The major burden of the human immunodeficiency (HIV) type 1 pandemic is nowadays carried by women from sub-Saharan Africa. Differences in the manifestations of HIV-1 infection between women and men have been long reported, and might be due to both socio-economic (gender) and biological (sex) factors. Several studies have shown that women are more susceptible to HIV-1 acquisition than men. Following HIV-1 infection, women have lower viral loads during acute infection and exhibit stronger antiviral responses than men, which may contribute to differences in the size of viral reservoirs. Oestrogen receptor signalling could represent an important mediator of sex differences in HIV-1 reservoir size and may represent a potential therapeutic target. Furthermore, immune activation, a hallmark of HIV-1 infection, is generally higher in women than in men and could be a central mechanism in the sex difference observed in the speed of HIV-1 disease progression. Here, we review the literature regarding sex-based differences in HIV-1 infection and discuss how a better understanding of the underlying mechanisms could improve preventive and therapeutic strategies.

INTRODUCTION

Infection by the HIV type 1 remains a global health issue with over 36 million HIV-1-infected people worldwide [1]. Women and girls, particularly in sub-Saharan Africa, are profoundly affected by the pandemic. They represent 52% of all people living with HIV-1 in low- and middle-income countries, while accounting for a much lower proportion in high-income countries. Differences between men and women in HIV-1 disease phenotypes and risk of acquisition have long been noted by epidemiologic studies. Early studies observed a more rapid clinical progression to AIDS in infected women but were attributed to delays in starting antiretroviral therapy (ART), to the higher occurrence of gynecological disorders including invasive cervical cancer and to other conditions preferentially affecting women, such as discrimination, violence and stigma [2,3]. Survival did not differ by sex among treated individuals [46], suggesting that overall sex differences in survival might come from differential access to HIV-1 treatment [5]. It is well acknowledged that women are at increased risk for HIV-1 acquisition via heterosexual contact, the major route of HIV-1 transmission in women in developing and industrialized countries. In eastern and southern Africa, young women are approximately twice as likely to acquire HIV-1 compared with their male counterparts [7]. Gender iniquities and cultural practices are significant drivers of women's increased susceptibility to HIV-1 infection. Societal factors are also relevant for men in the context of HIV-1 infection. Reports from the World Health Organization (WHO) identify higher HIV-related mortality rates among men receiving ART than women in some countries, including Malawi, South Africa, Uganda and the United Republic of Tanzania as a result of treatment access and adherence differences [712]. South-African HIV-1-infected men appeared to have higher mortality on ART than women after adjustment for measures of HIV-1 disease stages at the time of ART initiation, in the subset of patients who achieved virologic suppression, and among patients with good immune responses to treatment [13], suggesting an increased risk of comorbid phenomena in men. Indeed, it has been shown that younger African men may be more likely to die from traumatic causes and non-HIV-1 related tuberculosis [14]. The differences in the burden of comorbid risks and conditions and in socioeconomic factors are therefore partially responsible for the sex-based differences seen in HIV-1 infection.

The biological mechanisms underlying sex differences have often been overshadowed by these socioeconomic factors. However, increasing evidence of critical variations in biology between the sexes has been emerging. Together with strategies aiming at preventing gender iniquities, advancing the understanding of the biological factors involved in sex differences is now considered by the WHO as essential to the HIV response. Importantly, although sex may appear to be a clear cut-off denominator because of its categorical nature, it can be complicated by age (e.g. premenopausal compared with postmenopausal) and/or the use of hormonal contraceptives. Elucidating the mechanisms of sex-based differences is therefore challenging, requiring a careful analysis of demographic information and an appreciation of the interplay between socioeconomic and biological factors. As an adjunctive approach, studies in animal models offer the ability to approach questions in a more controlled environment. Although critical insights have been elucidated with studies in animal models in the past decade, very few studies have directly addressed the role of sex-based differences [15].

Despite several decades of cutting-edge research on HIV-1 infection and the major breakthroughs achieved with ART, there is still no cure or protective vaccine. Understanding the influence of sex hormones on HIV-1 acquisition may provide critical insights and potential points for intervention. Similarly, knowledge of sex differences in HIV-1 infection may provide information for future therapeutic strategies. Here, we review the current body of evidence with a focus on the biological factors influencing the differential outcomes of HIV-1 infection in women and men and how these data should be integrated in current therapeutic and prevention strategies. PubMed was used to search for relevant English language publications with the following terms: ‘sex differences AND immune activation’; ‘sex differences AND HIV-1 infection’; ‘sex differences AND viral load’; ‘sex differences AND reservoir’; ‘sex differences AND HIV-1 acquisition’; ‘oestrogen signalling AND HIV-1’. Abstracts were first scanned and relevant papers were retrieved. Table 1 summarizes key referenced studies on sex differences in HIV-1 infection, covering the main aspects.

Table 1
Key reference studies on sex differences in HIV-1 infection
ReferenceKey findings
[25,30These two key prospective analyses from the group of Thomas Quinn based on a large well-characterized cohort of HIV-infected adults first demonstrated the sex difference in HIV viral load and more importantly draw parallels with the rates of progression to AIDS. 
[48This well-designed study demonstrated a strong link between high-diversity cervicovaginal bacterial community structures and genital inflammation in vivo in both cross-sectional and longitudinal analyses. This study suggests a mechanism by which genital microbiota might increase HIV acquisition risk in women. 
[64This study reanalysed the data from the CAPRISA 004 phase IIb, randomized, placebo-controlled clinical trial assessing the safety and effectiveness of 1% tenofovir gel in preventing HIV-1 infection in women. These observations are consistent with a model in which preexisting systemic innate immune activation facilitates HIV-1 acquisition 
[74This prospective study following a large number of heterosexual African HIV-1 serodiscordant couples reported increased risk of HIV-1 acquisition in women using injectable contraceptive methods. Together with other studies, it initiated the important dialogue on the prevention of HIV-1 acquisition between governmental and non-governmental organizations. 
[85This study assessed the relationship between injectable hormonal contraception and increased HIV-1 risk using statistical approaches. The implications of this study are discussed in this review. 
[136Building on data by Berghoefer et al. (ref), this study reported significant sex-based differences in the IFNα response of pDCs to HIV-1, resulting in stronger immune activation in women compared with men for the same level of viral replication. 
[146This comprehensive review addresses the question of sex differences in the treatment of HIV-1 infection, exposing links between ART pharmacodynamics, adverse events rate and treatment adherence. 
[173This study reports the development a nonhuman primate model that replicates the sex differences in AIDS progression in humans. It further argues for a role of local innate immune responses and changes in the gut microbiota in increased disease susceptibility in females. 
[187This well-designed study demonstrated the involvement of ERα signalling in sex difference in pDC IFNα responses to TLR7 by combining results from a clinical trial and experiments of targeted genetic ablation in mice. 
[197This systematic review reveals an important sex imbalance in the recruitment of participants in clinical studies of HIV cure, not reflecting the national or international burdens of HIV-1 infection. 
ReferenceKey findings
[25,30These two key prospective analyses from the group of Thomas Quinn based on a large well-characterized cohort of HIV-infected adults first demonstrated the sex difference in HIV viral load and more importantly draw parallels with the rates of progression to AIDS. 
[48This well-designed study demonstrated a strong link between high-diversity cervicovaginal bacterial community structures and genital inflammation in vivo in both cross-sectional and longitudinal analyses. This study suggests a mechanism by which genital microbiota might increase HIV acquisition risk in women. 
[64This study reanalysed the data from the CAPRISA 004 phase IIb, randomized, placebo-controlled clinical trial assessing the safety and effectiveness of 1% tenofovir gel in preventing HIV-1 infection in women. These observations are consistent with a model in which preexisting systemic innate immune activation facilitates HIV-1 acquisition 
[74This prospective study following a large number of heterosexual African HIV-1 serodiscordant couples reported increased risk of HIV-1 acquisition in women using injectable contraceptive methods. Together with other studies, it initiated the important dialogue on the prevention of HIV-1 acquisition between governmental and non-governmental organizations. 
[85This study assessed the relationship between injectable hormonal contraception and increased HIV-1 risk using statistical approaches. The implications of this study are discussed in this review. 
[136Building on data by Berghoefer et al. (ref), this study reported significant sex-based differences in the IFNα response of pDCs to HIV-1, resulting in stronger immune activation in women compared with men for the same level of viral replication. 
[146This comprehensive review addresses the question of sex differences in the treatment of HIV-1 infection, exposing links between ART pharmacodynamics, adverse events rate and treatment adherence. 
[173This study reports the development a nonhuman primate model that replicates the sex differences in AIDS progression in humans. It further argues for a role of local innate immune responses and changes in the gut microbiota in increased disease susceptibility in females. 
[187This well-designed study demonstrated the involvement of ERα signalling in sex difference in pDC IFNα responses to TLR7 by combining results from a clinical trial and experiments of targeted genetic ablation in mice. 
[197This systematic review reveals an important sex imbalance in the recruitment of participants in clinical studies of HIV cure, not reflecting the national or international burdens of HIV-1 infection. 

INCREASED VULNERABILITY OF FEMALES TO HIV-1 ACQUISITION

Heterosexual transmission is the major route of HIV-1 transmission for both women and men, with 30–40% of annual HIV-1 infections worldwide occurring through heterosexual transmission in the female reproductive tract [16]. HIV-1 transmission is a relatively inefficient process, with estimated risks of HIV-1 transmission per-act via sexual exposures ranging from 4 per 10000 exposures for insertive penile–vaginal intercourse to 138 for receptive anal intercourse [17]. The probability of HIV-1 transmission derives from factors in both partners and is influenced by behavioural, biological, genetic and immunological risk factors of the host and the virus. There is a broad consensus that male-to-female transmission is more efficient than female-to-male transmission [1719].

It has been hypothesized that the lower efficiency of female-to-male transmission compared with male-to-female transmission observed in early studies on HIV-1-discordant couples (pre-ART era) might be due to a lower infectious potential of HIV-1-infected women. Plasma viral load [20] and viral load in genital secretions [21] strongly influence HIV-1 transmission. Consequently, HIV-1 transmission is also influenced by the stage of infection of the index case [22,23]. Based on a longitudinal study of 3400 African HIV-1-discordant heterosexual couples, Hughes and colleagues estimated a 2.9-fold increased per-act risk of transmission for each log10 increase in plasma HIV-1 RNA [24]. HIV-1-infected women exhibit lower viral loads than HIV-1-infected men [2530] with viral load differences between the sexes being most pronounced in early disease and waning in more advanced stages of infection. In keeping with these data on viral load, male-to-female or female-to-male transmission rates within strata of viral load were shown to be similar [20]. Furthermore, it has been shown that the rate of transmission from index cases in advanced stages of HIV-1 infection did not differ between sexes [31]. In the era of ART, the risk of horizontal HIV-1 transmission is minimal in the context of full viral suppression [32,33]. The landmark HIV Prevention Trials Network 052 Study, a multicentre, randomized controlled trial monitoring 1763 HIV-1-discordant couples, showed that early initiation of ART was associated with a 96% reduction in the number of linked HIV-1 transmissions relative to delayed ART initiation (i.e. ART started after clinical event occurred or CD4+ T-cell count declined to less than 250 cells/ml) [34]. But although HIV-1 transmission from fully suppressed index cases is very low, it is important to highlight that HIV-1-infected individuals are particularly at risk of transmitting the virus during primary HIV-1 infection when viraemia is high and HIV-1 status is frequently unknown. Thus, the early suggestion of differences in transmission efficiency pointed to a distinct biological finding of generally lower viral loads in women at specific stages of infection and underlined the importance of viral burden in determining transmission risk.

Factors other than viral load clearly also contribute to sex-based differences in transmission and disease susceptibility. A meta-analysis by Boily and colleagues revealed differences in transmission risk segregating by economic factors [35]. The adjusted low-income country female-to-male and male-to-female transmission estimates were very similar and linked to a higher prevalence of sexually transmitted infections (STIs) which promote acquisition [3638] and lower rates of male circumcision in developing countries which may account for higher rates of female-to-male transmission [39]. The association between pre-existing STIs and HIV-1 acquisition is clear, in particular for the herpes simplex virus 2, genital ulcer disease [40]. The relative contribution of behavioural and biological factors to this enhanced susceptibility has been difficult to parse [41]. Several studies have now highlighted potential biological mechanisms. First, STIs increase inflammation resulting in higher levels of target cells for HIV-1 at the mucosal site [42,43]. Consistent with this, bacterial vaginosis an alteration of normal vaginal flora, is a common factor for increased risk of acquisition of both STIs and HIV-1 and is highly prevalent in sub-Saharan Africa [4447]. In addition to the potential recruitment of cells that can support infection, bacterial vaginosis can also suppress protective innate immune effectors, which may increase the risk of STIs and HIV-1 acquisition. The healthy vaginal microbiota, mainly dominated by lactobacilli, plays an essential role in the natural defense system against HIV-1 and other STIs [47]. Recent studies with genetic analysis of bacterial communities have highlighted the differences in vaginal colonization patterns and the relationship to local inflammation [48]. These differences are linked to bacterial vaginosis, as demonstrated by the differences in alpha diversity (a measure of diversity and proportion of specific bacteria) in the vaginal microbiota of women with the condition compared with asymptomatic controls [49]. The mechanisms for these effects are still being delineated. Production of H2O2 was initially thought to mediate dominance of specific bacterial species, and more recent work suggests that lactic acid may inactivate HIV-1 in the setting of an acidic pH [47]. Importantly, these findings have the potential for clinical translation, as indigenous vaginal lactobacilli population can be restored by antibiotic therapy for bacterial vaginosis and can be further enhanced with probiotic administration [49].

Sex hormones can also enhance HIV-1 acquisition through pleiotropic effects including changes in the vaginal milieu and bacterial flora [50]. As a general rule, progesterone increases susceptibility whereas oestrogens protect against viral STIs, including HIV-1 [51]. Nevertheless, studies have suggested that hormonal contraception use, including progestin-only contraceptives, may reduce bacterial vaginosis possibly through reduction in menstruation [52,53]. Exogenous oestrogen in combination contraceptives is thought to promote lactobacillus colonization as lactobacilli metabolize glycogen from oestrogenized epithelial cells [52]. The mucosal epithelium is the first site of contact to the virus and, in addition to the inherent differences between men and women, the thickness is further influenced by female sex hormones [54]. In vivo studies in non-human primates have shown that HIV-1 rapidly penetrates through the cervicovaginal epithelium (within 30–60 min of exposure) [55] and encounters CD4+ T-cells as well as Langerhans cells (LCs), which will transport virions as they migrate to secondary lymphoid organs [16,56]. LCs are involved in the early diffusion of the virus beyond the site of viral entry [16] and men and women may differ in the target cell availability, including LCs, in the mucosa epithelium. The frequency of LCs in the vaginal epithelial can also be influenced by sex hormones [54,57]. The susceptibility of CD4+ T-cells to infection is also influenced by sex hormones through changes in the surface density of receptors and coreceptors on target cells. Progesterone increases the expression of HIV-1 receptors CD4, CCR5 and CXCR4 on human cervical CD4+ T-cells [5861]. As sex hormones have multiple effects on the reproductive tract, the interplay between sex hormones and bacterial colonization is one factor that must be considered in balancing benefits and risks of exogenous hormone administration in the form of contraception. Further research in this area is urgently needed; the complex relationship between endogenous and exogenous sex hormones in relation to susceptibility to infection requires careful and focused study and to date, the available data are inconclusive.

Modulation of innate immune responses in the genital tract is another point of sex-based variation and susceptibility. Li and colleagues’ work on a macaque model of simian immunodeficiency virus (SIV) infection has highlighted the exploitation of innate immune responses by SIV to overcome the limited availability of susceptible target cells, allowing for systemic viral dissemination. Work in the SIV model highlights the role of innate responses in recruiting susceptible target cells; endocervical epithelia respond to virus exposure with expression of macrophage inflammatory protein (MIP)-3α, recruiting plasmacytoid dendritic cells (pDCs), which in turn produce MIP-1α and MIP-1β and interferon (IFN) α that coordinate an influx of CCR5+ target cells [62]. The activation of innate immunity and role of inflammation in HIV-1 acquisition is another feature modulated by sex. It is well established that systemic innate immune activation is in general higher in women than men [63]. Data from the CAPRISA 004 phase IIb, randomized, placebo-controlled clinical trial assessing the safety and effectiveness of 1% tenofovir gel in preventing HIV-1 infection in women, highlighted the significance of systemic inflammation, demonstrating that women who acquired HIV-1 had significantly higher systemic innate immune activation prior to infection than women who remained uninfected, irrespective of microbicide use [64]. Studies on HIV-1-exposed seronegative cohorts have also implicated elevated immune activation as a risk factor for acquiring HIV-1 [65]. This is confirmed by recent work analysing the proteome in cervicovaginal lavages collected from high-risk, HIV-1-uninfected women, demonstrating an association between elevated mucosal cytokines and increased immune cell frequency [66]. The reductions in inflammation both systemically and locally are believed to limit the availability of activated CD4+ target cells and reduce recruitment of these targets to the mucosa. In addition, elevated inflammation has a significant impact on local tissue remodelling and barrier integrity, another pathway towards increased efficiency of infection [66].

Again, it is important to remember that biological and socio-economic vulnerabilities are intrinsically linked. Two recent studies have demonstrated that women who have experienced intimate partner violence were 50% more likely to have acquired HIV-1 than women who had not experienced violence [67,68]. From a physiological perspective, sexual violence causes genital injury and extragenital trauma in 87–92% of victims [69], causing systemic and local inflammation and increased presence of target cells for HIV-1 at the site of exposure, which in turn can increase susceptibility to HIV-1 acquisition.

Sex hormone effects on immune activation and inflammation are also supported by studies during the early infection period. Elevated cytokine concentrations in CVL samples during early HIV-1 infection (6 and 17 weeks postinfection), were associated with higher plasma viral load set point, which is predictive of time to AIDS [70]. Cytokine concentrations at later time points postinfection (30 and 55 weeks postinfection) were not associated with viral load set point. This study suggests that cytokine responses in the genital tract during the early stages of HIV-1 infection may influence disease outcome and that strategies to reduce genital inflammation, including treatment of STIs, may slow disease progression [70]. HIV-1 infection also appears to modulate the influence of sex hormones; progesterone has stronger inhibitory effects on T-cell proliferation and Th1-type cytokine production in HIV-1-infected individuals as compared with uninfected individuals [71]. Immune activation in the genital tract is thus a crucial component of increased risk of HIV-1 acquisition in women, can affect disease progression and is susceptible to modulation by sex hormones. Taken together, these data strongly support the involvement of biological mechanisms in women's increased susceptibility to HIV-1 infection.

Although there are multiple aspects by which female sex modulates the susceptibility to HIV-1 infection, the differences between men and women in immune activation are a critical factor in altering acquisition and pathogenesis, a theme that recurs throughout this discussion.

IMPACT OF HORMONAL CONTRACEPTION ON HIV-1 ACQUISITION

Contraception is a major component of women's healthcare, and given the biological consequences of exposure to sex hormones, it may be an important factor in determining risk of HIV-1 acquisition. Several studies have suggested that the use of hormonal contraception and in particular of depot medroxyprogesterone acetate (DMPA) may increase the risk of HIV-1 infection [7275]. DMPA is an injectable progesterone-based contraceptive commonly used in Sub-Saharan Africa, a region where HIV-1 prevalence is very high. A 10-year prospective study involving more than 1500 sex workers in Mombasa, Kenya revealed that women with DMPA had a 2-fold increased risk of acquiring HIV-1 than women without DMPA [7678]. Leclerc and colleagues observed similar findings in young African women, estimating that 6% of new HIV-1 cases are attributable to DMPA use [79]. Nevertheless, the extensive epidemiological data remain inconclusive and the impact of hormonal contraception of HIV-1 transmission is controversial [80]. Potential confounders, including number of sexual partners, condom use and sharing/reuse of needles for delivery of DMPA [81,82], are difficult to adequately control for in analyses, and most of the studies were in high-risk populations with a recent meta-analysis suggesting a reduced contribution of DMPA to acquisition in the general population [83]. In addition, recent analyses suggest no increase in risk associated with oral contraceptive pills [83,84]. Contraception has profound benefits, including reduced maternal and infant mortality and morbidity, enabling women to make choices about fertility, associated economic advances and a reduction in the number of babies born with HIV-1. Therefore, decisions regarding the availability of effective contraceptive options for women must be carefully considered against the potential for an increase in HIV-1 infections that may be very infrequent events [85]. It has been estimated that removing DMPA from the market and shifting to oral contraceptives or condoms could result in approximately 600 additional unplanned births for every 100 HIV-1 infections averted, whereas a shift to no contraceptive method at all could result in approximately 5400 additional births per 100 HIV infections averted [86]. However, in countries with high HIV-1 prevalence and high use of DMPA, such as South Africa, alternative contraceptive use might be beneficial [85]. Of note, hormonal contraceptive is not significantly associated with measures of HIV-1 disease progression [87].

Given the inconclusive nature of the epidemiologic evidence and the analysis of risks and benefits to country programmes, WHO and the Center for Disease Control have not recommended changes in policy, with no current restrictions on the use of any hormonal contraceptive method for women living with HIV-1 or at high risk of HIV-1 infection. Nevertheless, they correctly pointed out that more research is needed and that women using progestin-only injectable contraception should be strongly advised to also always use a condom [88,89].

Basic discovery work on the immune effects of DMPA offer several critical insights into the potential role of contraceptives in HIV-1 acquisition of pathogenesis, which may aid in the interpretation of the epidemiologic data. Several studies have suggested that DMPA may favour viral dissemination over early immune control during the acute phase of infection via altered cytokine production, although strong mechanistic data are lacking. Compared with controls not using hormonal contraceptives, DMPA users have decreased pDC-derived IFNα production in response to toll-like receptor (TLR)9 (but not TLR7/8) stimulation and reduced plasma and CVL levels of IFNα [90], in agreement with in vitro data showing medroxyprogesterone acetate (MPA)-mediated suppression of IFNα production by pDCs [91,92]. However, although pDC-derived IFNα may participate in antiviral response through the up-regulation of interferon-stimulated genes (ISGs), it may also favour viral dissemination [62] and the significance of these findings is unclear. Increased local inflammation has also been suggested as a biological mechanism for an increased risk of HIV-1 acquisition in DMPA users, but increased cytokine levels in the vaginal tract have not been consistently shown [90,93]. Similarly, conflicting results have been found regarding the influence of DMPA on the frequencies of target cell populations in the vaginal mucosa. Several studies have reported no effect of DMPA on LC density [90,9496] but the impact on the frequency of CCR5+CD4+ cells is unclear [9597]. A recent study showed that the expression density (by mean fluorescence intensity) of CCR5 in bulk, central and effector memory CD4+ T-cells was modestly increased (6–12%) in peripheral blood mononuclear cells (PBMCs) from uninfected pre-menopausal women taking progestin-only contraception (DMPA and levonorgestrel-releasing intrauterine device) compared with women with regular menstrual cycles [98]. In contrast, CCR5 expression was not altered on dendritic cells (DCs) and monocytes by hormonal contraceptives [98]. Thus progestin contraceptives may affect pDC cytokine production and surface density of HIV-1 coreceptor expression on some target cells, although the magnitude and consistency of this effect is unclear.

An alternative mechanism for MPA enhancement of susceptibility to HIV-1 infection is through enhancement of uptake and transcytosis of HIV-1 by human genital epithelial cells, favouring viral dissemination [99]. This work, in an in vitro model system, suggests that in the presence of MPA, small amounts of virus can still breach the barrier by transcytosis, despite a lack of inflammation [99]. Importantly, some of the observed changes in immune parameters in DMPA users may be related to chronic anovulation and reduced concentration of endogenous oestrogen rather than a direct effect of DMPA [94,95]. Studies in non-human primate models suggest that DMPA-mediated increase in SIV susceptibility is likely to be driven by its local effects on the genital tract rather than systemic effects. DMPA administration selectively abrogated the protective effect of an attenuated lentivirus-induced protection against intravaginal challenge with live-attenuated lentivirus [100,101] but did not alter protection after intravenous SIV challenge in female macaques immunized with a live-attenuated lentivirus [102].

Although there are numerous lines of evidence suggesting hormonal modulation of inflammation, target cell availability, local epithelial integrity and barrier function and immune activation, rigorous in vitro data, animal models and clinical studies remain urgently needed to more clearly quantify risks and direct appropriate interventions.

SEX HORMONES MAY MODULATE THE EFFICACY OF PREVENTIVE MEASURES AGAINST HIV-1 ACQUISITION

One major strategy to contain the HIV-1 pandemic is the development and implementation of efficient prevention measures. Appropriate animal models are crucial to test the efficiency of microbicide or antiretroviral pre-exposure prophylaxis (PrEP) and should take into account the impact of sex hormones. Rhesus macaques treated with DMPA have been widely used over the past 15 years. DMPA treatment enhanced vaginal transmission of SIV by more than 7-fold [103105] in part through thinning of the vaginal epithelium. This method allowed for reproducible infection of control animals with ‘intermediate’ doses of virus, facilitating comparisons. ‘Multiple dose’ rhesus macaque models have been developed to avoid the use of progesterone-based enhancement of infection. Unfortunately, variation in infection with a challenge virus reduced the power of these studies to determine whether a microbicide reduces the rate of transmission significantly and reproducibly [106].

Alternative approaches designed to avoid the issues of progesterone administration included the use of the pigtail macaque model. Pigtail macaques have higher susceptibility to vaginal challenge without hormones, and unlike rhesus macaques have regular menstrual cycles that confer variation in susceptibility to simian-human immunodeficiency virus (SHIV) infection [106109]. The pigtail macaque menstrual cycle, unlike rhesus macaques, is associated with loss of keratinizing vaginal epithelium, comparable to that of women [110] and with transcriptomic changes that can alter SHIV susceptibility [111]. These studies highlighted the expression of canonical ISGs such as ISG15, interferon-induced protein 44 (IFI44), 2′-5′-oligoadenylate synthetase (OAS) 1–3, myxovirus resistance (MX) 1/2 and signal transducers and activators of transcription 1 (STAT1) (triggered by IFNα/TLR response), critical components of innate antiviral defense that were increased in the luteal phase of the cycle [111]. No increase in leucocyte influx due to vaginal wall thickening was seen. An optimal dose of DMPA to recapitulate the effects in women was developed to suppress ovulation and induce modest changes in vaginal wall thickness. In this model, there was no change in mucosal virus shedding [108]. Thus, the pigtail macaque model offers an alternative model with the possibility of modelling some of the effects of hormone exposure in modulating acquisition. However, there is limited availability of pigtail macaques and the optimal model for preclinical microbicide studies remains controversial. Relevant animal models are thus required for addressing specific questions of HIV-1 transmission and vaginal susceptibility.

Even with an optimized model, it is important to take into account differences between humans and macaques, which might lead to discrepant results between the two species. First, the decrease in progesterone levels during the 3-monthly injection period may have different kinetics in blood and mucosal tissues among women and female macaques. An appropriate model will require the identification of a physiological DMPA dose that suppresses ovulation and mimics other biological effects seen in women including commensurate changes in other hormone levels [108]. The virus delivery medium differs between humans (semen) and macaques (culture medium). Last but not least, the effect of progesterone on the vaginal epithelium of humans may be less profound, with several studies actually reporting increased epithelial thickness caused by hyperplasia [96,112,113] or no thinning at all in women during the use of DMPA [94,112], contrary to what is observed in primates SIV model [114]. Overall, non-human primates represent a useful model to study biological mechanisms involved in HIV-1 acquisition; however, findings from this model have to be carefully validated in human studies before drawing broader conclusions on HIV-1 acquisition.

Another approach to prevention of HIV-1 infection is through PrEP using antiretroviral drugs, which has been demonstrated to have biological effectiveness in both men and women, when taken as prescribed [115]. As expected, results from clinical trials have highlighted the importance of adherence in PrEP efficiency, and there is evidence that there may be relevant differences between men and women. Pharmacokinetic studies have indicated significantly lower concentrations of tenofovir in vaginal than in rectal tissues [116,117], suggesting that PrEP may be less forgiving to suboptimal adherence for women compared with men. As a PrEP strategy with an efficiency of only 39% would be estimated to possibly prevent more than 44,000 infections among young women in one year [118], studies to define the tissue penetration and pharmacokinetic modelling to define optimal adherence and dosing are critical. The data suggest that prevention strategies should also target the reduction of immune activation and inflammation, critical pathways that promote HIV-1 acquisition.

SEX DIFFERENCES IN THE NATURAL COURSE OF HIV-1 INFECTION

The clinical course of HIV-1 infection is characterized by progressive decline in CD4+ T-cells with immunodeficiency and ultimately AIDS. The clinical parameters of HIV-1 viral load and total CD4+ T-cell count are critical tools in monitoring disease stage and assessing infectious risks. Sex-based differences in baseline CD4+ T-cell count have been suggested, with generally higher counts in HIV-1-negative women compared with HIV-1-negative men [119,120]. In HIV-1-infected individuals, discrepant results regarding sex differences in CD4+ T-cell counts have been reported, likely a consequence of the variable stages of HIV-1 infection at which the CD4+ T-cell counts were assessed [30,121126]. In contrast, the majority of studies assessing sex differences in viral load have shown lower viral load in women compared with men, with few exceptions [127129]. Several large studies have reported that women have HIV-1 RNA levels between 0.13–0.35 log10 (approximately 50%) lower than men early in infection [2529]. These differences in viral loads persisted for several years after seroconversion [30] before attenuating, resulting in comparable viral loads at later stages of infection [25,26,30]. Furthermore, it is important to note that differences in HIV-1 RNA viral load between men and women have been shown to be larger for HIV-1-infected individuals with higher CD4+ T-cell counts [130,131]. A recent study showed that viral load differences between women and men were approximately 0.2 log10 among persons with CD4+ T-cell counts up to 300 cells/mm3, but less than 0.1 log10 among subjects with a CD4+ T-cell counts below 50 cells/mm3 [132]. As discussed above, sex differences in viral load might contribute significantly to sex differences in HIV-1 transmission [24]. Even in the era of ART, as many transmission events occur during primary infection when viral load is high and HIV status is often unknown, sex-based differences in viral load may account for greater efficiency of male-to-female transmission.

On a population level, these differences in viral load and replication rates may contribute to distinct patterns of viral evolution in groups with different proportions of men and women. An analysis of the two largest risk groups for HIV-1 transmission [men who have sex with men (MSM) and heterosexuals] reported slower HIV-1 evolutionary rates in the heterosexuals datasets as compared with the MSM datasets [133]. Such differences may be the consequence of differences in the transmission dynamics that lead to distinctions in bottleneck size between the risk groups or because of differences in within-host viral replication. In line with the higher viral set-point observed in men compared with women, the authors suggested that sex ratio may be key to explaining the risk group-associated evolutionary rate differences. Indeed, more replication cycles per unit of time in male-dominated epidemics might imply more opportunities for nonsynonymous mutations to arise and subsequently become fixed if they are beneficial to viral fitness. Importantly, sex effects may impose different evolutionary pressure on HIV-1 at the epidemic level [133]. The mechanisms underlying these sex differences in viral loads remain largely unknown.

Variation in IFNα production between women and men that is further influenced by hormone levels, as discussed further below, may have a direct effect on the observed sex differences in viral load. Increased IFNα production in women may enhance expression of IFNα-stimulated antiviral host restriction factors and attenuate viral replication. However, as lower viral loads are also seen in girls compared with boys [134], it appears that sex hormones alone cannot fully account for sex differences in viraemia and that more complex mechanisms, including genes encoded on the X-chromosome, are most likely involved.

Recent investigation has focused on tissue viral burden, in addition to plasma viral load. Among untreated HIV-1-infected individuals, women had slightly lower frequencies of HIV-1 RNA-producing cells in lymph nodes (LN) than men, but this difference accounted for less than half of the sex-based differences in plasma viral load [135]. Women with the same viral load as men might have a larger burden of productively infected cells in the LN with possible consequences for time to rebound in the absence of ART. An open question is whether fewer virions per HIV-1 RNA-producing cell are produced in women compared with men; this is plausible if there is differential induction of intrinsic antiviral activity between the sexes. More efficient clearance of extracellular HIV-1 in women as compared with men could account for the sex-based discordance between HIV-1 RNA-producing cells and viral load and might arise from the higher levels of immune activation observed in female patients [136138], or a lower transfer rate of virus released from lymphoid tissue into the blood. With respect to the latter, both virus-trapping and -retention on follicular DCs are mediated primarily by specific antibodies and/or complement proteins coupled with immune complex receptors on follicular DCs [139142]. In vaccine trials, titres of neutralizing antibodies against HIV-1 are generally higher in women compared with men [143,144] suggesting that differences in antibody function may contribute to lower levels of viraemia. Differences in immune activation may also contribute to sex variation in tissue viral burden, however after controlling for percentage of HLA-DR+CD38+CD4+ T-cells, race, age and CD4+ T-cell count, women still had an HIV viral load in LN that was 0.66 log10 copies/ml lower than men [135]. In light of these differences, the high (and comparable) viral load in men and women in late stage of disease [145] may be linked to the destruction of lymphoid tissue architecture with release of large quantities of virus that occurs with disease progression.

SEX DIFFERENCES IN ADVERSE EVENTS RATE AND PHARMACOKINETICS OF ARV DRUGS

Women tend to be more susceptible to adverse events in response to all classes of antiretroviral drugs [146,147], including nausea and vomiting [148], protease inhibitor-associated allergic reactions [149152], nucleoside/nucleotide reverse transcriptase inhibitors-induced life-threatening lactic acidosis, nevirapine-associated hepatotoxicity, morphological alterations and metabolic abnormalities. Higher ARV concentrations are observed in females compared with males, which may lead to greater drug toxicity [153,154]. Sex differences in drug pharmacokinetics (in bioavailability, distribution, metabolism and elimination) and subsequent toxicity are not specific to antiretroviral drugs [155,156]. Several mechanisms including differential body weight and composition, sex hormone exposure, expression of the drug transporter P-glycoprotein and renal and hepatic function are likely operative [146,157]. It is important to note that the majority of drugs including ARVs are administered at the same dose in all adult subjects irrespective of sex and body weight. Poor tolerability due to effectively higher exposure can affect adherence to prescribed medications and lead to treatment interruptions. Consistent with this possibility, women are more likely to discontinue or change their ART regimen because of treatment-related side effects [125,158]. Differences in treatment discontinuation may account for some subtle distinctions in treatment outcomes; after adjusting for adherence sex-based differences in the rate of HIV-1 rebound rates did not hold [159]. As discussed above, social and behavioural factors may also contribute to lower adherence to ART in women than in men. An important body of evidence supports sex differences in pharmacokinetics, adverse events and adherence. As new therapeutics are developed for both preventative, suppressive and eradication/cure indications, it is crucial to consider sex differences in pharmacokinetics, adverse events and adherence.

IMMUNE ACTIVATION AND IFNα RESPONSES AS A KEY FACTOR IN SEX DIFFERENCES IN HIV-1 PATHOGENESIS

Persistent immune activation is a major driver of the pathogenesis of HIV-1 infection, dictating in part the rate of disease progression [160]. Immune activation contributes to the continuous maintenance of a pool of activated target CD4+ T-cells for HIV-1 replication and spread. The increased cytokine production characteristic of immune activation may increase HIV-1 replication and contributes to depletion of CD4+ T-cells through bystander apoptosis. This inflammation has other deleterious effects, contributing to accelerated immune aging or increased cardiovascular morbidity in HIV-1-infected individuals. In some studies, immune activation has been found to be a better correlate of clinical disease progression than CD4+ T-cell count or HIV-1 RNA levels [161,162]. Even with effective ART and full suppression of HIV-1 viraemia, elevated immune activation persists when compared with uninfected individuals [163,164]. This residual immune activation in HIV-1-infected individuals contributes to increased risk of serious non-AIDS-related morbidity and mortality, such as cardiovascular disease, kidney disease, liver disease and non-AIDS-defining malignancies [163,165168]. High levels of immune activation can be maintained directly by HIV-1 replication and indirectly through changes in the microbiome, microbial translocation, co-infection with pathogens including cytomegalovirus, immune deregulation and lymphoid tissue fibrosis [169172]. Thus, multiple pathways converge to initiate and maintain an elevated inflammatory setpoint in the setting of HIV-1 infection.

Chronic immune activation is characterized by the up-regulation of many inflammatory markers, including increased expression of HLADR, CD38 and Ki67 on CD4+ and CD8+ T-cells, caused in part by antigen-specific T-cell activation, but mostly by bystander activation resulting from the general activation of innate immune responses. Significantly, the activation driven by innate responses has been shown to vary between the sexes in humans and animal model studies. A recent study in rhesus macaques observed that female animals infected intrarectally with SHIV progressed faster to disease than their male counterparts [173]. Sex disparity in basal immune activation in the rectal mucosa was excluded as a major contributing factor. Instead, differences in the local innate immune responses to SHIV infection were most remarkable [173].

Innate immunity is the first line of defense against invading pathogens and requires recognition by pathogen recognition receptors including the TLR family. Excessive activation of these receptors and dysregulation of their signalling pathways alters immune responses contributing to chronic immune activation. pDCs are critical components of the antiviral responses with an unmatched capacity to produce high amounts of IFNα upon TLR7/9 activation [174]. HIV-1 encodes multiple TLR7/8 ligands that stimulate pDC IFNα production in vitro [175]. Classically, pDCs are described as being refractory to IFNα production upon repeated stimulation with synthetic TLR7 or TLR9 agonists, which is thought to be a protective mechanism against excessive immune activation [176,177]. In contrast, HIV-1 seems to uniquely allow for persistent stimulation of pDCs [178]. Excessive IFNα production by pDCs may promote HIV-1 pathogenesis through multiple distinct mechanisms, including the chemoattraction of CCR5+CD4+ T-cells to mucosal sites, therefore favouring systemic spread of the virus [179], the up-regulation of T-cell activation [180] and the induction of the immunosuppressive enzyme indoleamine (2,3)-dioxygenase (IDO), thus altering the Th17/regulatory T-cell balance [174,181,182]. Studies in SIV infection of rhesus macaques, the non-natural host of SIV, have shown an association between high levels of IFNα production, immune activation and viral pathogenesis which is not observed in SIV infection of sooty mangabeys, the natural host of SIV [183,184]. Indeed, a key distinction between the two models is that innate immune activation is rapidly resolved in SIV-infected natural hosts, whereas up-regulation of the type I IFN response and expression of ISGs persists in SIV-infected macaques, highlighting the potential pathogenic role of the magnitude and longevity of the IFNα response in SIV/HIV-1 disease [183,184].

The significance of the type I IFN response in HIV-1 disease has particular implications for sex differences in pathogenesis. pDCs derived from females produced markedly more IFNα in response to HIV-1-encoded TLR7/8 ligands than pDCs derived from males, resulting in stronger secondary activation of CD8+ T-cells [136]. Furthermore, increased levels of a subset of ISGs, including CCR5, MX-1 and ISG15, were observed in CD4+ and CD8+ T-cells from treatment-naïve HIV-1-infected women when compared with men, and similar findings were observed during chronic HIV-1 infection after controlling for HIV-1 viral load [185]. The up-regulation of those ISGs was linked to higher levels of immune activation in chronic HIV-1 infection [185]. The higher production of IFNα by pDCs in response to TLR7 has also been observed for healthy women as compared with healthy men [186]. This is in agreement with data suggesting that systemic innate immune activation is in general higher in women than men [63]. TLR7 is encoded on the X chromosome, however sex differences in pDC responses to TLR7 stimulation do not seem to be linked to gene dosage or higher expression of TLR7 [186]. Using a conditional mouse model, the pDC IFNα response to TLR7 has been shown to be positively regulated by E2 through oestrogen receptor α (ERα) during pDC lineage differentiation from progenitors [187]. The impact of E2 on IFNα production was pDC specific, as no difference in cytokine production by monocytes was observed [187]. More recently, our group identified the interferon regulatory factor 5 (IRF5) as a potential mediator of the sex differences observed in the IFNα response by pDCs [188]. pDCs from women express more IRF5 than pDCs from men, and basal IRF5 levels correlated to the percentage of IFNα-secreting pDCs upon TLR7 stimulation. Furthermore, mice with a conditional knockout of the ERα in the DC lineage had lower IRF5 levels and reduced TLR7-mediated IFNα production.

Taken together, these findings indicate the importance of innate responses including the type I IFN pathway in determining immune activation and inflammation with critical implications for disease progression. Further, the sex-specific modulation of pDC production of IFNα captures a significant portion of the biological variability in innate responses to HIV-1 in men and women. These data suggest that strategies aiming at minimizing residual chronic immune activation by targeting the pDC/type I IFNs pathways should be further evaluated as a complement to standard ART.

SEX DIFFERENCES IN THE CONTEXT OF THE ERADICATION STRATEGIES

Despite the development of potent antiretroviral therapies, there is currently no cure for HIV-1. HIV-1 persistence in a stable reservoir that shows little degradation over time represents a major challenge in HIV-1 eradication. These reservoirs are established very early during the acute phase of HIV-1 infection [189] and persist in individuals receiving ART [190]. Comparisons of reservoir size and activity between men and women are the subject of recent investigation. Interestingly, it has been recently reported that women had a higher probability of reaching low HIV-1-DNA levels (a measure of reservoir) after long-term ART [191]. This cross-sectional study recruited over 500 chronically HIV-1-infected adult patients in France, who had been receiving potent ART with sustained viral load suppression for at least 2 years. It has been hypothesized that lower HIV-1-DNA levels in women may result from a better control of virus replication during the acute phase of HIV-1 infection, although this has not been clearly demonstrated.

Reflecting back on the sex-based differences in innate immune activation, data from a clinical trial using the histone deacetylase inhibitor panobinostat identified innate immunity, including natural killer (NK) cells and pDCs frequencies, as the major immune correlate of the decrease in HIV-1 DNA levels during panobinostat treatment [192]. Increase in the relative proportions of pDCs and the expression patterns of ISGs during panobinostat treatment were associated with a decline in the HIV-1 reservoir measured by viral DNA [192]. Thus, sex-based differences in pDCs/type I IFNs response may have important implications for virus reactivation and control. In addition, several studies have shown that the magnitude of the viral reservoir is strongly associated with the residual levels of immune activation that persist during ART [190]. Reduction of immune activation may therefore efficiently interfere with the maintenance of the HIV-1 reservoir [190]. It would be important to determine if there are differences in HIV-1 reservoir size, potential for reactivation and residual inflammation between fully suppressed men and women.

Oestrogen receptor signalling could represent an important mediator of sex differences in HIV-1 reservoir size. It has been shown that ESR1 agonists inhibit HIV-1 transcription in vitro in PBMCs [193]. In particular, 17β-estradiol induces complex formation between ERα and β-catenin, which tethers on the HIV LTR to repress HIV promoter activity [193]. Interestingly, preliminary work from Karn [194] have indicated a sex-specific inhibitory effect of oestradiol on proviral reactivation. Although oestradiol effect was modest in men, it strongly inhibited proviral reactivation in women [194]. The sensitivity of latency reversal to oestrogen opens a potential therapeutic avenue; selective oestrogen receptor modulators are well-established drugs. They have been studied for a variety of indications, primarily in women but also in men [195]. Tamoxifen is one of the most well described drugs in this class, an oestrogen receptor antagonist that has been used for the treatment of breast cancer since the 1970s [196]. Selective oestrogen receptor modulators could be envisaged as components of clinical studies aimed at inducing proviral reactivation, and at the very least, hormonal milieu should be considered in trial design as a potential confounder of efficacy assessments [194]. A recent systematic review suggests that participation in clinical studies of HIV-1 curative interventions does not accurately reflect international burden of infection in women [197] with only approximately 18% of study participants being women in studies where both men and women were eligible. Interestingly, inclusion of women varied by intervention, with fewer than 1% women participating in cell therapy or reactivation studies [197]. Altogether, these data emphasized the need for better consideration of men/women ratio and sex hormones in therapeutic strategies for HIV-1 eradication both to identify potential pathways for intervention, and to rationally control for biological differences relevant to efficacy outcomes.

CONCLUSION

Numerous epidemiological studies have documented differences between men and women in acquisition rates and manifestations of HIV-1 infection. These data have been controversial, and in many cases there is a clear contribution of underlying socioeconomic factors. However, there are clear biological mechanisms of sex-based differences. One major and very consistent finding revealed by those studies is the lower viraemia observed in HIV-1-infected women compared with HIV-1-infected men, in particular during early stages of infection. It is also generally acknowledged that women display a greater susceptibility to HIV-1 acquisition. To date, considerably fewer studies have addressed the mechanisms underlying those sex differences. Recent data have pointed towards an important role of sex hormones in mediating variations of innate immune responses to HIV-1 infection. Figure 1 summarizes key findings on sex differences in HIV-1 pathogenesis. Understanding this pathogenesis may inform key aspects of efforts at prevention of infection and reduction of residual immune activation in treated disease. Early data suggest that modulation of oestrogen signalling may represent an attractive target in the reduction of HIV-1 viral reservoirs, which bears further research. Similarly, the role of genes encoded by the X chromosome, such as TLR7, TLR8 and FoxP3, are an important focus for investigation given the evidence for sex differences prior to the onset of puberty. An association between an X chromosomal single-nucleotide polymorphism and HIV-1 disease progression has been demonstrated in women, but not in men [198]. Finally, rigorous consideration of sex in experimental design and analysis, including potential pharmacokinetics differences, is critical. To conclude, additional efforts are needed to dissect the molecular mechanisms responsible for observed differences in the manifestations of HIV-1 disease between women and men and these studies may illuminate fundamental aspects of infection in both sexes and potential targets for therapeutic intervention.

Summary of the key findings on sex differences in HIV-1 pathogenesis

Figure 1
Summary of the key findings on sex differences in HIV-1 pathogenesis

Several studies have reported increased susceptibility to HIV-1 acquisition in women compared with men. The pre-infection levels of immune activation at the site of infection appeared to be a major contributing factor, with recent data suggesting an important role of the vaginal microbiome. Sex hormones also contribute to enhanced susceptibility by affecting the vaginal mucosa. Importantly, ERα signalling was shown to directly impact the production of IFNα by pDCs in response to HIV-1. Increased IFNα production in women may be responsible for lower viral setpoints during primary HIV-1 infection reported in women as well as increased levels of immune activation in chronic infection. Very recent data also suggest that women might exhibit lower viral reservoirs. Critical information can be retrieved from studies on sex differences in HIV-1 infection and should be integrated in therapeutic and preventive strategies.

Figure 1
Summary of the key findings on sex differences in HIV-1 pathogenesis

Several studies have reported increased susceptibility to HIV-1 acquisition in women compared with men. The pre-infection levels of immune activation at the site of infection appeared to be a major contributing factor, with recent data suggesting an important role of the vaginal microbiome. Sex hormones also contribute to enhanced susceptibility by affecting the vaginal mucosa. Importantly, ERα signalling was shown to directly impact the production of IFNα by pDCs in response to HIV-1. Increased IFNα production in women may be responsible for lower viral setpoints during primary HIV-1 infection reported in women as well as increased levels of immune activation in chronic infection. Very recent data also suggest that women might exhibit lower viral reservoirs. Critical information can be retrieved from studies on sex differences in HIV-1 infection and should be integrated in therapeutic and preventive strategies.

CONFLICT OF INTEREST

Morgane Griesbeck is currently employed by BD (Becton, Dickinson and Company).

FUNDING

This work was supported by the National Institute of Health (NIAID) (to E.S.).

Abbreviations

     
  • ART

    antiretroviral therapy

  •  
  • DC

    dendritic cells

  •  
  • DMPA

    depot medroxyprogesterone acetate

  •  
  • ERα

    oestrogen receptor α

  •  
  • IFN

    interferon

  •  
  • IRF5

    interferon regulatory factor 5

  •  
  • ISG

    interferon-stimulated genes

  •  
  • LC

    Langerhans cells

  •  
  • LN

    lymph nodes

  •  
  • MSM

    men who have sex with men

  •  
  • MPA

    medroxyprogesterone acetate

  •  
  • PBMC

    peripheral blood mononuclear cells

  •  
  • pDC

    plasmacytoid dendritic cells

  •  
  • PrEP

    pre-exposure prophylaxis

  •  
  • SHIV

    simian-human immunodeficiency virus

  •  
  • SIV

    simian immunodeficiency virus

  •  
  • STI

    sexually transmitted infections

  •  
  • TLR

    toll-like receptor

  •  
  • WHO

    World Health Organization

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