Sex Differences in HIV Infection

Abstract

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

The Impact of Cellular Proliferation on the HIV-1 Reservoir

“…Sex-biases in our understanding of the HIV reservoir must also be addressed. Many studies conducted in the developed world are heavily biased towards male participants, which is concerning given the large body of evidence that suggests there are known sex-specific differences for disease progression and response to therapies (reviewed [80]).…”

“…Intact proviruses decayed at a rate of −0.38 to −0.2/year with a half-life of 1.8 to 3.4 years in individuals on ART for >10 years [70]. Additionally, some recent work proposes sex-specific differences in the size and composition of the latent viral reservoir [78,79] (sex-specific infection differences reviewed [80]). Despite the gradual loss of intact proviruses over time in treated people, the quantity of cellular clones with intact, replication-competent provirus, and sometimes extreme proliferation rates, challenges previous perceptions of the contribution of proliferating clones containing non-replicating HIV DNA.…”

Enhanced immunovirological response in women compared to men after antiretroviral therapy initiation during acute and early HIV‐1 infection: results from a longitudinal study in the French ANRS Primo cohort

“…Differences in the innate function of human plasmacytoid dendritic cells (pDCs) have been established, with pDCs from women exhibiting enhanced TLR7‐mediated IFN‐α production than pDCs from men [4]. Moreover, both oestrogen and progesterone have been reported to modulate pDCs IFN‐α secretion (reviewed by [5,6]).…”

“…Women have shown a lower risk of both mortality and AIDS‐related mortality than men in a setting with free access to healthcare and reduced gender inequalities [8]. The effectiveness of antiretroviral therapy (ART) in terms of CD4 + T‐cell recovery and viral suppression appears to be generally comparable across sexes in chronic infection [6,9]. Nevertheless, research on acute and early HIV infection (hereafter referred to as AHI (acute and early HIV‐1 infection)) tends to be preferentially carried out on men who have sex with men [10], and few studies have assessed sex‐related disparities in treatment outcomes when ART was initiated during AHI.…”

“…A previous study reported similar rates of virological suppression and CD4 + T‐cell gains between men and women [11]. Finally, recent reviews have highlighted the lack of data on sex‐related differences in the establishment and size of the viral reservoir [6,12]. Previous studies have described lower total HIV DNA in women than in men in the first months after infection [13] and under long‐term suppressive ART [14‐16] but no study has assessed it longitudinally.…”