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J Clin Invest
J Clin Invest
J Clin Invest
The Journal of Clinical Investigation
0021-9738
1558-8238
American Society for Clinical Investigation

180075
10.1172/JCI180075
Review Series
The impact of sex on HIV immunopathogenesis and therapeutic interventions
Mihealsick Erin emiheal1@jhmi.edu
1
Word Anna 1
https://orcid.org/0000-0002-6687-6051
Scully Eileen P. escully1@jhmi.edu
2
1 Graduate Program in Immunology and
2 Division of Infectious Diseases, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Address correspondence to: Eileen P. Scully, 855 North Wolfe Street, Rangos Building, Room 536, Baltimore, Maryland 21205, USA. Email: Escully1@jhmi.edu.
17 9 2024
17 9 2024
17 9 2024
134 18 e180075© 2024 Mihealsick et al.
2024
Mihealsick et al.
https://creativecommons.org/licenses/by/4.0/ This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
This article is available online at https://www.jci.org/articles/view/180075
Globally, the majority of people living with HIV are women or girls, but they have been a minority of participants in clinical trials and observational studies of HIV. Despite this underrepresentation, differences in the pathogenesis of HIV have been observed between men and women, with contributions from both gender- and sex-based factors. These include differences in the risk of HIV acquisition, in viral load set point and immune activation in responses to viremia, and differences in HIV reservoir maintenance. These differences obligate adequate study in both males and females in order to optimize treatments, but also provide a powerful leverage point for delineating the mechanisms of HIV pathogenesis. The shifts in exposure to sex steroid hormones across a lifespan introduce additional complexity, which again can be used to focus on either genetic or hormonal influences as the driver of an outcome. In this Review, we discuss consistent and reproducible differences by sex across the spectrum of HIV, from acquisition through pathogenesis, treatment, and cure, and explore potential mechanisms and gaps in knowledge.
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pmcOverview

The HIV pandemic has claimed more than 40 million lives and has been a galvanizing force in research into the prevention, pathogenesis, and treatment of infectious diseases. It has also brought into sharp relief the tremendous variation in the effect of HIV infection when considered across a broad population, ranging from elite control (1, 2) to rapid disease progression (3). Sex and gender are linked to distinct risks of HIV acquisition, pathogenesis, and reservoir maintenance, concordant with the impact of sex on a variety of infectious and inflammatory conditions (4–6). Gender differences in health-associated behavior, access to care and resources, and social stressors have a profound role in health outcomes (7). Although this Review discusses HIV infection and outcomes through the lens of biological sex, particularly genetic and hormonal differences, all studies must be considered within the context of potential gender-based confounders and effects. Approaches to considering risk and research in a gender framework have been expertly discussed elsewhere (8, 9). We focus on differences by sex in the context of HIV, noting where gender factors may intervene, but seeking to leverage sex to identify mechanisms of pathogenesis and potential points for therapeutic intervention. Throughout the Review, we discuss studies of people living with HIV (PLWH) and, when discussing characteristics related to genetic (e.g., XX versus XY) and anatomic features (reproductive organs), specifically use the terms female and male. We have used the terms women and men to refer to cisgender individuals unless otherwise indicated and in describing data from studies in which these terms were used to describe the participants.

Herein, we indicate gaps and opportunities in the data and attempt to highlight comparisons where there are major confounders. A primary consideration is whether studies have adequate inclusion across sex and gender for valid conclusions. The initial description of AIDS as an acquired immune deficiency syndrome among men who have sex with men (10, 11) reflected the epidemic in the US and Europe, which has been dominated by men. This contrasts with the global epidemic, in which women account for 53% of PLWH (12). In sub-Saharan Africa, women constitute more than 61% of PLWH and 62% of new HIV diagnoses in this region (12) (Table 1). Distribution of the infection has important implications for the available data: a high proportion of biomedical research and funding originate in regions with male-dominated epidemics, contributing to an underrepresentation of female study participants (13–15). Elucidating immunologic mechanisms of phenotypic differences by sex across the spectrum from HIV acquisition through efforts towards a cure may facilitate the development of interventions that will serve all PLWH.

Acquisition

Due to the very early integration of HIV into the host cell genome, viral eradication presents a formidable challenge, and a preventive vaccine remains crucial to ending the epidemic. In this section, we explore sex-specific features of HIV acquisition, including through vertical transmission, that inform the development of protective vaccines and deployment of preventive strategies including pre-exposure prophylaxis.

Anatomic risks for HIV acquisition.

HIV can be acquired via parenteral exposure to blood products or through sexual activity. Although we lack significant data about sex-differential risk related to parenteral exposures, as discussed below, there is emerging data in the context of vertical transmission.

There are clear distinctions in acquisition risk thresholds based on sexual transmission. Broadly, the risk of sexual acquisition is dictated by the availability of cells that can be infected. This, in turn, is determined by anatomy and the levels of local inflammation (16). Receptive anal intercourse has the highest risk of transmission (17), with studies suggesting that the density of CD4+ T cells and inflammatory environment conditioned by the microbiome may contribute to elevating risk of acquisition, and that this risk may change with age (18). Penile-vaginal intercourse is associated with a higher risk of transmission to the female partner in high-income countries, with a more modest difference in other settings, notably where male circumcision is less common (19). Langerhans cells and CD4+ T cells present in the vaginal mucosa and penile foreskin are the primary targets for early HIV-1 infection (16, 20, 21). Medical male circumcision has been shown to significantly decrease the risk of HIV acquisition, likely both by reducing the local target cell populations and by eliminating inflammatory components of the foreskin microbiome (22). For females, there has been significant debate about the effect of hormone exposure on the vaginal mucosal environment. Two meta-analyses reported an approximately 40% increase in risk of HIV acquisition associated with use of depot medroxyprogesterone acetate (DMPA, a contraceptive injection under the brand name Depo-Provera) (23, 24). Suggested mechanisms include alterations in the epithelial layer, change in frequency of target cells, and inflammation and alterations in the microbiome. However, this is not supported by the results of a prospective randomized trial comparing DMPA with other contraceptive methods, in which there was not a substantial increase in risk (25). Importantly, this study also highlights that hormone exposure must be considered in context of the alternatives, which here would be alternative contraceptive methods or a pregnancy with the associated maternal risks (26). Nevertheless, a greater understanding of the influence of hormones on the local environment may provide information on factors that favor transmission. Further exploration of the effect of exogenous sex steroid hormone exposure in transgender individuals will also be important in order to optimize and target prevention efforts in this population (27).

In parallel with the risk for HIV acquisition that is conferred by the local availability of targets at a mucosal site is the potential protection conferred by vaccine-induced HIV-specific immune responses at these mucosal sites. With respect to humoral immunity, a meta-analysis of mucosal antibody titers across six vaccine platforms of HIV envelope immunogens demonstrated a robust correlation between seminal plasma and rectal mucosal antibody titers in males but poor correlation between cervical and rectal antibody titers in females (28). The authors suggested that sex-specific features in the relationship between serum and genital/rectal mucosal antibody titers may affect the degree of protection (28). Emerging data from phase IIb trials of prophylactic administration of the broadly neutralizing antibody (bNAb) VRC01 provide some further insight into the function of humoral responses at mucosal sites (29). In these trials, one enrolling at-risk cisgender men and transgender individuals in Europe and the Americas and the other enrolling at-risk cisgender women in sub-Saharan Africa, VRC01 was not effective, but both trials showed a signal of preventive efficacy against viruses sensitive to neutralization by VRC01 that was linked to antibody concentration (29). In a separate analysis of the mucosal penetration of VRC01 in healthy volunteers, both rectal and vaginal explants demonstrated resistance to ex vivo challenge with sensitive strains of HIV (30). As strategies of combinations of antibodies for prevention with targeted modifications of the Fc region to enhance mucosal penetration and effector function are pursued, careful evaluation of the sex-specific accumulation and efficacy of these agents will be essential.

Impact of local inflammation on HIV acquisition.

Both the efficacy of local immune responses and available target cells are directly affected by inflammation that may arise from either sexually transmitted infections (STIs) or as a result of the composition of the local microbiome. STIs including HSV-2, syphilis, gonorrhea, and chlamydia cause an increased risk of HIV acquisition during vaginal intercourse (31–35). A systematic review of the effect of herpes found that a relative risk of HIV acquisition was 2.7-fold higher with prevalent HSV-2 in the general population and 4.7-fold higher with incident infection, with no sex difference observed in the estimates (36). Likewise, an analysis of the impact of nonviral STIs demonstrated increased risk of HIV acquisition with coincident STI, although notably the data for males were sparse (37). Some of the enhanced risk may be attributable to behavioral patterns associated with STIs. Biological mechanisms include the influx of target cells to both the male and female genital tracts as a result of an STI (38–43); increased genital shedding of HIV driven by HSV-2 coinfection, which may directly influence HIV-1 acquisition (44); and disruption of the protective epithelial layer by genital ulceration in the setting of syphilis, chancroid, and HSV-2 infection (45, 46).

HIV seroconversion is also more likely when there is more inflammation, as defined by cervicovaginal levels of inflammatory cytokines such as MIP-1α, MIP-1β, and IP-10, which actively recruit target cells for HIV (47). In the absence of an STI, the specific composition of the vaginal microbiota, including when this shifts to a clinical diagnosis of bacterial vaginosis, is linked to increased risk of HIV acquisition (48–51). Inflammation driven by microbiota can activate Langerhans cells and CD4+ T cells, raising the risk of HIV acquisition (52, 53). Specific formulations of oral contraceptives have been linked to more-favorable vaginal microbial communities and to a lower frequency of STIs, suggesting that hormone modulation is a potential risk-modifying strategy (54, 55). The vaginal microbiome is also a critical consideration for topical pre-exposure prophylaxis, as certain species metabolize the antiviral drug tenofovir, lowering its preventive efficacy for HIV (56). Thus, the vaginal microbiome can confer risk, and understanding variations based on region, ethnicity, and local environment will be important to optimize prevention interventions (51, 57, 58). In parallel, the penile microbiome comprises specific microbial components that promote risk of acquisition, with the notable difference that medical male circumcision can significantly ameliorate, although not eliminate, the risk of seroconversion (22, 59, 60).

Vertical transmission.

Intrauterine transmission is an emerging area of sex differential HIV transmission. In a recent single-site cohort study of infants with intrauterine acquisition of HIV, females outnumbered males 1.7:1, consistent with prior studies. This ratio contrasts with the sex ratios of HIV-exposed but uninfected infants and to the overall ratio of sex at birth in the study region (50.6% male) (61). Since the 1990s, multiple studies have assessed the risk of vertical transmission in the context of intrapartum antiretroviral therapy (ART), ART during pregnancy, and various approaches to infant treatment, with very early signals of an increased risk for female infants (62). In a large cohort study in Zimbabwe of 4,495 women living with HIV and their infants between 1997 and 2000, female infants were at greater risk of in utero acquisition (OR 1.53, 95% CI 1.23–1.91), despite 50.4% of all births being male (63, 64). An analysis of more than 2,000 women in Malawi in the 1990s reported higher rates of intrauterine acquisition in female infants (OR 1.4, 95% CI 0.2–2.2) and, notably, in 8 sets of sex-discordant twin pairs, 7 female infants and 1 male infant acquired HIV in utero (65). This finding is important, as it implies a selective pressure from the infant, given that the maternal environment of these twin pregnancies is identical. Separate work from Malawi in the early 2000s again reported a higher risk for female infants (OR 2.06, 95% CI 1.49–2.85), and this estimate was adjusted for maternal viral load, a strong independent predictor of transmission (66). Beyond the African context, the European Collaborative Study of vertical transmission noted that among infants delivered by elective cesarean section (effectively eliminating risk of intrapartum transmission), female infants are at higher risk (2.14, 95% CI 1.14–4.00) after adjustment for antenatal ART use and time period (67). An Italian registry had similar findings of lower risk for male infants (68). While modern ART has substantially reduced vertical transmission, the enhanced risk in female infants appears to persist. A prospective infant treatment trial screened 10,622 infants between 2015 and 2018, identified 42 with HIV within 96 hours of birth, and enrolled 40. Of the 40 infants enrolled in the trial, 78% were female (69). While there are multiple features to consider — including maternal ART, survival of male versus female infants independent of HIV risk, and differences in transmission risk across the timing of delivery — the weight of the collective data indicates that there is a higher risk of intrauterine transmission of HIV to female infants.

The mechanism of this differential risk is unclear; the twin data suggest that there are features of the infant that drive the difference. Of note, recent work has indicated that viruses recovered from female infants were more likely to be interferon resistant and have differences in replication capacity (61, 70). Production of type I interferon in response to TLR7 stimulation is a prominent feature of sex differential immune responses, as discussed below, and may contribute to this difference in early life.

Pathogenesis

Viral load.

Multiple studies have demonstrated that in the absence of HIV treatment, females have lower set point viral loads than males, although this difference attenuates with progression to advanced disease (71–79). In a study of individuals not on ART, females had less plasma virus associated with each HIV RNA+ CD4+ T cell in lymph node biopsies, suggesting that lower plasma viremia is associated with each HIV-infected cell in females (80). The lower systemic viral load is not protective, and males and females exhibit a similar time course of disease progression following seroconversion. This discordance meant that early on in the HIV epidemic, treatment guidelines based on viral load excluded women who were at risk for disease progression (79), highlighting the need for analysis of population variation for health policy–level decisions.

There are also important sex differences in the rates of the rare phenomenon of spontaneous control. In multiple large medical record database studies, rates of viremic and elite control are substantially higher in females, with the OR of female control ranging from 1.9 to 5 (81–84). Female participation in studies of elite controllers has not been representative; for example, an international cohort of 9,705 participants in a study that investigated the genetic determinants of HIV control was 82% male (85), leaving open questions about the effect of sex on this phenotype. Separate from spontaneous control is the phenomenon of posttreatment control, in which individuals who have been viremic are able to maintain viral suppression after a period of ART despite subsequent treatment discontinuation. The determinants of this type of control are under active investigation as a potential model of a functional cure. In one cohort of primary HIV infection, female sex was associated with a higher rate of posttreatment control (86). In other cohorts, there was not a clear signal for enrichment of control among females (87, 88), although the identification of individuals demonstrating posttreatment control was biased by the same factors that have led to the overrepresentation of males in other studies of HIV control described above. In a prospective trial assessing whether short-course ART in primary HIV infection leads to prolonged time to disease progression after ART interruption (89), female sex was a strong predictor of maintaining a viral load of fewer than 400 copies/mL for a longer period of time (90). However, the 40% of participants in the trial who were female were almost exclusively enrolled in African sites, and the contributions of the various geographic locations and HIV-1 virus clades cannot be completely separated from the contributions of the sex of the participants. In an analysis of ART discontinuation in more than 1,000 postpartum women treated during pregnancy as part of the PROMISE trial, 25% of the women remained virally suppressed (<400 copies/mL) at 12 weeks. This is a substantially higher level than the 6.4% of participants who maintained suppression at the same time point after treatment interruption in a comparator group of studies; notably, the comparator group was more than 90% male (91). Again, the effects of location, HIV virus clade, and pregnancy are difficult to disentangle from the effects of sex on the timing of viral rebound. Taken together, the data suggest a higher likelihood of spontaneous control in females, and there are suggestions of a higher likelihood of posttreatment control or significantly prolonged time to viral rebound in females.

Innate and adaptive immune activation.

A key driver of HIV pathogenesis is immune activation, with early studies demonstrating the association of T cell activation with progression to advanced disease (92, 93) (Figure 1). While females tend to have lower viral loads, the level of T cell activation for a given viral load is higher in females than in males (94). In untreated disease, type 1 interferon gene signatures were also higher in females, when controlled for viral load (95). Beyond HIV, females are generally described as having higher antiviral immune responses, a higher proportion of CD4+ T cells, increased production of IFN-α, and enhanced antibody production (4, 96, 97). Thus, one hypothesis is that a more robust response to HIV, as seen in higher production of IFN-α from plasmacytoid DCs (pDCs) after stimulation by HIV or other TLR7 ligands (94, 98, 99), may have two possible consequences: The first is a higher likelihood of virologic control as observed in the higher frequency of female spontaneous controllers discussed above. The second is a higher level of ongoing inflammation despite failure to control or eliminate the virus; this outcome would be linked to greater immune activation and risk of disease progression at a lower level of virus exposure. In studies assessing the rates of disease progression in males and females, lower viral load is not protective, with women progressing at similar rates despite lower median viral load levels (79); at least one study suggests that women progress at a faster rate (100). Higher levels of interferon-induced gene signatures in females may also be linked to the cell-intrinsic restriction of HIV replication and potentially lower per-cell production of HIV observed in lymph node CD4+ T cells in females (80). This has been described in macrophages, where female-derived cells had lower levels of HIV replication and higher levels of SAMHD1-based restriction (101). In recent work from murine model systems, isolated immune cells (macrophages, T and B cells) showed distinct patterns of interferon-stimulated gene transcription, notably with cells from female animals responding faster across all conditions (102). Taken together, the data suggest that a robust early antiviral response by females may be linked to lower viral loads, but at the cost of higher immune activation in chronic untreated HIV.

Emerging data about sex differences in intrauterine transmission again show links to interferon-based restriction, with viruses transmitted to females more likely to be interferon resistant (61, 70). Separate studies have confirmed that TLR7/TLR8 responses are lower in male infants (~2 months of age), confirming that differences in this axis are present even in early life (103). This immediately raises the question of which features of sex — genetic composition, sex steroid hormone exposure, epigenetic regulation — are underlying drivers of differences in immune response phenotype and viral restriction given the changes in these factors over a lifetime.

Sex steroid hormones.

Sex steroid hormones and the expression and function of their receptors affect immune responses. In females, 17β-estradiol (E2), and progesterone concentrations fluctuate during the menstrual cycle and throughout life, while male androgen levels remain relatively consistent after puberty (104). In vitro studies showed that lower sex hormone concentrations, modeling the mid-proliferation hormone phase, are associated with higher levels of HIV transcription compared with the higher-concentration, midsecretory phase, suggesting that HIV replication is linked to hormone level (105).

Much of the literature on sex differences in HIV replication has focused on E2 and estrogen receptor α (ERα). ERα is activated upon E2 binding and is expressed in immune cells, and most studies have not demonstrated differences in expression at the transcriptional (106) or protein level (107) between males and females. ERα activation can induce nuclear localization and direct DNA binding at estrogen response elements (EREs) or indirect transcription effects via tethering transcription factors such as RUNX1, AP-1, and Sp1 (108–111). EREs have been found in the promoter region of many immune-related genes that affect activation (112), but it is unclear how the effect of E2 exposure intersects with direct immune-activating signals. Beyond the indirect effects E2 may have on host transcriptional machinery, in vitro studies demonstrated suppression of HIV replication by E2/ERα signaling (113). However, viral load levels in prepubertal females are lower than those in males even when E2 concentrations are similar between the sexes (114). The role of E2 in HIV transcriptional control in the context of ART is further discussed below in Cure.

Beyond these direct effects on viral dynamics, sex steroid hormones can also modulate immune pathways. Notably, the level of interferon regulatory factor 5 (IRF5), a downstream signaling component in the TLR7 response, is higher in pDCs from females and correlates with IFN-α production and with expression of ERα (115). TLR7 is also a canonical example of sex-specific genetic features, as discussed below.

Genetics.

At the most basic level, sex differences in gene expression can arise from the chromosomal complement. Females have two copies of the X chromosome (XX), while males only have one (XY). One X chromosome in females undergoes X inactivation to normalize gene dosage between males and females, but X inactivation escape has emerged as a key contributor to sex differences (96, 116, 117). There are multiple immune active genes on the X chromosome, including TLR7, which has been shown to have dual expression in XX females and in XXY males (Klinefelter syndrome) in the immune system, with consequences for diseases including systemic lupus erythematosus (SLE) (118–121). Thus, females have higher TLR7 expression, and estrogen enhances the downstream signaling through IRF5. Further complicating this system is the recent identification that XIST, the long noncoding RNA that mediates X chromosome inactivation, acts as an endogenous TLR7 ligand, contributing to SLE pathogenesis (122, 123). Notably, a hypomorphic variant of TLR7 has been described to have an effect on acute HIV viremia specifically in females, highlighting the sex-specific relationship between interferon and viral load (124). Taken together, the data indicate that gene dosage, hormone exposure, and epigenetic regulation all contribute to differences between males and females in the TLR7/interferon pathway.

Notwithstanding the importance of the sex chromosomes, the majority of sex-based gene expression variation in immune cells is derived from autosomal genes (106). There has been limited exploration of how sex-specific autosomal gene expression contributes to HIV outcomes. A recent study tested for sex chromosome and sex-stratified genomic markers in the largest GWAS of HIV set point viral load and spontaneous control (125). The analysis was limited by the relatively low representation of females in the cohort (<20%) but identified a gene-based association with set point viral load on chromosome 19 in males only and other gene variants with sex-discordant associations with set point viral load in potentially immune-active genes (125). Further work is needed to elucidate whether baseline or stimulated gene expression differences contribute to observed differences in immune response to HIV. In addition, another key gap in knowledge is the very limited body of work exploring immune cell function in transgender individuals with discordant sex chromosome complement and sex hormone exposure.

Sex differences in the context of ART

Treatment responses and comorbid conditions.

In general, both women and men achieve viral load suppression with ART, as predicted for medications that target viral proteins. As with many types of medications, for some ART agents there is a higher level of reported adverse effects in women and there are pharmacokinetic differences (126, 127). Analyses have historically been limited by low representation of women in clinical trials, which, although improving, still does not proportionally represent the epidemic, particularly regarding the inclusion of African women (15). For current ART, a major challenge is management of weight (128). The ADVANCE trial, a prospective randomized trial of three ART regimens, identified specific regimens as being linked to weight gain that is most pronounced among women (129, 130). The mechanisms by which these ART regimens promote weight gain are incompletely understood, and the intersection with sex may provide a key leverage point for understanding how these medications are affecting metabolism (131). Emerging work in preclinical models suggests that there may be an interaction among dolutegravir, estradiol, and mitochondrial function that may contribute to weight changes (132). Other possibilities — including effects of ART on the gut microbiome, which at baseline has sex-specific features (133) — are still under investigation.

Outside of the adverse effects of ART lies the residual inflammation from HIV even with near complete viral suppression. This inflammation is thought to be a driver of comorbid conditions and remains a key target of novel treatment strategies developed to ameliorate the effect of chronic HIV. Notably, HIV confers a proportionally greater increase in risk of cardiovascular and cerebrovascular disease in women as compared with men (134–137). These findings are consistent with sex-specific features of the burden of comorbid conditions, with changes also noted through reproductive aging in women (138–140). Some of this may reflect gender, with specific health-related behaviors including smoking that contribute to outcomes in women living with HIV. In the sub-Saharan African setting, male mortality exceeds female mortality, again thought to be driven in part by gendered differences in access to testing and care (141, 142). To optimize preventive health interventions across cis- and transgender individuals and in a variety of settings, more studies are needed to identify the HIV- and non-HIV-related drivers of inflammation and associations with comorbid illness and to separate gender- and sex-related mechanisms for disparities in outcomes.

Cure.

Aside from eliminating residual inflammation, the other frontier of modern HIV clinical science is the effort to develop a curative intervention. Cure is variably defined as elimination of all replication-competent virus (eradication) or functional cure, whereby individuals no longer require daily ART to suppress HIV replication. The latter is a model of inducing a controller status and refers to the models of spontaneous control and posttreatment control described above with the notable influence of sex (143). Interestingly, all three individuals in the anecdotal reports characterized as having undergone spontaneous cure — i.e., no recovered replication-competent virus despite extensive sampling — were female (144–146). This, along with data suggesting that females are more likely to have a delayed rebound time after treatment interruption (discussed above) suggest that female sex may be associated with greater propensity to have sustained control (Figure 2).

Given the differences in set point viral load, studies directly explored whether there are differences in the low level of residual HIV expression observed under suppressive ART. In a cohort of matched reproductive-age men and women in the US, levels of HIV DNA were comparable, but levels of multiply spliced cell-associated HIV and low-level viremia by single-copy assay were lower in women (107). Lower levels of cell-associated HIV RNA in females were also observed in a retrospective analysis (147) and in a study of CMV/HIV coinfection (148). While some studies of peripheral blood mononuclear cells have suggested lower levels of total HIV DNA (149, 150), in the majority of studies, levels of HIV DNA (total and/or integrated) are comparable in men and women (107, 147, 148, 151, 152). This suggests tighter control of latent HIV expression in females as compared with males. It is unknown whether there is a difference in the replication competent reservoir; in one study, females had lower levels of ex vivo inducible HIV (152), but in another, there was no significant difference in measures of intact virus and outgrowth (151). These apparent differences in the stringency of latency maintenance are key to the feasibility of some curative strategies. Specifically, the approach of inducing HIV expression to allow identification and elimination of HIV reservoir–harboring cells, known as “shock and kill,” would be predicted to have a higher barrier in females (153). Alternatively, the strategy of “block and lock,” whereby integrated proviruses are maintained in a permanently silenced state of deep latency, might be easier to achieve in females (154). Given the challenges with achieving cure, even small differences in efficacy may be significant.

Potential mechanisms of sex differences in HIV latency.

There is substantial interest in the potential mechanisms for sex-differential latency control. In an unbiased shRNA screen for host factors critical to maintenance of HIV latency, ERα emerged in three independent screens of a cell line model as a key latency regulator (155). This association was further tested using a primary cell model of latency and by assessing the effect of both estradiol and selective estrogen receptor antagonists designed to block or activate ERα. These studies consistently demonstrated that estrogen signaling blocked HIV latency reversal (155). In samples from PLWH, estradiol exposure blocked HIV RNA induction, and antagonists of ERα enhanced the latency reversal activity of other treatments, including the histone deacetylase inhibitor suberoylanilide hydroxamic acid (SAHA, also known as vorinostat) (107, 155). A clinical trial in postmenopausal women testing whether the selective estrogen receptor modulator tamoxifen could augment latency reversal with SAHA failed to show an increase in HIV RNA expression (156). This study was limited by the relatively poor latency reversal efficacy of SAHA and also by the low levels of detectable HIV RNA in trial participants, with substantially more participants having undetectable HIV RNA than in prior studies of male participants (156). In addition, this trial enrolled only postmenopausal women due to genotoxocity concerns around the use of SAHA. Subsequent work has highlighted that there is a higher level of HIV reactivation potential as women move through menopause with waning exposure to estradiol (157), suggesting that estradiol and tamoxifen are likely less impactful in postmenopausal women. Taken together, data support a role for estrogen and ERα in the regulation of HIV transcription, with a changing magnitude across the reproductive lifespan. The precise mechanism of this effect remains unknown.

Another potential mechanistic pathway for differences in HIV latency is sex specificity in epigenetic regulators. HIV latency induction and maintenance is partially mediated through epigenetic marks that suppress transcription through repressive nucleosome arrangements, DNA methylation, and histone methylation (158). Women have globally higher levels of DNA methylation in whole blood (159), and analyses of sex-biased gene expression across tissues suggest sex-differential epigenetic marks as a mechanism of differential gene expression (160). Again there is evidence of hormone modulation of these effects, with a smaller difference observed in postmenopausal women relative to men (161), highlighting the need to consider multiple features as potential mediators of differences.

A novel regulator of HIV infection susceptibility and reservoir maintenance lies in the metabolic state of the immune cell (162). HIV infection is less efficient in CD4+ T cells in glucose-deprived conditions, highlighting the importance of metabolic balance on HIV replication (163–165). Differences in metabolism between cisgender men and women are well appreciated, with women having higher body fat percentages than men and different adipose storage distribution, but there is limited exploration of the impact of sex on immunometabolism (166). The potential role of sex in metabolic control of immune cell function has not yet been explored in the context of HIV, but it may be identified as contributor to reservoir maintenance and anti-HIV responses.

Curative therapies that may have sex-specific effects.

As highlighted in the previous section, sex differences in epigenetic regulation may lead to differences in therapeutic responses to latency reversal agents in this class of drugs. Another area of interest for latency reversal is TLR agonism, with a dual goal of boosting HIV expression and inducing immune responses to promote reservoir clearance (167, 168). Nonhuman primate studies had promising results, and several small clinical trials have explored the effect of TLR7 and TLR9 agonism on induction of HIV expression and reduction of reservoir size, with variable results (169–173). Representation of females was limited in these trials, insufficient to allow sex-specific analyses, but the abundant data on sex-specific features of TLR7 regulation and function suggest that this should be carefully considered.

Another potential source of variation is in strategies aimed at enhancing endogenous immune responses to more efficiently eliminate the reservoir. One approach is the use of immune checkpoint blockade therapies used in cancer therapy with the goal of reinvigorating the T cell response to eliminate HIV-infected cells (174, 175). In the prospective cohort of ART-suppressed participants exploring sex differences in reservoir activity, immunophenotyping showed lower expression of programmed cell death 1 (PD-1) on bulk CD4+ and CD8+ T cells from women as compared with men, although these measures do not provide information on antigen-specific responses (107). In cancer therapeutics, there are sex-specific patterns of response to checkpoint therapies across different tumors (176, 177). Taken together, “kill” strategies leveraging checkpoint blockade may be less effective in women. Conversely, other “kill” strategies may be more effective in women; therapeutic vaccines designed to augment and redirect the immune response to eliminate HIV reservoir cells are another potential immune-modulating strategy. A broad range of literature demonstrates generally more robust vaccine responses in females (reviewed in refs. 5, 178), arguing that these “kill” strategies may perform better in females.

Opportunities

Sex differences in HIV acquisition and pathogenesis and their consequences for comorbidities and HIV cure efforts highlight multiple levels of the immune response to HIV (Table 2). They also highlight the risks of narrow representation in clinical trials and importance of testing interventions against population variation. Comparisons by sex remain a rich source of scientific discovery. Moving forward, further work is still necessary to clarify the role of sex steroid hormones and genetic and epigenetic controls in mediating differences in phenotype by sex. Work is needed to increase representation of cisgender women across the spectrum of clinical research and to investigate the unique setting of transgender individuals to allow the development of personalized care approaches. Deconvoluting the overall mechanisms of differences by sex in outcomes of HIV will be critical to developing prevention, treatment, and cure strategies that are efficacious across all people.

The authors would like to dedicate this review to Ada Adimora, whose brilliant research, leadership, and committed advocacy advanced the cause of women living with HIV. EM, AW, and EPS are supported by the National Institute of Allergy and Infectious Diseases (NIAID) and Office of Research on Women’s Health (ORWH; R01AI154541-04) and through a subaward from P30AI18436 to EPS.

Version 1 09/17/2024

Electronic publication

Figure 1 Multilevel effect of sex on HIV pathogenesis.

TLR7 escape from X inactivation in female plasmacytoid DCs (pDC) induces increased IFN-α levels. Increased IFN-α is in part a result of 17β-estradiol– (E2-) and ERα-dependent increases in IRF5 expression. Expression of the long noncoding RNA XIST, which mediates epigenetic silencing of one X chromosome, also provides a source of TLR7 ligands that may enhance IFN-α. IFN-α promotes expression of interferon-stimulated genes (ISG) linked to increased immune cell activation. This enhanced response may contribute to higher frequency of controller phenotypes in females, but in chronic infection it drives CD4+ T cell decline and comorbidities.

Figure 2 Sex differences in strategies for HIV cure.

Female sex is associated with tighter control of latent HIV that may be a barrier to latency reversal. Mechanisms may include epigenetic repression and latency promotion via E2 signaling. Immune-enhancing strategies including checkpoint inhibition and vaccination may also have sex-differential efficacy. LRA, latency reversal agent; pTEFb, positive transcription elongation factor b; LTR, long terminal repeat; CTL, cytotoxic T lymphocyte.

Table 1 Regional estimates of the proportion of PLWH who are women

Table 2 Summary of sex differences in HIV acquisition, pathogenesis, and response to cure and treatment strategies; and identification of knowledge gaps and directions for future research

Conflict of interest: The authors have declared that no conflict of interest exists.

Copyright: © 2024, Mihealsick et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.

Reference information: J Clin Invest. 2024;134(18):e180075. https://doi.org/10.1172/JCI180075.
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1 Blankson JN Siliciano RF Elite suppression of HIV-1 replication Immunity 2008 29 6 845 847 10.1016/j.immuni.2008.12.002 19100698
2 Deeks SG Walker BD Human immunodeficiency virus controllers: mechanisms of durable virus control in the absence of antiretroviral therapy Immunity 2007 27 3 406 416 10.1016/j.immuni.2007.08.010 17892849
3 Olson AD et al Evaluation of rapid progressors in HIV infection as anextreme phenotype J Acquir Immune Defic Syndr 2014 67 1 15 21 10.1097/QAI.0000000000000240 24872130
4 Klein SL Flanagan KL Sex differences in immune responses Nat Rev Immunol 2016 16 10 626 638 10.1038/nri.2016.90 27546235
5 Klein SL et al The Xs and Y of immune responses to viral vaccines Lancet Infect Dis 2010 10 5 338 349 10.1016/S1473-3099(10)70049-9 20417416
6 Markle JG Fish EN SeXX matters in immunity Trends Immunol 2014 35 3 97 104 10.1016/j.it.2013.10.006 24239225
7 Mauvais-Jarvis F et al Sex and gender: modifiers of health, disease, and medicine Lancet 2020 396 10250 565 582 10.1016/S0140-6736(20)31561-0 32828189
8 Barr E et al Centring the health of women across the HIV research continuum Lancet HIV 2024 11 3 e186 e194 10.1016/S2352-3018(24)00004-3 38417977
9 Frew PM et al Socioecological factors influencing women’s HIV risk in the United States: qualitative findings from the women’s HIV SeroIncidence study (HPTN 064) BMC Public Health 2016 16 1 803 10.1186/s12889-016-3364-7 27530401
10 Centers for Disease Control Kaposi’s sarcoma and Pneumocystis pneumonia among homosexual men--New York City and California MMWR Morb Mortal Wkly Rep 1981 30 25 305 308 6789108
11 Centers for Disease Control Pneumocystis pneumonia--Los Angeles MMWR Morb Mortal Wkly Rep 1981 30 21 250 252 6265753
12 ReliefWeb. Global HIV & AIDS statistics — Fact sheet 2023. 2023. https://reliefweb.int/report/world/global-hiv-aids-statistics-fact-sheet-2023 Updated July 23, 2023. Accessed August 7, 2024
13 Curno MJ et al A systematic review of the inclusion (or exclusion) of women in HIV research: from clinical studies of antiretrovirals and vaccines to cure strategies J Acquir Immune Defic Syndr 2016 71 2 181 188 10.1097/QAI.0000000000000842 26361171
14 Johnston RE Heitzeg MM Sex, age, race and intervention type in clinical studies of HIV cure: a systematic review AIDS Res Hum Retroviruses 2015 31 1 85 97 10.1089/aid.2014.0205 25313793
15 Pepperrell T et al Phase 3 trials of new antiretrovirals are not representative of the global HIV epidemic J Virus Erad 2020 6 2 70 73 10.1016/S2055-6640(20)30019-4 32405424
16 Hladik F McElrath MJ Setting the stage: host invasion by HIV Nat Rev Immunol 2008 8 6 447 457 10.1038/nri2302 18469831
17 Patel P et al Estimating per-act HIV transmission risk: a systematic review AIDS 2014 28 10 1509 1519 10.1097/QAD.0000000000000298 24809629
18 Ackerley CG et al The rectal mucosal immune environment and HIV susceptibility among young men who have sex with men Front Immunol 2022 13 972170 10.3389/fimmu.2022.972170 36341414
19 Boily M-C et al Heterosexual risk of HIV-1 infection per sexual act: systematic review and meta-analysis of observational studies Lancet Infect Dis 2009 9 2 118 129 10.1016/S1473-3099(09)70021-0 19179227
20 Ballweber L et al Vaginal langerhans cells nonproductively transporting HIV-1 mediate infection of T cells J Virol 2011 85 24 13443 13447 10.1128/JVI.05615-11 21976645
21 Zhou Z et al HIV-1 efficient entry in inner foreskin is mediated by elevated CCL5/RANTES that recruits T cells and fuels conjugate formation with Langerhans cells PLoS Pathog 2011 7 6 e1002100 10.1371/journal.ppat.1002100 21738469
22 Prodger JL et al How does voluntary medical male circumcision reduce HIV risk? Curr HIV/AIDS Rep 2022 19 6 484 490 10.1007/s11904-022-00634-w 36308579
23 Morrison CS et al Hormonal contraception and the risk of HIV acquisition: an individual participant data meta-analysis PLoS Med 2015 12 1 e1001778 10.1371/journal.pmed.1001778 25612136
24 Polis CB et al Update on hormonal contraceptive methods and risk of HIV acquisition in women: a systematic review of epidemiological evidence, 2016 AIDS 2016 30 17 2665 2683 10.1097/QAD.0000000000001228 27500670
25 Onono M Comparison of pregnancy incidence among African women in a randomized trial of intramuscular depot medroxyprogesterone acetate (DMPA-IM), a copper intrauterine device (IUDs) or a levonorgestrel (LNG) implant for contraception Contracept X 2020 2 100026 10.1016/j.conx.2020.100026 32577615
26 Thomson KA et al Increased risk of HIV Acquisition among women throughout pregnancy and during the postpartum period: a prospective per-coital-act analysis among women with HIV-infected partners J Infect Dis 2018 218 1 16 25 10.1093/infdis/jiy113 29514254
27 Schuetz A et al Distinct mucosal and systemic immunological characteristics in transgender women potentially relating to HIV acquisition JCI Insight 2023 8 16 e169272 10.1172/jci.insight.169272 37432754
28 Seaton KE et al Meta-analysis of HIV-1 vaccine elicited mucosal antibodies in humans NPJ Vaccines 2021 6 1 56 10.1038/s41541-021-00305-8 33859204
29 Corey L et al Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition N Engl J Med 2021 384 11 1003 1014 10.1056/NEJMoa2031738 33730454
30 Astronomo RD et al Rectal tissue and vaginal tissue from intravenous VRC01 recipients show protection against ex vivo HIV-1 challenge J Clin Invest 2021 131 16 e146975 10.1172/JCI146975 34166231
31 Brown JM et al Incident and prevalent herpes simplex virus type 2 infection increases risk of HIV acquisition among women in Uganda and Zimbabwe AIDS 2007 21 12 1515 1523 10.1097/QAD.0b013e3282004929 17630545
32 Chun HM et al The role of sexually transmitted infections in HIV-1 progression: a comprehensive review of the literature J Sex Transm Dis 2013 2013 176459 10.1155/2013/176459 26316953
33 Freeman EE et al Herpes simplex virus 2 infection increases HIV acquisition in men and women: systematic review and meta-analysis of longitudinal studies AIDS 2006 20 1 73 83 10.1097/01.aids.0000198081.09337.a7 16327322
34 Masson L et al Inflammatory cytokine biomarkers to identify women with asymptomatic sexually transmitted infections and bacterial vaginosis who are at high risk of HIV infection Sex Transm Infect 2016 92 3 186 193 10.1136/sextrans-2015-052072 26511781
35 Masson L et al Genital inflammation and the risk of HIV acquisition in women Clin Infect Dis 2015 61 2 260 269 10.1093/cid/civ298 25900168
36 Looker KJ et al Effect of HSV-2 infection on subsequent HIV acquisition: an updated systematic review and meta-analysis Lancet Infect Dis 2017 17 12 1303 1316 10.1016/S1473-3099(17)30405-X 28843576
37 Barker EK et al Risk of human immunodeficiency virus acquisition among high-risk heterosexuals with nonviral sexually transmitted infections: a systematic review and meta-analysis Sex Transm Dis 2022 49 6 383 397 10.1097/OLQ.0000000000001601 35034049
38 Hladik F et al Coexpression of CCR5 and IL-2 in human genital but not blood T cells: implications for the ontogeny of the CCR5+ Th1 phenotype J Immunol 1999 163 4 2306 2313 10.4049/jimmunol.163.4.2306 10438976
39 Levine WC et al Increase in endocervical CD4 lymphocytes among women with nonulcerative sexually transmitted diseases J Infect Dis 1998 177 1 167 174 10.1086/513820 9419184
40 Patterson BK et al Repertoire of chemokine receptor expression in the female genital tract: implications for human immunodeficiency virus transmission Am J Pathol 1998 153 2 481 490 10.1016/S0002-9440(10)65591-5 9708808
41 Sheffield JS et al Effect of genital ulcer disease on HIV-1 coreceptor expression in the female genital tract J Infect Dis 2007 196 10 1509 1516 10.1086/522518 18008231
42 Johnson KE et al Effects of HIV-1 and herpes simplex virus type 2 infection on lymphocyte and dendritic cell density in adult foreskins from Rakai, Uganda J Infect Dis 2011 203 5 602 609 10.1093/infdis/jiq091 21220779
43 Prodger JL et al Impact of asymptomatic Herpes simplex virus-2 infection on T cell phenotype and function in the foreskin AIDS 2012 26 10 1319 1322 10.1097/QAD.0b013e328354675c 22516874
44 Nagot N et al Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus N Engl J Med 2007 356 8 790 799 10.1056/NEJMoa062607 17314338
45 Piot P Laga M Genital ulcers, other sexually transmitted diseases, and the sexual transmission of HIV BMJ 1989 298 6674 623 624 10.1136/bmj.298.6674.623 2496785
46 Weiler AM et al Genital ulcers facilitate rapid viral entry and dissemination following intravaginal inoculation with cell-associated simian immunodeficiency virus SIVmac239 J Virol 2008 82 8 4154 4158 10.1128/JVI.01947-07 18272571
47 Masson L 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 8 580 587 10.1136/sextrans-2014-051601 25107710
48 Anahtar MN et al Cervicovaginal bacteria are a major modulator of host inflammatory responses in the female genital tract Immunity 2015 42 5 965 976 10.1016/j.immuni.2015.04.019 25992865
49 McClelland RS et al Evaluation of the association between the concentrations of key vaginal bacteria and the increased risk of HIV acquisition in African women from five cohorts: a nested case-control study Lancet Infect Dis 2018 18 5 554 564 10.1016/S1473-3099(18)30058-6 29396006
50 Mitchell C et al Hydrogen peroxide-producing lactobacilli are associated with lower levels of vaginal interleukin-1β, independent of bacterial vaginosis Sex Transm Dis 2015 42 7 358 363 10.1097/OLQ.0000000000000298 26222747
51 Ravel J et al Vaginal microbiome of reproductive-age women Proc Natl Acad Sci U S A 2011 108 suppl 1 4680 4687 10.1073/pnas.1002611107 20534435
52 Gosmann C et al Lactobacillus-deficient cervicovaginal bacterial communities are associated with increased HIV acquisition in young South African women Immunity 2017 46 1 29 37 10.1016/j.immuni.2016.12.013 28087240
53 van Teijlingen NH et al Immune activation of vaginal human Langerhans cells increases susceptibility to HIV-1 infection Sci Rep 2023 13 1 3283 10.1038/s41598-023-30097-x 36841916
54 Balle C et al Hormonal contraception and risk of STIs and bacterial vaginosis in South African adolescents: secondary analysis of a randomised trial Sex Transm Infect 2021 97 2 112 117 10.1136/sextrans-2020-054483 32989170
55 Balle C et al Hormonal contraception alters vaginal microbiota and cytokines in South African adolescents in a randomized trial Nat Commun 2020 11 1 5578 10.1038/s41467-020-19382-9 33149114
56 Klatt NR et al Vaginal bacteria modify HIV tenofovir microbicide efficacy in African women Science 2017 356 6341 938 945 10.1126/science.aai9383 28572388
57 Gupta VK et al Geography, ethnicity or subsistence-specific variations in human microbiome composition and diversity Front Microbiol 2017 8 1162 10.3389/fmicb.2017.01162 28690602
58 Roachford OSE et al Insights into the vaginal microbiome in a diverse group of women of African, Asian and European ancestries PeerJ 2022 10 e14449 10.7717/peerj.14449 36518275
59 Kaul R et al The penis, the vagina and HIV risk: key differences (aside from the obvious) Viruses 2022 14 6 1164 10.3390/v14061164 35746636
60 Prodger JL et al Penile bacteria associated with HIV seroconversion, inflammation, and immune cells JCI Insight 2021 6 8 e147363 10.1172/jci.insight.147363 33884964
61 Adland E et al Sex-specific innate immune selection of HIV-1 in utero is associated with increased female susceptibility to infection Nat Commun 2020 11 1 1767 10.1038/s41467-020-15632-y 32286302
62 Temmerman M et al Risk factors for mother-to-child transmission of human immunodeficiency virus-1 infection Am J Obstet Gynecol 1995 172 2 pt 1 700 705 10.1016/0002-9378(95)90597-9 7856710
63 Marinda E et al Child mortality according to maternal and infant HIV status in Zimbabwe Pediatr Infect Dis J 2007 26 6 519 526 10.1097/01.inf.0000264527.69954.4c 17529870
64 Piwoz EG et al Effects of infant sex on mother-to-child transmission of HIV-1 according to timing of infection in Zimbabwe AIDS 2006 20 15 1981 1984 10.1097/01.aids.0000247123.04703.6e 16988523
65 Biggar RJ et al Higher in utero and perinatal HIV infection risk in girls than boys J Acquir Immune Defic Syndr 2006 41 4 509 513 10.1097/01.qai.0000191283.85578.46 16652061
66 Taha TE et al Gender differences in perinatal HIV acquisition among African infants Pediatrics 2005 115 2 e167 e172 10.1542/peds.2004-1590 15687425
67 Thorne C et al Are girls more at risk of intrauterine-acquired HIV infection than boys? AIDS 2004 18 2 344 347 10.1097/00002030-200401230-00033 15075561
68 Galli L et al Lower mother-to-child HIV-1 transmission in boys is independent of type of delivery and antiretroviral prophylaxis: the Italian Register for HIV Infection in Children J Acquir Immune Defic Syndr 2005 40 4 479 485 10.1097/01.qai.0000164247.49098.0e 16280705
69 Maswabi K et al Safety and efficacy of starting antiretroviral therapy in the first week of life Clin Infect Dis 2021 72 3 388 393 10.1093/cid/ciaa028 31927562
70 Bengu N et al Sustained aviremia despite anti-retroviral therapy non-adherence in male children after in utero HIV transmission [published online June 6, 2024]. Nat Med 10.1038/s41591-024-03105-4 38843818
71 Anastos K et al Association of race and gender with HIV-1 RNA levels and immunologic progression J Acquir Immune Defic Syndr 2000 24 3 218 226 10.1097/00126334-200007010-00004 10969345
72 Evans JS et al Serum levels of virus burden in early-stage human immunodeficiency virus type 1 disease in women J Infect Dis 1997 175 4 795 800 10.1086/513973 9086132
73 Farzadegan H et al Sex differences in HIV-1 viral load and progression to AIDS Lancet 1998 352 9139 1510 1514 10.1016/S0140-6736(98)02372-1 9820299
74 Gandhi M et al Does patient sex affect human immunodeficiency virus levels? Clin Infect Dis 2002 35 3 313 322 10.1086/341249 12115098
75 Katzenstein DA et al The relation of virologic and immunologic markers to clinical outcomes after nucleoside therapy in HIV-infected adults with 200 to 500 CD4 cells per cubic millimeter. AIDS Clinical Trials Group Study 175 Virology Study Team N Engl J Med 1996 335 15 1091 1098 10.1056/NEJM199610103351502 8813039
76 Lyles CM 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 1024 10.1086/314980 10479126
77 Napravnik S et al Gender difference in HIV RNA levels: a meta-analysis of published studies J Acquir Immune Defic Syndr 2002 31 1 11 19 10.1097/00126334-200209010-00002 12352145
78 Sterling TR et al Sex differences in longitudinal human immunodeficiency virus type 1 RNA levels among seroconverters J Infect Dis 1999 180 3 666 672 10.1086/314967 10438353
79 Sterling TR et al Initial plasma HIV-1 RNA levels and progression to AIDS in women and men N Engl J Med 2001 344 10 720 725 10.1056/NEJM200103083441003 11236775
80 Meditz AL et al CCR5 expression is reduced in lymph nodes of HIV type 1-infected women, compared with men, but does not mediate sex-based differences in viral loads J Infect Dis 2014 209 6 922 930 10.1093/infdis/jit575 24179109
81 Crowell TA et al Hospitalization rates and reasons among HIV elite controllers and persons with medically controlled HIV infection J Infect Dis 2015 211 11 1692 1702 10.1093/infdis/jiu809 25512624
82 Madec Y et al Spontaneous control of viral load and CD4 cell count progression among HIV-1 seroconverters AIDS 2005 19 17 2001 2007 10.1097/01.aids.0000194134.28135.cd 16260907
83 Price MA et al Control of the HIV-1 load varies by viral subtype in a large cohort of African adults with incident HIV-1 infection J Infect Dis 2019 220 3 432 441 10.1093/infdis/jiz127 30938435
84 Yang OO et al Demographics and natural history of HIV-1-infected spontaneous controllers of viremia AIDS 2017 31 8 1091 1098 10.1097/QAD.0000000000001443 28301422
85 International HIVCS et al The major genetic determinants of HIV-1 control affect HLA class I peptide presentation Science 2010 330 6010 1551 1557 10.1126/science.1195271 21051598
86 Goujard C 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 1009 10.3851/IMP2273 22865544
87 Namazi G et al The control of HIV after antiretroviral medication pause (CHAMP) study: posttreatment controllers identified from 14 clinical studies J Infect Dis 2018 218 12 1954 1963 10.1093/infdis/jiy479 30085241
88 Saez-Cirion A 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 10.1371/journal.ppat.1003211 23516360
89 Investigators ST et al Short-course antiretroviral therapy in primary HIV infection N Engl J Med 2013 368 3 207 217 10.1056/NEJMoa1110039 23323897
90 Stohr W et al Duration of HIV-1 viral suppression on cessation of antiretroviral therapy in primary infection correlates with time on therapy PLoS One 2013 8 10 e78287 10.1371/journal.pone.0078287 24205183
91 Le CN et al Time to viral rebound and safety after antiretroviral treatment interruption in postpartum women compared with men AIDS 2019 33 14 2149 2156 10.1097/QAD.0000000000002334 31373919
92 Giorgi JV et al Shorter survival in advanced human immunodeficiency 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 4 859 870 10.1086/314660 10068581
93 Deeks SG et al Immune activation set point during early HIV infection predicts subsequent CD4+ T-cell changes independent of viral load Blood 2004 104 4 942 947 10.1182/blood-2003-09-3333 15117761
94 Meier A et al Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1 Nat Med 2009 15 8 955 959 10.1038/nm.2004 19597505
95 Chang JJ 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 5 830 838 10.1093/infdis/jit262 23757341
96 Forsyth KS et al The conneXion between sex and immune responses Nat Rev Immunol 2024 24 7 487 502 10.1038/s41577-024-00996-9 38383754
97 Bongen E et al Sex differences in the blood transcriptome identify robust changes in immune cell proportions with aging and influenza infection Cell Rep 2019 29 7 1961 1973 10.1016/j.celrep.2019.10.019 31722210
98 Berghöfer B et al TLR7 ligands induce higher IFN-α production in females J Immunol 2006 177 4 2088 2096 10.4049/jimmunol.177.4.2088 16887967
99 Ziegler SM et al Human pDCs display sex-specific differences in type I interferon subtypes and interferon α/β receptor expression Eur J Immunol 2017 47 2 251 256 10.1002/eji.201646725 27891600
100 Parsa N et al The rapid CD4+ T-lymphocyte decline and human immunodeficiency virus progression in females compared to males Sci Rep 2020 10 1 16816 10.1038/s41598-020-73852-0 33033335
101 Szaniawski MA et al Sex influences SAMHD1 activity and susceptibility to human immunodeficiency virus-1 in primary human macrophages J Infect Dis 2019 219 5 777 785 10.1093/infdis/jiy583 30299483
102 Gal-Oz ST et al Microheterogeneity in the kinetics and sex-specific response to type I IFN J Immunol 2024 213 1 96 104 10.4049/jimmunol.2300453 38775402
103 Wang JP et al Plasmacytoid dendritic cell interferon-α production to R-848 stimulation is decreased in male infants BMC Immunol 2012 13 35 10.1186/1471-2172-13-35 22769054
104 Hoffmann JP et al Sex hormone signaling and regulation of immune function Immunity 2023 56 11 2472 2491 10.1016/j.immuni.2023.10.008 37967530
105 Asin SN et al Estradiol and progesterone regulate HIV type 1 replication in peripheral blood cells AIDS Res Hum Retroviruses 2008 24 5 701 716 10.1089/aid.2007.0108 18462082
106 Schmiedel BJ et al Impact of genetic polymorphisms on human immune cell gene expression Cell 2018 175 6 1701 1715 10.1016/j.cell.2018.10.022 30449622
107 Scully EP et al Sex-based differences in human immunodeficiency virus type 1 reservoir activity and residual immune activation J Infect Dis 2019 219 7 1084 1094 10.1093/infdis/jiy617 30371873
108 Cheung E et al Altered pharmacology and distinct coactivator usage for estrogen receptor-dependent transcription through activating protein-1 Proc Natl Acad Sci U S A 2005 102 3 559 564 10.1073/pnas.0407113102 15642950
109 Cheung E Kraus WL Genomic analyses of hormone signaling and gene regulation Annu Rev Physiol 2010 72 191 218 10.1146/annurev-physiol-021909-135840 20148673
110 Porter W et al Functional synergy between the transcription factor Sp1 and the estrogen receptor Mol Endocrinol 1997 11 11 1569 1580 10.1210/mend.11.11.9916 9328340
111 Stender JD et al Genome-wide analysis of estrogen receptor alpha DNA binding and tethering mechanisms identifies Runx1 as a novel tethering factor in receptor-mediated transcriptional activation Mol Cell Biol 2010 30 16 3943 3955 10.1128/MCB.00118-10 20547749
112 Hewagama A et al Overexpression of X-linked genes in T cells from women with lupus J Autoimmun 2013 41 60 71 10.1016/j.jaut.2012.12.006 23434382
113 Szotek EL et al 17β-estradiol inhibits HIV-1 by inducing a complex formation between β-catenin and estrogen receptor α on the HIV promoter to suppress HIV transcription Virology 2013 443 2 375 383 10.1016/j.virol.2013.05.027 23769242
114 Ruel TD et al Sex differences in HIV RNA level and CD4 cell percentage during childhood Clin Infect Dis 2011 53 6 592 599 10.1093/cid/cir484 21840929
115 Griesbeck M et al Sex differences in plasmacytoid dendritic cell levels of IRF5 drive higher IFN-α production in women J Immunol 2015 195 11 5327 5336 10.4049/jimmunol.1501684 26519527
116 Dunford A et al Tumor-suppressor genes that escape from X-inactivation contribute to cancer sex bias Nat Genet 2017 49 1 10 16 10.1038/ng.3726 27869828
117 Libert C et al The X chromosome in immune functions: when a chromosome makes the difference Nat Rev Immunol 2010 10 8 594 604 10.1038/nri2815 20651746
118 Hagen SH et al Heterogeneous escape from X Chromosome inactivation results in sex differences in type I IFN responses at the single human pDC level Cell Rep 2020 33 10 108485 10.1016/j.celrep.2020.108485 33296655
119 Souyris M et al TLR7 escapes X chromosome inactivation in immune cells Sci Immunol 2018 3 19 eaap8855 10.1126/sciimmunol.aap8855 29374079
120 Souyris M et al Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation Semin Immunopathol 2019 41 2 153 164 10.1007/s00281-018-0712-y 30276444
121 Laffont S et al X-Chromosome complement and estrogen receptor signaling independently contribute to the enhanced TLR7-mediated IFN-α production of plasmacytoid dendritic cells from women J Immunol 2014 193 11 5444 5452 10.4049/jimmunol.1303400 25339659
122 Crawford JD et al , Thomas MA, et al. The XIST lncRNA is a sex-specific reservoir of TLR7 ligands in SLE JCI Insight 2023 8 20 e169344 10.1172/jci.insight.169344 37733447
123 Dou DR et al Xist ribonucleoproteins promote female sex-biased autoimmunity Cell 2024 187 3 733 749 10.1016/j.cell.2023.12.037 38306984
124 Azar P et al TLR7 dosage polymorphism shapes interferogenesis and HIV-1 acute viremia in women JCI Insight 2020 5 12 e136047 10.1172/jci.insight.136047 32554924
125 Vergara C et al Multiancestry sex-stratified genomic associations with HIV viral load and controller status from the ICGH JCI Insight 2023 8 11 e170068 10.1172/jci.insight.170068 37097752
126 Ofotokun I Pomeroy C Sex differences in adverse reactions to antiretroviral drugs Top HIV Med 2003 11 2 55 59 12717043
127 Umeh OC Currier JS Sex differences in pharmacokinetics and toxicity of antiretroviral therapy Expert Opin Drug Metab Toxicol 2006 2 2 273 283 10.1517/17425255.2.2.273 16866613
128 Sax PE et al Weight gain following initiation of antiretroviral therapy: risk factors in randomized comparative clinical trials Clin Infect Dis 2020 71 6 1379 1389 10.1093/cid/ciz999 31606734
129 Sokhela S et al Final 192-week efficacy and safety results of the ADVANCE trial, comparing 3 first-line antiretroviral regimens Open Forum Infect Dis 2024 11 3 ofae007 10.1093/ofid/ofae007 38529213
130 Venter WDF et al Dolutegravir plus two different prodrugs of tenofovir to treat HIV N Engl J Med 2019 381 9 803 815 10.1056/NEJMoa1902824 31339677
131 Chandiwana NC et al Weight gain after HIV therapy initiation: pathophysiology and implications J Clin Endocrinol Metab 2023 109 2 e478 e487 10.1210/clinem/dgad411 37437159
132 Jung I et al Dolutegravir suppresses thermogenesis via disrupting uncoupling protein 1 expression and mitochondrial function in brown/beige adipocytes in preclinical models J Infect Dis 2022 226 9 1626 1636 10.1093/infdis/jiac175 35512127
133 Markle JG et al Sex differences in the gut microbiome drive hormone-dependent regulation of autoimmunity Science 2013 339 6123 1084 1088 10.1126/science.1233521 23328391
134 Chow FC et al 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 4 351 358 10.1097/QAI.0b013e31825c7f24 22580566
135 Chow FC et al Elevated ischemic stroke risk among women living with HIV infection AIDS 2018 32 1 59 67 10.1097/QAD.0000000000001650 28926405
136 Raghavan A et al Sex differences in select non-communicable HIV-associated comorbidities: exploring the role of systemic immune activation/inflammation Curr HIV/AIDS Rep 2017 14 6 220 228 10.1007/s11904-017-0366-8 29080122
137 Triant VA et al Increased acute myocardial infarction rates and cardiovascular risk factors among patients with human immunodeficiency virus disease J Clin Endocrinol Metab 2007 92 7 2506 2512 10.1210/jc.2006-2190 17456578
138 Collins LF et al The effect of menopausal status, age, and human immunodeficiency virus (HIV) on non-AIDS comorbidity burden among US women Clin Infect Dis 2023 76 3 e755 e758 10.1093/cid/ciac465 35686432
139 Collins LF et al The prevalence and burden of non-AIDS comorbidities among women living with or at risk for human immunodeficiency virus infection in the United States Clin Infect Dis 2021 72 8 1301 1311 10.1093/cid/ciaa204 32115628
140 Pond RA et al Sex differences in non-AIDS comorbidities among people with human immunodeficiency virus Open Forum Infect Dis 2021 8 12 ofab558 10.1093/ofid/ofab558 34888399
141 Dovel K et al Men’s heightened risk of AIDS-related death: the legacy of gendered HIV testing and treatment strategies AIDS 2015 29 10 1123 1125 10.1097/QAD.0000000000000655 26035315
142 Kerkhoff AD et al Mortality estimates by age and sex among persons living with HIV after ART initiation in Zambia using electronic medical records supplemented with tracing a sample of lost patients: A cohort study PLoS Med 2020 17 5 e1003107 10.1371/journal.pmed.1003107 32401797
143 Li JZ Blankson JN How elite controllers and posttreatment controllers inform our search for an HIV-1 cure J Clin Invest 2021 131 11 e149414 10.1172/JCI149414 34060478
144 Jiang C et al Distinct viral reservoirs in individuals with spontaneous control of HIV-1 Nature 2020 585 7824 261 267 10.1038/s41586-020-2651-8 32848246
145 Turk G et al A possible sterilizing cure of HIV-1 infection without stem cell transplantation Ann Intern Med 2022 175 1 95 100 10.7326/L21-0297 34781719
146 Uruena A et al Prolonged posttreatment virologic control and complete seroreversion after advanced human immunodeficiency virus-1 infection Open Forum Infect Dis 2021 8 1 ofaa613 10.1093/ofid/ofaa613 33511235
147 Gandhi RT et al Levels of HIV-1 persistence on antiretroviral therapy are not associated with markers of inflammation or activation PLoS Pathog 2017 13 4 e1006285 10.1371/journal.ppat.1006285 28426825
148 Gianella S et al Sex differences in CMV replication and HIV persistence during suppressive ART Open Forum Infect Dis 2020 7 8 ofaa289 10.1093/ofid/ofaa289 32793766
149 Cuzin L et al Levels of intracellular HIV-DNA in patients with suppressive antiretroviral therapy AIDS 2015 29 13 1665 1671 10.1097/QAD.0000000000000723 26372277
150 Fourati S et al Factors associated with a low HIV reservoir in patients with prolonged suppressive antiretroviral therapy J Antimicrob Chemother 2014 69 3 753 756 10.1093/jac/dkt428 24187041
151 Falcinelli SD et al Impact of biological sex on immune activation and frequency of the latent HIV reservoir during suppressive antiretroviral therapy J Infect Dis 2020 222 11 1843 1852 10.1093/infdis/jiaa298 32496542
152 Prodger JL et al Reduced HIV-1 latent reservoir outgrowth and distinct immune correlates among women in Rakai, Uganda JCI Insight 2020 5 14 e139287 10.1172/jci.insight.139287 32544096
153 Deeks SG HIV: Shock and kill Nature 2012 487 7408 439 440 10.1038/487439a 22836995
154 Elsheikh MM et al Deep latency: a new insight into a functional HIV cure EBioMedicine 2019 45 624 629 10.1016/j.ebiom.2019.06.020 31227439
155 Das B et al Estrogen receptor-1 is a key regulator of HIV-1 latency that imparts gender-specific restrictions on the latent reservoir Proc Natl Acad Sci U S A 2018 115 33 E7795 E7804 10.1073/pnas.1803468115 30061382
156 Scully EP et al Impact of tamoxifen on vorinostat-induced human immunodeficiency virus expression in women on antiretroviral therapy: AIDS Clinical Trials Group A5366, the MOXIE trial Clin Infect Dis 2022 75 8 1389 1396 10.1093/cid/ciac136 35176755
157 Gianella S et al Sex differences in human immunodeficiency virus persistence and reservoir size during aging Clin Infect Dis 2022 75 1 73 80 10.1093/cid/ciab873 34612493
158 Verdikt R et al Epigenetic mechanisms of HIV-1 persistence Vaccines (Basel) 2021 9 5 514 10.3390/vaccines9050514 34067608
159 Grant OA et al Characterising sex differences of autosomal DNA methylation in whole blood using the Illumina EPIC array Clin Epigenetics 2022 14 1 62 10.1186/s13148-022-01279-7 35568878
160 Oliva M et al The impact of sex on gene expression across human tissues Science 2020 369 6509 eaba3066 10.1126/science.aba3066 32913072
161 Jansen R et al Sex differences in the human peripheral blood transcriptome BMC Genomics 2014 15 33 10.1186/1471-2164-15-33 24438232
162 Sáez-Cirión A Sereti I Immunometabolism and HIV-1 pathogenesis: food for thought Nat Rev Immunol 2021 21 1 5 19 10.1038/s41577-020-0381-7 32764670
163 Clerc I et al Entry of glucose- and glutamine-derived carbons into the citric acid cycle supports early steps of HIV-1 infection in CD4 T cells Nat Metab 2019 1 7 717 730 10.1038/s42255-019-0084-1 32373781
164 Hegedus A et al HIV-1 pathogenicity and virion production are dependent on the metabolic phenotype of activated CD4+ T cells Retrovirology 2014 11 98 10.1186/s12977-014-0098-4 25421745
165 Valle-Casuso JC et al Cellular metabolism is a major determinant of HIV-1 reservoir seeding in CD4+ T cells and offers an opportunity to tackle infection Cell Metab 2019 29 3 611 626 10.1016/j.cmet.2018.11.015 30581119
166 Manuel RSJ Liang Y Sexual dimorphism in immunometabolism and autoimmunity: impact on personalized medicine Autoimmun Rev 2021 20 4 102775 10.1016/j.autrev.2021.102775 33609790
167 Macedo AB et al Dual TLR2 and TLR7 agonists as HIV latency-reversing agents JCI Insight 2018 3 19 e122673 10.1172/jci.insight.122673 30282829
168 Martinsen JT et al The use of toll-like receptor agonists in HIV-1 cure strategies Front Immunol 2020 11 1112 10.3389/fimmu.2020.01112 32595636
169 Krarup AR et al The TLR9 agonist MGN1703 triggers a potent type I interferon response in the sigmoid colon Mucosal Immunol 2018 11 2 449 461 10.1038/mi.2017.59 28766555
170 Riddler SA et al Vesatolimod, a toll-like receptor 7 agonist, induces immune activation in virally suppressed adults living with human immunodeficiency virus-1 Clin Infect Dis 2020 72 11 e815 e824 10.1093/cid/ciaa1534 33043969
171 SenGupta D et al The TLR7 agonist vesatolimod induced a modest delay in viral rebound in HIV controllers after cessation of antiretroviral therapy Sci Transl Med 2021 13 599 eabg3071 10.1126/scitranslmed.abg3071 34162752
172 Vibholm L et al Short-course Toll-like receptor 9 agonist treatment impacts innate immunity and plasma viremia in individuals with human immunodeficiency virus infection Clin Infect Dis 2017 64 12 1686 1695 10.1093/cid/cix201 28329286
173 Vibholm LK et al Effects of 24-week Toll-like receptor 9 agonist treatment in HIV type 1+ individuals AIDS 2019 33 8 1315 1325 10.1097/QAD.0000000000002213 30932955
174 Gubser C et al Immune checkpoint blockade in HIV EBioMedicine 2022 76 103840 10.1016/j.ebiom.2022.103840 35123267
175 Gay CL et al Clinical trial of the anti-PD-L1 antibody BMS-936559 in HIV-1 infected participants on suppressive antiretroviral therapy J Infect Dis 2017 215 11 1725 1733 10.1093/infdis/jix191 28431010
176 Conforti F et al Sex-based differences in response to anti-PD-1 or PD-L1 treatment in patients with non-small-cell lung cancer expressing high PD-L1 levels. A systematic review and meta-analysis of randomized clinical trials ESMO Open 2021 6 5 100251 10.1016/j.esmoop.2021.100251 34455288
177 Jang SR et al Association between sex and immune checkpoint inhibitor outcomes for patients with melanoma JAMA Netw Open 2021 4 12 e2136823 10.1001/jamanetworkopen.2021.36823 34854905
178 Fink AL Klein SL Sex and gender impact immune responses to vaccines among the elderly Physiology (Bethesda) 2015 30 6 408 416 10.1152/physiol.00035.2015 26525340
179 UNAIDS. The urgency of now: AIDS at a crossroads — 2024 Global AIDS Update. Joint United Nations Programme on HIV/AIDS; 2024. https://www.unaids.org/en/resources/documents/2024/global-aids-update-2024 Accessed August 19, 2024
