The Microbiological Context of HIV Resistance: Vaginal Microbiota and Mucosal Inflammation at the Viral Point of Entry

Abstract

Immune activation is increasingly recognized as a critical element of HIV infection and pathogenesis, causing expansion of virus founder populations at the mucosal port of entry and eventual exhaustion of cellular immune effectors. HIV susceptibility is well known to be influenced by concurrent sexually transmitted infections; however, the role of commensal vaginal microbiota is poorly characterized. Bacterial vaginosis (BV) is a risk factor for HIV acquisition in studies worldwide; however, the etiology of BV remains enigmatic, and the mechanisms by which BV increases HIV susceptibility are not fully defined. A model of how vaginal microbiota influences HIV transmission is considered in the context of a well-established cohort of HIV-exposed seronegative (HESN) commercial sex workers (CSW) in Nairobi, Kenya, many of whom have increased levels of anti-inflammatory factors in vaginal secretions and reduced peripheral immune activation (immune quiescence). Elucidation of the relationship between complex microbial communities and inflammatory mucosal responses underlying HIV infection should be a priority for future prevention-focussed research.

Figure 1

Mechanisms of vaginal HIV transmission. (a) Overview of the major anatomical features of the female genital tract (FGT). (b) Overview of hypothetical mechanisms of HIV transmission in the female genital tract. See text for details.

Figure 2

A mucosal catastrophe. Overview of the “fast phase” of HIV infection in the days following infection, including the eclipse phase (a), the viral broadcast phase (b), peak viremia (c), and subsequent chronic immune activation (d). See text for details.

Figure 3

The microbiological context of HIV resistance. Vaginal microbiology influences susceptibility of the mucosal layer to HIV infection in multiple interrelated ways, including (1) direct effects on viral particles or infected allogenic cells via binding, mannose scavenging, or bacterial metabolites (acid, H₂O₂), (2) alteration of quantity/viscosity/permeability of mucin network in mucus layer via proteases, (3) stimulation of innate mucosal defence molecules and cells via TLR stimulation, and (4) modulation of T-cell activation and susceptibility via conditioning by TLR-stimulated dendritic cells, macrophages, or epithelial cells.