJ Jr. Gender difference in HIV RNA levels: a meta-analysis of published studies. J Acquir Immune Defic Syndr. 2002;31(1):11–9.
  26. Sterling TR, Lyles CM, Vlahov D, Astemborski J, Margolick JB, Quinn TC. Sex differences in longitudinal human immunodefi- ciency virus type 1 RNA levels among seroconverters. J Infect Dis. 1999;180(3):666–72. https://doi.org/10.1086/314967.
  27. Sterling TR, Vlahov D, Astemborski J, Hoover DR, Margolick JB, Quinn TC. Initial plasma HIV-1 RNA levels and progression to AIDS in women and men. N Engl J Med. 2001;344(10):720–5. https://doi.org/10.1056/NEJM200103083441003.
  28. Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, Kulkarni S, et al. Sex differences in the toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med. 2009;15(8):955– 9. https://doi.org/10.1038/nm.2004.
  29. Chang JJ, Woods M, Lindsay RJ, Doyle EH, Griesbeck M, Chan ES, et al. Higher expression of several interferon-stimulated genes in HIV-1-infected females after adjusting for the level of viral replication. J Infect Dis. 2013;208(5):830–8. https://doi.org/10. 1093/infdis/jit262.
  30. Deeks SG, Kitchen CM, Liu L, Guo H, Gascon R, Narvaez AB, et al. Immune activation set point during early HIV infection pre- dicts subsequent CD4+ T-cell changes independent of viral load. Blood. 2004;104(4):942–7. https://doi.org/10.1182/blood-2003- 09-3333.
  31. Giorgi JV, Hultin LE, McKeating JA, Johnson TD, Owens B, Jacobson LP, et al. Shorter survival in advanced human immuno- deficiency virus type 1 infection is more closely associated with T lymphocyte activation than with plasma virus burden or virus chemokine coreceptor usage. J Infect Dis. 1999;179(4):859–70. https://doi.org/10.1086/314660.
  32. Hunt PW, Lee SA, Siedner MJ. Immunologic biomarkers, mor- bidity, and mortality in treated HIV infection. J Infect Dis.

Curr HIV/AIDS Rep (2018) 15:136–146 143

https://doi.org/10.1128/CVI.00123-08
https://doi.org/10.1128/CVI.00123-08
https://doi.org/10.1016/S1473-3099(10)70049-9
https://doi.org/10.1056/NEJMoa0908492
https://doi.org/10.1056/NEJMoa0908492
https://doi.org/10.1038/gene.2009.12
https://doi.org/10.1038/nrendo.2012.206
https://doi.org/10.1038/nrendo.2012.206
https://doi.org/10.1016/j.jprot.2012.02.001
https://doi.org/10.1056/NEJMoa1011205
https://doi.org/10.1056/NEJMoa1108524
https://doi.org/10.1056/NEJMoa1402269
https://doi.org/10.1056/NEJMoa1202614
https://doi.org/10.1056/NEJMoa1202614
https://doi.org/10.1097/COH.0b013e32835847ae
https://doi.org/10.1097/COH.0b013e32835847ae
https://doi.org/10.1086/651483
https://doi.org/10.1056/NEJMoa1506110
https://doi.org/10.1056/NEJMoa1602046
https://doi.org/10.1126/science.aai9383
https://doi.org/10.1126/science.aai9383
https://doi.org/10.7554/eLife.04525
https://doi.org/10.1371/journal.ppat.1005374
https://doi.org/10.1371/journal.ppat.1005374
https://doi.org/10.1016/S0140-6736(98)02372-1
https://doi.org/10.1016/S0140-6736(98)02372-1
https://doi.org/10.1086/341249
https://doi.org/10.1086/341249
https://doi.org/10.1056/NEJM199610103351502
https://doi.org/10.1056/NEJM199610103351502
https://doi.org/10.1086/314980
https://doi.org/10.1016/S0140-6736(98)05379-3
https://doi.org/10.1016/S0140-6736(98)05379-3
https://doi.org/10.1086/314967
https://doi.org/10.1056/NEJM200103083441003
https://doi.org/10.1038/nm.2004
https://doi.org/10.1093/infdis/jit262
https://doi.org/10.1093/infdis/jit262
https://doi.org/10.1182/blood-2003-09-3333
https://doi.org/10.1182/blood-2003-09-3333
https://doi.org/10.1086/314660
2016;214(Suppl 2):S44–50. https://doi.org/10.1093/infdis/ jiw275.

  1. Raghavan A, Rimmelin DE, Fitch KV, Zanni MV. Sex differences in select non-communicable HIV-associated comorbidities: ex- ploring the role of systemic immune activation/inflammation. Curr HIV/AIDS Rep. 2017;14:220–8. https://doi.org/10.1007/ s11904-017-0366-8.
  2. Blankson JN. Control of HIV-1 replication in elite suppressors. Discov Med. 2010;9(46):261–6.
  3. Deeks SG, Walker BD. Human immunodeficiency virus control- lers: mechanisms of durable virus control in the absence of anti- retroviral therapy. Immunity. 2007;27(3):406–16. https://doi.org/ 10.1016/j.immuni.2007.08.010.
  4. Saag M, Deeks SG. How do HIVelite controllers do what they do? Clin Infect Dis. 2010;51(2):239–41. https://doi.org/10.1086/ 653678.
  5. Saez-Cirion A, Bacchus C, Hocqueloux L, Avettand-Fenoel V, Girault I, Lecuroux C, et al. Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI study. PLoS Pathog. 2013;9(3):e1003211. https://doi.org/10.1371/journal. ppat.1003211.
  6. Crowell TA, Gebo KA, Blankson JN, Korthuis PT, Yehia BR, Rutstein RM, et al. Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection. J Infect Dis. 2015;211(11):1692–702. https://doi.org/10. 1093/infdis/jiu809.
  7. Madec Y, Boufassa F, Porter K, Meyer L, Collaboration C. Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters. AIDS. 2005;19(17):2001–7.
  8. Goujard C, Girault I, Rouzioux C, Lecuroux C, Deveau C, Chaix ML, et al. HIV-1 control after transient antiretroviral treatment initiated in primary infection: role of patient characteristics and effect of therapy. Antivir Ther. 2012;17(6):1001–9. https://doi. org/10.3851/IMP2273.
  9. Matthews LT, Giddy J, Ghebremichael M, Hampton J, Guarino AJ, Ewusi A, et al. A risk-factor guided approach to reducing lactic acidosis and hyperlactatemia in patients on antiretroviral therapy. PLoS One. 2011;6(4):e18736. https://doi.org/10.1371/ journal.pone.0018736.
  10. Ofotokun I, Pomeroy C. Sex differences in adverse reactions to antiretroviral drugs. Top HIV Med. 2003;11(2):55–9.
  11. Soon GG, Min M, Struble KA, Chan-Tack KM, Hammerstrom T, Qi K, et al. Meta-analysis of gender differences in efficacy out- comes for HIV-positive subjects in randomized controlled clinical trials of antiretroviral therapy (2000-2008). AIDS Patient Care STDs. 2012;26(8):444–53. https://doi.org/10.1089/apc.2011. 0278.
  12. Currier J, Averitt Bridge D, Hagins D, Zorrilla CD, Feinberg J, Ryan R, et al. Sex-based outcomes of darunavir-ritonavir therapy: a single-group trial. Ann Intern Med. 2010;153(6):349–57. https:// doi.org/10.7326/0003-4819-153-6-201009210-00002.
  13. Squires K, Feinberg J, Bridge DA, Currier J, Ryan R, Seyedkazemi S, et al. Insights on GRACE (gender, race, and clinical experience) from the patient’s perspective: GRACE par- ticipant survey. AIDS Patient Care STDs. 2013;27(6):352–62. https://doi.org/10.1089/apc.2013.0015.
  14. Squires K, Bekker LG, Katlama C, Yazdanpanah Y, Zhou Y, Rodgers AJ, et al. Influence of sex/gender and race on responses to raltegravir combined with tenofovir-emtricitabine in treatment- naive human immunodeficiency virus-1 infected patients: pooled analyses of the STARTMRK and QDMRK studies. Open Forum Infect Dis. 2017;4(1):ofw047. https://doi.org/10.1093/ofid/ ofw047.
  15. Squires K, Kityo C, Hodder S, Johnson M, Voronin E, Hagins D, et al. Integrase inhibitor versus protease inhibitor based regimen

for HIV-1 infected women (WAVES): a randomised, controlled, double-blind, phase 3 study. Lancet HIV. 2016;3(9):e410–e20. https://doi.org/10.1016/S2352-3018 (16)30016-9.

  1. Squires KE, Young B, Santiago L, Dretler RH, Walmsley SL, Zhao HH, et al. Response by gender of HIV-1-infected subjects treated with abacavir/lamivudine plus atazanavir, with or without ritonavir, for 144 weeks. HIV AIDS (Auckl). 2017;9:51–61. https://doi.org/10.2147/HIV.S108756.
  2. Norwood J, Turner M, Bofill C, Rebeiro P, Shepherd B, Bebawy S, et al. Brief report: weight gain in persons with hiv switched from efavirenz-based to integrase strand transfer inhibitor-based regimens. J Acquir Immune Defic Syndr. 2017;76(5):527–31. https://doi.org/10.1097/QAI.0000000000001525.
  3. Gandhi RT, Spritzler J, Chan E, Asmuth DM, Rodriguez B, Merigan TC, et al. Effect of baseline- and treatment-related factors on immunologic recovery after initiation of antiretroviral therapy in HIV-1-positive subjects: results from ACTG 384. J Acquir Immune Defic Syndr. 2006;42(4):426–34. https://doi.org/10. 1097/01.qai.0000226789.51992.3f.
  4. Ticona E, Bull ME, Soria J, Tapia K, Legard J, Styrchak SM, et al. Biomarkers of inflammation in HIV-infected Peruvian men and women before and during suppressive antiretroviral therapy. AIDS. 2015;29(13):1617–22. https://doi.org/10.1097/QAD. 0000000000000758.
  5. Mathad JS, Gupte N, Balagopal A, Asmuth D, Hakim J, Santos B, et al. Sex-related differences in inflammatory and immune activa- tion markers before and after combined antiretroviral therapy ini- tiation. J Acquir Immune Defic Syndr. 2016;73(2):123–9. https:// doi.org/10.1097/QAI.0000000000001095.
  6. Lakoski SG, Herrington DM. Effects of hormone therapy on C- reactive protein and IL-6 in postmenopausal women: a review article. Climacteric. 2005;8(4):317–26. https://doi.org/10.1080/ 13697130500345109.
  7. Freiberg MS, Chang CC, Kuller LH, Skanderson M, Lowy E, Kraemer KL, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013;173(8):614–22. https://doi. org/10.1001/jamainternmed.2013.3728.
  8. Triant VA, Lee H, Hadigan C, Grinspoon SK. Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease. J Clin Endocrinol Metab. 2007;92(7):2506–12. https://doi.org/10.1210/ jc.2006-2190.
  9. Fitch KV, Srinivasa S, Abbara S, Burdo TH, Williams KC, Eneh P, et al. Noncalcified coronary atherosclerotic plaque and immune activation in HIV-infected women. J Infect Dis. 2013;208(11): 1737–46. https://doi.org/10.1093/infdis/jit508.
  10. Chow FC, Regan S, Feske S, Meigs JB, Grinspoon SK, Triant VA. Comparison of ischemic stroke incidence in HIV-infected and non-HIV-infected patients in a US health care system. J Acquir Immune Defic Syndr. 2012;60(4):351–8. https://doi.org/10.1097/ QAI.0b013e31825c7f24.
  11. Sico JJ, Chang CC, So-Armah K, Justice AC, Hylek E, Skanderson M, et al. HIV status and the risk of ischemic stroke among men. Neurology. 2015;84(19):1933–40. https://doi.org/ 10.1212/WNL.0000000000001560.
  12. Chow FC, Regan S, Zanni MV, Looby SE, Bushnell CD, Meigs JB, et al. Elevated ischemic stroke risk among women living with HIV infection. AIDS. 2017 https://doi.org/10.1097/QAD. 0000000000001650.
  13. Stone L, Looby SE, Zanni MV. Cardiovascular disease risk among women living with HIV in North America and Europe. Curr Opin HIV AIDS. 2017;12(6):585–93. https://doi.org/10.1097/COH. 0000000000000413.
  14. Kim Y, Anderson JL, Lewin SR. Getting the “kill” into “shock and kill”: strategies to eliminate latent HIV. Cell Host Microbe. 2018;23(1):14–26. https://doi.org/10.1016/j.chom.2017.12.004.

144 Curr HIV/AIDS Rep (2018) 15:136–146

https://doi.org/10.1093/infdis/jiw275
https://doi.org/10.1093/infdis/jiw275
https://doi.org/10.1007/s11904-017-0366-8
https://doi.org/10.1007/s11904-017-0366-8
https://doi.org/10.1016/j.immuni.2007.08.010
https://doi.org/10.1016/j.immuni.2007.08.010
https://doi.org/10.1086/653678
https://doi.org/10.1086/653678
https://doi.org/10.1371/journal.ppat.1003211
https://doi.org/10.1371/journal.ppat.1003211
https://doi.org/10.1093/infdis/jiu809
https://doi.org/10.1093/infdis/jiu809
https://doi.org/10.3851/IMP2273
https://doi.org/10.3851/IMP2273
https://doi.org/10.1371/journal.pone.0018736
https://doi.org/10.1371/journal.pone.0018736
https://doi.org/10.1089/apc.2011.0278
https://doi.org/10.1089/apc.2011.0278
https://doi.org/10.7326/0003-4819-153-6-201009210-00002
https://doi.org/10.7326/0003-4819-153-6-201009210-00002
https://doi.org/10.1089/apc.2013.0015
https://doi.org/10.1093/ofid/ofw047
https://doi.org/10.1093/ofid/ofw047
https://doi.org/10.1016/S2352-3018 (16)30016-9
https://doi.org/10.2147/HIV.S108756
https://doi.org/10.1097/QAI.0000000000001525
https://doi.org/10.1097/01.qai.0000226789.51992.3f
https://doi.org/10.1097/01.qai.0000226789.51992.3f
https://doi.org/10.1097/QAD.0000000000000758
https://doi.org/10.1097/QAD.0000000000000758
https://doi.org/10.1097/QAI.0000000000001095
https://doi.org/10.1097/QAI.0000000000001095
https://doi.org/10.1080/13697130500345109
https://doi.org/10.1080/13697130500345109
https://doi.org/10.1001/jamainternmed.2013.3728
https://doi.org/10.1001/jamainternmed.2013.3728
https://doi.org/10.1210/jc.2006-2190
https://doi.org/10.1210/jc.2006-2190
https://doi.org/10.1093/infdis/jit508
https://doi.org/10.1097/QAI.0b013e31825c7f24
https://doi.org/10.1097/QAI.0b013e31825c7f24
https://doi.org/10.1212/WNL.0000000000001560
https://doi.org/10.1212/WNL.0000000000001560
https://doi.org/10.1097/QAD.0000000000001650
https://doi.org/10.1097/QAD.0000000000001650
https://doi.org/10.1097/COH.0000000000000413
https://doi.org/10.1097/COH.0000000000000413
https://doi.org/10.1016/j.chom.2017.12.004

  1. Fourati S, Flandre P, Calin R, Carcelain G, Soulie C, Lambert- Niclot S, et al. Factors associated with a low HIV reservoir in patients with prolonged suppressive antiretroviral therapy. J Antimicrob Chemother. 2014;69(3):753–6. https://doi.org/10. 1093/jac/dkt428.
  2. Cuzin L, Pugliese P, Saune K, Allavena C, Ghosn J, Cottalorda J, et al. Levels of intracellular HIV-DNA in patients with suppressive antiretroviral therapy. AIDS. 2015;29(13):1665–71. https://doi. org/10.1097/QAD.0000000000000723.
  3. Johnston RE, Heitzeg MM. Sex, age, race and intervention type in clinical studies of HIV cure: a systematic review. AIDS Res Hum Retrovir. 2015;31(1):85–97. https://doi.org/10.1089/AID.2014. 0205.
  4. Eriksson S, Graf EH, Dahl V, Strain MC, Yukl SA, Lysenko ES, et al. Comparative analysis of measures of viral reservoirs in HIV- 1 eradication studies. PLoS Pathog. 2013;9(2):e1003174. https:// doi.org/10.1371/journal.ppat.1003174.
  5. Williams JP, Hurst J, Stohr W, Robinson N, Brown H, Fisher M, et al. HIV-1 DNA predicts disease progression and post-treatment virological control. elife. 2014;3:e03821. https://doi.org/10.7554/ eLife.03821.
  6. Katzenstein TL, Oliveri RS, Benfield T, Eugen-Olsen J, Nielsen C, Gerstoft J, et al. Cell-associated HIV DNA measured early during infection has prognostic value independent of serum HIV RNA measured concomitantly. Scand J Infect Dis. 2002;34(7): 529–33.
  7. Goujard C, Bonarek M, Meyer L, Bonnet F, Chaix ML, Deveau C, et al. CD4 cell count and HIV DNA level are independent predic- tors of disease progression after primary HIV type 1 infection in untreated patients. Clin Infect Dis. 2006;42(5):709–15. https://doi. org/10.1086/500213.
  8. Sogaard OS, Graversen ME, Leth S, Olesen R, Brinkmann CR, Nissen SK, et al. The depsipeptide romidepsin reverses HIV-1 latency in vivo. PLoS Pathog. 2015;11(9):e1005142. https://doi. org/10.1371/journal.ppat.1005142.
  9. Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, et al. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppres- sive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV. 2014;1(1):e13–21. https://doi.org/10.1016/S2352- 3018(14)70014-1.
  10. Elliott JH, Wightman F, Solomon A, Ghneim K, Ahlers J, Cameron MJ, et al. Activation of HIV transcription with short- course vorinostat in HIV-infected patients on suppressive antire- troviral therapy. PLoS Pathog. 2014;10(10):e1004473. https://doi. org/10.1371/journal.ppat.1004473.
  11. Archin NM, Bateson R, Tripathy MK, Crooks AM, Yang KH, Dahl NP, et al. HIV-1 expression within resting CD4+ Tcells after multiple doses of vorinostat. J Infect Dis. 2014;210(5):728–35. https://doi.org/10.1093/infdis/jiu155.
  12. Dronca RS, Dong H. A gender factor in shaping T-cell immunity to melanoma. Front Oncol. 2015;5:8. https://doi.org/10.3389/ fonc.2015.00008.
  13. Nosrati A, Tsai KK, Goldinger SM, Tumeh P, Grimes B, Loo K, et al. Evaluation of clinicopathological factors in PD-1 response: derivation and validation of a prediction scale for response to PD-1 monotherapy. Br J Cancer. 2017;116(9):1141–7. https://doi.org/ 10.1038/bjc.2017.70.
  14. Sheth AN, Rolle CP, Gandhi M. HIV pre-exposure prophylaxis for women. J Virus Erad. 2016;2(3):149–55.
  15. Butler K, Ritter JM, Ellis S, Morris MR, Hanson DL, McNicholl JM, et al. A depot medroxyprogesterone acetate dose that models human use and its effect on vaginal SHIV acquisition risk. J Acquir Immune Defic Syndr. 2016;72(4):363–71. https://doi.org/ 10.1097/QAI.0000000000000975.
  16. Hild-Petito S, Veazey RS, Larner JM, Reel JR, Blye RP. Effects of two progestin-only contraceptives, depo-provera and Norplant-II, on the vaginal epithelium of rhesus monkeys. AIDS Res Hum Retrovir. 1998;14(Suppl 1):S125–30.
  17. Marx PA, Spira AI, Gettie A, Dailey PJ, Veazey RS, Lackner AA, et al. Progesterone implants enhance SIV vaginal transmission and early virus load. Nat Med. 1996;2(10):1084–9.
  18. Bahamondes MV, Castro S, Marchi NM, Marcovici M, Andrade LA, Fernandes A, et al. Human vaginal histology in long-term users of the injectable contraceptive depot-medroxyprogesterone acetate. Contraception. 2014;90(2):117–22. https://doi.org/10. 1016/j.contraception.2014.01.024.
  19. Chandra N, Thurman AR, Anderson S, Cunningham TD, Yousefieh N, Mauck C, et al. Depot medroxyprogesterone acetate increases immune cell numbers and activation markers in human vaginal mucosal tissues. AIDS Res Hum Retrovir. 2013;29(3): 592–601. https://doi.org/10.1089/aid.2012.0271.
  20. Mauck CK, Callahan MM, Baker J, Arbogast K, Veazey R, Stock R, et al. The effect of one injection of depo-provera on the human vaginal epithelium and cervical ectopy. Contraception. 1999;60(1):15–24.
  21. Miller L, Patton DL, Meier A, Thwin SS, Hooton TM, Eschenbach DA. Depomedroxyprogesterone-induced hypoestrogenism and changes in vaginal flora and epithelium. Obstet Gynecol. 2000;96(3):431–9.
  22. Mitchell CM, McLemore L, Westerberg K, Astronomo R, Smythe K, Gardella C, et al. Long-term effect of depot medroxyprogesterone acetate on vaginal microbiota, epithelial thickness and HIV target cells. J Infect Dis. 2014;210(4):651–5. https://doi.org/10.1093/infdis/jiu176.
  23. Byrne EH, Anahtar MN, Cohen KE, Moodley A, Padavattan N, Ismail N, et al. Association between injectable progestin-only con- traceptives and HIV acquisition and HIV target cell frequency in the female genital tract in south African women: a prospective cohort study. Lancet Infect Dis. 2016;16(4):441–8. https://doi. org/10.1016/S1473-3099(15)00429-6.
  24. Fichorova RN, Chen PL, Morrison CS, Doncel GF, Mendonca K, Kwok C, et al. The contribution of cervicovaginal infections to the immunomodulatory effects of hormonal contraception. MBio. 2015;6(5):e00221-15. https://doi.org/10.1128/mBio.00221-15.
  25. Szotek EL, Narasipura SD, Al-Harthi L. 17beta-estradiol inhibits HIV-1 by inducing a complex formation between beta-catenin and estrogen receptor alpha on the HIV promoter to suppress HIV transcription. Virology. 2013;443(2):375–83. https://doi.org/10. 1016/j.virol.2013.05.027.
  26. Hughes GC, Thomas S, Li C, Kaja MK, Clark EA. Cutting edge: progesterone regulates IFN-alpha production by plasmacytoid dendritic cells. J Immunol. 2008;180(4):2029–33.
  27. Griesbeck M, Ziegler S, Laffont S, Smith N, Chauveau L, Tomezsko P, et al. Sex differences in plasmacytoid dendritic cell levels of IRF5 drive higher IFN-alpha production in women. J Immunol. 2015;195(11):5327–36. https://doi.org/10.4049/ jimmunol.1501684.
  28. Laffont S, Rouquie N, Azar P, Seillet C, Plumas J, Aspord C, et al. X-chromosome complement and estrogen receptor signaling inde- pendently contribute to the enhanced TLR7-mediated IFN-alpha production of plasmacytoid dendritic cells from women. J Immunol. 2014;193(11):5444–52. https://doi.org/10.4049/ jimmunol.1303400.
  29. Seillet C, Laffont S, Tremollieres F, Rouquie N, Ribot C, Arnal JF, et al. The TLR-mediated response of plasmacytoid dendritic cells is positively regulated by estradiol in vivo through cell-intrinsic estrogen receptor alpha signaling. Blood. 2012;119(2):454–64. https://doi.org/10.1182/blood-2011-08-371831.
  30. Berthois Y, Katzenellenbogen JA, Katzenellenbogen BS. Phenol red in tissue culture media is a weak estrogen: implications

Curr HIV/AIDS Rep (2018) 15:136–146 145

https://doi.org/10.1093/jac/dkt428
https://doi.org/10.1093/jac/dkt428
https://doi.org/10.1097/QAD.0000000000000723
https://doi.org/10.1097/QAD.0000000000000723
https://doi.org/10.1089/AID.2014.0205
https://doi.org/10.1089/AID.2014.0205
https://doi.org/10.1371/journal.ppat.1003174
https://doi.org/10.1371/journal.ppat.1003174
https://doi.org/10.7554/eLife.03821
https://doi.org/10.7554/eLife.03821
https://doi.org/10.1086/500213
https://doi.org/10.1086/500213
https://doi.org/10.1371/journal.ppat.1005142
https://doi.org/10.1371/journal.ppat.1005142
https://doi.org/10.1016/S2352-3018(14)70014-1
https://doi.org/10.1016/S2352-3018(14)70014-1
https://doi.org/10.1371/journal.ppat.1004473
https://doi.org/10.1371/journal.ppat.1004473
https://doi.org/10.1093/infdis/jiu155
https://doi.org/10.3389/fonc.2015.00008
https://doi.org/10.3389/fonc.2015.00008
https://doi.org/10.1038/bjc.2017.70
https://doi.org/10.1038/bjc.2017.70
https://doi.org/10.1097/QAI.0000000000000975
https://doi.org/10.1097/QAI.0000000000000975
https://doi.org/10.1016/j.contraception.2014.01.024
https://doi.org/10.1016/j.contraception.2014.01.024
https://doi.org/10.1089/aid.2012.0271
https://doi.org/10.1093/infdis/jiu176
https://doi.org/10.1016/S1473-3099(15)00429-6
https://doi.org/10.1016/S1473-3099(15)00429-6
https://doi.org/10.1128/mBio.00221-15
https://doi.org/10.1016/j.virol.2013.05.027
https://doi.org/10.1016/j.virol.2013.05.027
https://doi.org/10.4049/jimmunol.1501684
https://doi.org/10.4049/jimmunol.1501684
https://doi.org/10.4049/jimmunol.1303400
https://doi.org/10.4049/jimmunol.1303400
https://doi.org/10.1182/blood-2011-08-371831
concerning the study of estrogen-responsive cells in culture. Proc Natl Acad Sci U S A. 1986;83(8):2496–500.

  1. Cao Z, West C, Norton-Wenzel CS, Rej R, Davis FB, Davis PJ, et al. Effects of resin or charcoal treatment on fetal bovine serum and bovine calf serum. Endocr Res. 2009;34(4):101–8. https://doi. org/10.3109/07435800903204082.
  2. Zevin AS, Xie IY, Birse K, Arnold K, Romas L, Westmacott G, et al. Microbiome composition and function drives wound-healing impairment in the female genital tract. PLoS Pathog. 2016;12(9): e1005889. https://doi.org/10.1371/journal.ppat.1005889.
  3. Markle JG, Frank DN, Mortin-Toth S, Robertson CE, Feazel LM, Rolle-Kampczyk U, et al. Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity. Science. 2013;339(6123):1084–8. https://doi.org/10.1126/science. 1233521.
  4. Yurkovetskiy L, Burrows M, Khan AA, Graham L, Volchkov P, Becker L, et al. Gender bias in autoimmunity is influenced by microbiota. Immunity. 2013;39(2):400–12. https://doi.org/10. 1016/j.immuni.2013.08.013.
  5. Dominianni C, Sinha R, Goedert JJ, Pei Z, Yang L, Hayes RB, et al. Sex, body mass index, and dietary fiber intake influence the human gut microbiome. PLoS One. 2015;10(4):e0124599. https:// doi.org/10.1371/journal.pone.0124599.
  6. Haro C, Rangel-Zuniga OA, Alcala-Diaz JF, Gomez-Delgado F, Perez-Martinez P, Delgado-Lista J, et al. Intestinal microbiota is influ- enced by gender and body mass index. PLoS One. 2016;11(5): e0154090. https://doi.org/10.1371/journal.pone.0154090.
  7. Mueller S, Saunier K, Hanisch C, Norin E, Alm L, Midtvedt T, et al. Differences in fecal microbiota in different European study populations in relation to age, gender, and country: a cross- sectional study. Appl Environ Microbiol. 2006;72(2):1027–33. https://doi.org/10.1128/AEM.72.2.1027-1033.2006.
  8. Ghorai A, Ghosh U. miRNA gene counts in chromosomes vary widely in a species and biogenesis of miRNA largely depends on transcription or post-transcriptional processing of coding genes. Front Genet. 2014;5:100. https://doi.org/10.3389/fgene.2014. 00100.
  9. Ruel TD, Zanoni BC, Ssewanyana I, Cao H, Havlir DV, Kamya M, et al. Sex differences in HIV RNA level and CD4 cell percent- age during childhood. Clin Infect Dis. 2011;53(6):592–9. https:// doi.org/10.1093/cid/cir484.
  10. Dillon S, Aggarwal R, Harding JW, Li LJ, Weissman MH, Li S, et al. Klinefelter’s syndrome (47,XXY) among men with systemic lupus erythematosus. Acta Paediatr. 2011;100(6):819–23. https:// doi.org/10.1111/j.1651-2227.2011.02185.x.
  11. Carrel L, Brown CJ. When the Lyon(ized chromosome) roars: ongoing expression from an inactive X chromosome. Philos Trans R Soc Lond Ser B Biol Sci. 2017;372(1733):20160355. https://doi.org/10.1098/rstb.2016.0355.
  12. Dunford A, Weinstock DM, Savova V, Schumacher SE, Cleary JP, Yoda A, et al. Tumor-suppressor genes that escape from X- inactivation contribute to cancer sex bias. Nat Genet. 2017;49(1):10–6. https://doi.org/10.1038/ng.3726.
  13. International HIVCS, Pereyra F, Jia X, PJ ML, Telenti A, de Bakker PI, et al. The major genetic determinants of HIV-1 control affect HLA class I peptide presentation. Science. 2010;330(6010): 1551–7. https://doi.org/10.1126/science.1195271.
  14. Holterhus PM, Bebermeier JH, Werner R, Demeter J, Richter-Unruh A, Cario G, et al. Disorders of sex development expose transcription- al autonomy of genetic sex and androgen-programmed hormonal sex in human blood leukocytes. BMC Genomics. 2009;10:292. https:// doi.org/10.1186/1471-2164-10-292.
  15. Mamrut S, Avidan N, Staun-Ram E, Ginzburg E, Truffault F, Berrih-Aknin S, et al. Integrative analysis of methylome and tran- scriptome in human blood identifies extensive sex- and immune cell-specific differentially methylated regions. Epigenetics.

2015;10(10):943–57. https://doi.org/10.1080/15592294.2015. 1084462.

  1. Distelmaier K, Schrutka L, Wurm R, Seidl V, Arfsten H, Cho A, et al. Gender-related impact on outcomes of high density lipopro- tein in acute ST-elevation myocardial infarction. Atherosclerosis. 2016;251:460–6. https://doi.org/10.1016/j.atherosclerosis.2016. 06.037.
  2. Miller YI, Choi SH, Wiesner P, Fang L, Harkewicz R, Hartvigsen K, et al. Oxidation-specific epitopes are danger-associated molec- ular patterns recognized by pattern recognition receptors of innate immunity. Circ Res. 2011;108(2):235–48. https://doi.org/10.1161/ CIRCRESAHA.110.223875.
  3. Toribio M, Fitch KV, Sanchez L, Burdo TH, Williams KC, Sponseller CA, et al. Effects of pitavastatin and pravastatin on markers of immune activation and arterial inflammation in HIV. AIDS. 2017;31(6):797–806. https://doi.org/10.1097/QAD. 0000000000001427.
  4. Krebs SJ, Slike BM, Sithinamsuwan P, Allen IE, Chalermchai T, Tipsuk S, et al. Sex differences in soluble markers vary before and after the initiation of antiretroviral therapy in chronically HIV- infected individuals. AIDS. 2016;30(10):1533–42. https://doi. org/10.1097/QAD.0000000000001096.
  5. Curno MJ, Rossi S, Hodges-Mameletzis I, Johnston R, Price MA, Heidari S. A systematic review of the inclusion (or exclusion) of women in HIVresearch: from clinical studies of antiretrovirals and vaccines to cure strategies. J Acquir Immune Defic Syndr. 2016;71(2):181–8. https://doi.org/10.1097/QAI. 0000000000000842.
  6. Klein SL, Flanagan KL. Sex differences in immune responses. Nat Rev Immunol. 2016;16(10):626–38. https://doi.org/10.1038/nri. 2016.90.
  7. Griesbeck M, Scully E, Altfeld M. Sex and gender differences in HIV-1 infection. Clin Sci (Lond). 2016;130(16):1435–51. https:// doi.org/10.1042/CS20160112.
  8. Gandhi M, Aweeka F, Greenblatt RM, Blaschke TF. Sex differ- ences in pharmacokinetics and pharmacodynamics. Annu Rev Pharmacol Toxicol. 2004;44:499–523. https://doi.org/10.1146/ annurev.pharmtox.44.101802.121453.
  9. Poteat T, Scheim A, Xavier J, Reisner S, Baral S. Global epide- miology of HIV infection and related syndemics affecting trans- gender people. J Acquir Immune Defic Syndr. 2016;72(Suppl 3): S210–9. https://doi.org/10.1097/QAI.0000000000001087.
  10. Quinn VP, Nash R, Hunkeler E, Contreras R, Cromwell L, Becerra-Culqui TA, et al. Cohort profile: study of transition, out- comes and gender (STRONG) to assess health status of transgen- der people. BMJ Open. 2017;7(12):e018121. https://doi.org/10. 1136/bmjopen-2017-018121.
  11. Clayton JA, Collins FS. Policy: NIH to balance sex in cell and animal studies. Nature. 2014;509(7500):282–3.
  12. Geretti AM, Loutfy M, D’Arminio Monforte A, Latysheva I, Perez Elias MJ, Rymer J, et al. Out of focus: tailoring the cascade of care to the needs of women living with HIV. HIV Med. 2017;18(Suppl 2):3–17. https://doi.org/10.1111/hiv.12533.
  13. Grewe ME, Ma Y, Gilbertson A, Rennie S, Tucker JD. Women in HIV cure research: multilevel interventions to improve sex equity in recruitment. J Virus Erad. 2016;2:49–51.
  14. Falcon R, Bridge DA, Currier J, Squires K, Hagins D, Schaible D, et al. Recruitment and retention of diverse populations in antire- troviral clinical trials: practical applications from the gender, race and clinical experience study. J Women’s Health (Larchmt). 2011;20(7):1043–50. https://doi.org/10.1089/jwh.2010.2504.
  15. Zanni MV, Fitch K, Rivard C, Sanchez L, Douglas PS, Grinspoon S, et al. Follow YOUR heart: development of an evidence-based cam- paign empowering older women with HIV to participate in a large- scale cardiovascular disease prevention trial. HIV Clin Trials. 2017;18(2):83–91. https://doi.org/10.1080/15284336.2017.1297551.

146 Curr HIV/AIDS Rep (2018) 15:136–146

https://doi.org/10.3109/07435800903204082
https://doi.org/10.3109/07435800903204082
https://doi.org/10.1371/journal.ppat.1005889
https://doi.org/10.1126/science.1233521
https://doi.org/10.1126/science.1233521
https://doi.org/10.1016/j.immuni.2013.08.013
https://doi.org/10.1016/j.immuni.2013.08.013
https://doi.org/10.1371/journal.pone.0124599
https://doi.org/10.1371/journal.pone.0124599
https://doi.org/10.1371/journal.pone.0154090
https://doi.org/10.1128/AEM.72.2.1027-1033.2006
https://doi.org/10.3389/fgene.2014.00100
https://doi.org/10.3389/fgene.2014.00100
https://doi.org/10.1093/cid/cir484
https://doi.org/10.1093/cid/cir484
https://doi.org/10.1111/j.1651-2227.2011.02185.x
https://doi.org/10.1111/j.1651-2227.2011.02185.x
https://doi.org/10.1098/rstb.2016.0355
https://doi.org/10.1038/ng.3726
https://doi.org/10.1126/science.1195271
https://doi.org/10.1186/1471-2164-10-292
https://doi.org/10.1186/1471-2164-10-292
https://doi.org/10.1080/15592294.2015.1084462
https://doi.org/10.1080/15592294.2015.1084462
https://doi.org/10.1016/j.atherosclerosis.2016.06.037
https://doi.org/10.1016/j.atherosclerosis.2016.06.037
https://doi.org/10.1161/CIRCRESAHA.110.223875
https://doi.org/10.1161/CIRCRESAHA.110.223875
https://doi.org/10.1097/QAD.0000000000001427
https://doi.org/10.1097/QAD.0000000000001427
https://doi.org/10.1097/QAD.0000000000001096
https://doi.org/10.1097/QAD.0000000000001096
https://doi.org/10.1097/QAI.0000000000000842
https://doi.org/10.1097/QAI.0000000000000842
https://doi.org/10.1038/nri.2016.90
https://doi.org/10.1038/nri.2016.90
https://doi.org/10.1042/CS20160112
https://doi.org/10.1042/CS20160112
https://doi.org/10.1146/annurev.pharmtox.44.101802.121453
https://doi.org/10.1146/annurev.pharmtox.44.101802.121453
https://doi.org/10.1097/QAI.0000000000001087
https://doi.org/10.1136/bmjopen-2017-018121
https://doi.org/10.1136/bmjopen-2017-018121
https://doi.org/10.1111/hiv.12533
https://doi.org/10.1089/jwh.2010.2504
https://doi.org/10.1080/15284336.2017.1297551
Sex Differences in HIV Infection
Abstract
Abstract
Abstract
Abstract
Introduction
Prevention
Sex-Specific Acquisition Risks
Vaccine Responses
Pre-Exposure Prophylaxis
Pathogenesis
Disease Progression
Response to Treatment
Non-AIDS Morbidity and Mortality
HIV Eradication and Functional Cure
Potential Mechanisms
Sex Hormone Effects
Microbiome
Genetic Differences
Immunological Differences
Gaps in Knowledge and Opportunities
Conclusion
References

Order your essay today and save 10% with the discount code ESSAYHELP