HIV Pathogenesis in the Human Female Reproductive Tract

Abstract

Purpose of review: Women remain disproportionately affected by the HIV/AIDS pandemic. The primary mechanism for HIV acquisition in women is sexual transmission, yet the immunobiological factors that contribute to HIV susceptibility remain poorly characterized. Here, we review current knowledge on HIV pathogenesis in women, focusing on infection and immune responses in the female reproductive tract (FRT).

Recent findings: We describe recent findings on innate immune protection and HIV target cell distribution in the FRT. We also review multiple factors that modify susceptibility to infection, including sex hormones, microbiome, trauma, and how HIV risk changes during women's life cycle. Finally, we review current strategies for HIV prevention and identify barriers for research in HIV infection and pathogenesis in women. A complex network of interrelated biological and sociocultural factors contributes to HIV risk in women and impairs prevention and cure strategies. Understanding how HIV establishes infection in the FRT can provide clues to develop novel interventions to prevent HIV acquisition in women.

Keywords: Female reproductive tract; HIV; Immune; Pathogenesis; PrEP; Sex hormones; Women.

Figure 1.. HIV pathogenesis in the female reproductive tract (FRT).

A) Anatomy of the FRT. The FRT is divided into a lower tract (vagina and ectocervix), and an upper tract (endocervix, endometrium, Fallopian tubes and ovaries). The transformation zone is located between the endo and ectocervix, where the stratified epithelium characteristic of the lower tract transitions into a single layer columnar epithelium, which lines the upper tract. B) The immune system in healthy genital tissues is specialized in balancing protection from pathogens with facilitation of reproductive functions. Relevant for HIV pathogenesis, immune cells including T cells (CD8+ and CD4+ subsets), dendritic cells (DC), macrophages, neutrophils, NK cells and B cells are present throughout the FRT in healthy women. However, immune subsets and functions are regulated by anatomical location, tissue environment and hormones. The epithelium, coated with mucus, provides physical and immunological defense and maintains a Lactobacillus-dominated vaginal microbiome with anti-inflammatory and anti-HIV properties. AMP: Antimicrobial peptides. C) Recent updates in HIV pathogenesis. New studies confirm that HIV targets T cells that express CCR5 and CD69 throughout the tract [65, 66], but while Th17 cells are most susceptible in the lower tract, preferential targets in the EM are not Th17 [66]. HIV infection of endometrial T cells results in cell modifications that prolong cell survival (BIRC5) and facilitate dissemination (CCR7) [66]. Resident CD4+ T cells expressing CD69 in the cervix serve as cellular reservoirs for HIV [65]. CD14+ DCs preferentially capture HIV throughout the tract [130, 129] and at least in the cervix, they co-express Siglec-1 [134]. New DC subsets that support HIV replication have been identified in the vagina (CD1a+ DCs and CD11c+ epidermal DCs) [132, 135]. Neutrophils throughout the tract release NETs to trap and inactivate HIV, preventing infection of target cells [138]. Innate CD1c+ B cells that naturally bind gp120 are reduced in HIV-exposed uninfected women, suggesting an important role in natural HIV protection [152]. Microbiome dysbiosis is linked to genital inflammation and HIV acquisition risk [171]. Microbiome alterations modify mucus properties [184] and increase metalloproteinases (MMP) presence [185], facilitating HIV access to target cells. Presence of Gardnerella in the vaginal microbiome has been linked to reduced efficacy of topical microbicides [168, 226].