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
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
According to the United States National Science Foundation 2015 report on women, minorities and persons with disabilities in science and engineering , 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 ..
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 . Indeed, only in the last decade or so have doctoral degrees awarded to women reached parity with those awarded to men .
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’ , at all stages of their careers. A recent study  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 . 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 .
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 . 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 . 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 .
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 . 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 . 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% . 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 . 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 . Perhaps not surprisingly, women are less satisfied with their careers as scientists than are men .
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.
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 , 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.
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
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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
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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 . 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  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 , 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.
We thank Ms Oratai Butterworth for her help in preparing this manuscript.
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
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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
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.
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 , 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  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
- Eileen P. Scully [email protected]
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
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.
Sex differences in both adverse effects and the efficacy of protective responses to vaccination are well described . 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 . 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  although subsequent work sug- gested that specific epitopes may be preferentially recognized in women . Systems biology analysis of gene expression profiles after yellow fever vaccine identified sex-specific pro- grams of gene induction , 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 . In terms of immune correlates of pro- tection, differences in humoral and cell-mediated immune re- sponses have been seen in multiple vaccines . Mechanistically, there is evidence for more potent induction of inflammatory pathways in cytotoxic T cells from women ; 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  and that antibody glycosylation pat- terns are influenced by sex  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.
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  and in
serodiscordant couples , 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  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 , although the VOICE study, which was limited by low adherence, did not show efficacy in the vaginal gel arm . 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 . As studies defining the effects of topical exposure at the rectal mucosa have suggested that tenofovir may increase certain inflammatory mediators , 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.
Sex is a clear contributor to disease pathogenesis in multiple infectious diseases , 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 . Similarly, the expression of interferon-stimulated genes was higher in women when con- trolling for HIV viral load . 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) . 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 . 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 . 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  and yielded critical insights into the barriers to participation by women (discussed further below) . 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) , 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 . 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 . Other cohorts have reported similar differences in response to treat- ment, although inconsistent differences in baseline levels . 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 . 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 . The excess risk of cardiovascular events in people living with HIV  is amplified in women  and linked to higher levels of circulating markers of monocyte activation . Likewise, the increased risk of cerebrovascular events in HIV-infected individuals [76, 77] is exaggerated in women . 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 . 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 ; this is an important divergence from the direct antiviral agents used
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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 . 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 . 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  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.
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 . 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 . There are additional inter- sections between sex hormone levels and inflammation in- duced by microbiome composition and concurrent infections . 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 . 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 . 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.
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  and direct microbial me- tabolism of tenofovir associated with reduced efficacy of PrEP in the female genital tract . 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.
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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 .
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 . 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 . Growing evidence demonstrates that up to 20% of X
chromosome genes escape inactivation ; this has clinical implications, with recent work suggesting that these genes may determine a portion of sex-specific susceptibility to can- cer . 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 . 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 . 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
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differences in immune responses . Given the potential use of epigenetic modifiers in latency reversal, sex-specific patterns of epigenetic regulation should be explored.
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 . 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 . 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 . 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 . 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 , HIV disease pathogene- sis , and pharmacokinetics/pharmacodynamics , 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  and growing evidence for the feasibility of high-quality studies in this pop- ulation , 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 , 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 . 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 . 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.
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.
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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.
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Sex Differences in HIV Infection
Sex-Specific Acquisition Risks
Response to Treatment
Non-AIDS Morbidity and Mortality
HIV Eradication and Functional Cure
Sex Hormone Effects
Gaps in Knowledge and Opportunities