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Try out PMC Labs and tell us what you think. Learn More. This review will outline the multilevel effects of biological sex on HIV acquisition, pathogenesis, treatment response, and prospects for cure. Potential mechanisms will be discussed along with future research directions. 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. Biological sex remains an important variable in determining the risk of HIV infection and subsequent viral pathogenesis, 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. 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 genetic complement, hormonal environment, and behavioral and social Ladies seeking sex Cascade Virginia, 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 modulated 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 prevention, pathogenesis, and cure research, and then outline potential biological mechanisms for these differences. Finally, barriers to research on sex differences and to enrolling women in clinical trials are discussed, along with the opportunities to circumvent these obstacles. The risk of HIV seroconversion per heterosexual act is estimated to be approximately twofold higher for the female compared to male partner [ 1 ], with multiple contributing factors.
The unique characteristics of the female genital tract as compared with rectal and penile mucosal surfaces confer differences in transmission risk. Inflammation at the cervicovaginal mucosa lowers the barrier to HIV infection [ 2 — 5 ], and both the vaginal microbiome itself [ 6 ] and sexually transmitted infections [ 7 — 11 ] are important determinants of the levels of local inflammation.
The association of depot medroxyprogesterone DMPA hormonal contraception with enhanced risk of infection hazard ratio of 1. 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 [ 15 ]. These differences are of clinical ificance as seen in the higher rates of vaccine-associated severe viscerotropic yellow fever disease in women [ 1617 ] and the HSV glycoprotein vaccine that was protective only in women [ 18 ].
The mechanisms driving these differences are not totally clear; no specific immunologic correlate was reported for the sex differences in the HSV vaccine trial [ 18 ] although subsequent work suggested that specific epitopes may be preferentially recognized in women [ 19 ]. Systems biology analysis of gene expression profiles after yellow fever vaccine identified sex-specific programs 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 RV study, protective efficacy was estimated In terms of immune correlates of protection, differences in humoral and cell-mediated immune responses 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 enhanced by estrogen [ 23 ] and that antibody glycosylation patterns 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 enhance responses. For example, sex-specific induction of type 1 interferons Ladies seeking sex Cascade Virginia the inflammasome might indicate a role for specific adjuvanting strategies in men versus women. Given the challenges of vaccine development, all avenues for optimization bear consideration. In the absence of an effective vaccine, pharmacologic strategies have become a critical adjunct to the prevention of transmission. 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, that were attributed to very low adherence to study drug [ 2728 ].
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. 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 warranted.
Further studies are necessary to define the optimal approach to risk reduction in both men and women; advantages 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 adherence, along with critical differences in pharmacologic properties and the microenvironment at sites of acquisition in men and women. Considering these differences will be critical in the de and implementation of chemoprophylaxis strategies. 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 lo early during infection but despite this difference, disease progression is comparable between the sexes [ 36 Ladies seeking sex Cascade Virginia 46 ].
Similarly, the expression of interferon-stimulated genes was higher in women when controlling for HIV viral load [ 48 ]. Given the role of immune activation Ladies seeking sex Cascade Virginia driving HIV disease progression [ 4950 ] and in comorbidities that emerge during effective ART [ 5152 ], the sex difference in immune setpoint likely has clinical consequences. In selected individuals, HIV disease progression is attenuated, with either spontaneous control of viral replication in the absence of drug therapy [ 53 — 55 ] or sustained viral suppression 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 [ 5758 ] although the determinants of this advantage have not been elucidated. Again, sex-specific mechanisms of protection have not been defined within this group, and it should be noted that the total s 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. 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, consistent with the improved therapeutic index of modern antiretrovirals [ 65 — 67 ].
Complications of immune reconstitution such as the immune reconstitution inflammatory 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 soluble CD, a marker of monocyte activation [ 70 ].
Other cohorts have reported similar differences in response to treatment, although inconsistent differences in baseline levels [ 71 ]. Further work will be necessary to dissect the direct contribution of HIV and ART as compared with concurrent inflammatory 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. 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 consequences 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 [ 7677 ] is exaggerated in women [ 78 ]. Of note, the epidemiology of these comorbid conditions varies Ladies seeking sex Cascade Virginia across different social and geographic contexts obligating thoughtful de of trials to assess for the contribution of sex [ 79 ].
The differences in risk profile between men and women highlight the potential for studies of sex differences to identify causal pathways or biomarkers of disease pathogenesis. 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 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 reservoir size and dynamics. However, data from a prospectively enrolled cohort of ART-treated men and women did not show any ificant 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.
In general, conclusions are limited by the underrepresentation of women in studies relevant to cure [ 83 ]. Specifically, in seminal work comparing different methods of reservoir quantitation, Ladies seeking sex Cascade Virginia were no XX participants and only 2 of 30 are identified as transgender male to female without data about exogenous hormone exposure [ 84 ]. Of participants 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 [ 9293 ] have shown sex-specificity in other contexts that should be considered carefully in the development of clinical trials.
Outlined above are multiple features of HIV acquisition, prevention, pathogenesis, and persistence that show sex variation. 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 adherence 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 contributing to differences and can be exploited to therapeutic benefit Fig. Summary of five critical domains of sex differences with relevance for HIV infection and potential or demonstrated mechanisms for their effects.
As noted above, there is an association with DMPA contraceptive use and enhanced rates of infection. The precise mechanisms 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 — ]. Recent data identified endogenous and exogenously administered progesterone-induced variations in the frequency of cervical HIV-susceptible target cells [ ]. There are additional intersections between sex hormone levels and inflammation induced by microbiome composition and concurrent infections [ ].
Given the global need for effective family planning Ladies seeking sex Cascade Virginia and widespread use of hormonal contraception, determining 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. work has demonstrated that the estrogen receptor can be indirectly recruited to the HIV-1 long terminal repeat LTR and act to repress transcriptional activity [ ].
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. Ex vivo studies using primary cells from both men and women confirmed that estrogen is repressive to latency reversal, and that blockade of the estrogen receptor can enhance reactivation Karn et al. Sex hormones have also been reported to have a variety of direct effects on immune cell function.
Of note, the presence of estrogenic compounds in standard cell culture media components  and the difficulty in replicating the in vivo balance of hormones 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 relationship, with specific microbiome components associated with alterations in wound healing [ ] and direct microbial metabolism 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 . Studies have confirmed sex variation in gut microbial contents in humans [ — ] and further work will be necessary to determine if these differences have consequences for inflammation in HIV disease. Interventions to reshape the microbiome e. The sex-specific chromosomal complement is an additional pathway to biological differences.Ladies seeking sex Cascade Virginia
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