Mucosa: Key Interactions Determining Sexual Transmission of the HIV Infection

Abstract

In the context of HIV sexual transmission at the genital mucosa, initial interactions between the virus and the mucosal immunity determine the outcome of the exposure. Hence, these interactions have been deeply explored in attempts to undercover potential targets for developing preventative strategies. The knowledge gained has led to propose a hypothetical model for mucosal HIV transmission. Subsequent research studies on this topic further revealed new mechanisms and identified new host-HIV interactions. This review aims at integrating these findings to inform better and update the current model of HIV transmission. At the earliest stage of virus exposure, the epithelial integrity and the presence of antiviral factors are critical in preventing viral entry to the submucosa. However, the virus has been shown to enter to the submucosa in the presence of physical abrasion or via epithelial transmigration using paracellular passage or transcytosis mechanisms. The efficiency of these processes is greater with cell-associated viral inoculums and can be influenced by the presence of viral and immune factors, and by the structure of the exposed epithelium. Once the virus reaches the submucosa, dendritic cells and fibroblasts, as recently described, have been shown in vitro of being capable of facilitating the transfer of viral particles to susceptible cells, leading to viral dissemination, most likely in a trans-infection manner. The presence of activated CD4⁺ T cells in submucosa increases the probability of infection, where the predominant microbiota could be implicated through the modulation of an inflammatory microenvironment. Other factors such as genital fluids and hormones could also play an essential role in HIV transmission. Here, we review the most recent evidence described for mucosal HIV-transmission contributing with the understanding of this phenomenon.

Keywords: HIV exposure; HIV infection; HIV trans-infection; dendritic cells; mucosal immunity; mucosal transmission; vaginal microbiota.

Figure 1

During HIV transmission at female Reproductive Tract (FRT), the initial interactions that occur between the virus and the immune response determine whether the virus is eradicated or if the infection is established and disseminated. (1) At mucosal epithelium presence of genital fluids and antiviral factors such as Beta-defensins, cathelicidin, SLPI, and others, with potent inhibitory capacity against HIV can reduce the infectivity of viral particles; however, these factors may not be enough to avoid the entry of virions into the submucosal space. Viral particles can penetrate the epithelium through physical abrasions that occur during intercourse or by two different mechanisms in intact epithelium: (2) transcytosis; viral particles can bind extracellular receptors expressed on epithelial cells leading to internalization of virions into multivesicular compartments where they retain their infectiveness. After stimuli inducing reorganization of actin-cytoskeleton (e.g., pro-inflammatory cytokines TNF-a or IFN-y, the interaction of LFA-1 on intraepithelial lymphocytes and ICAM-1 on epithelial cells) the virions can be released to infect other susceptible cells. Further, (3) interaction of viral proteins and surface receptors on epithelial cells can induce activation of MCL-MCLK leads to the destabilization of zonula occludens proteins (ZO-1) with the subsequent internalization of occludin and claudins and thus, loss of tight junctions, allowing (4) paracellular passage. The use of one mechanism or another partially relies on the conformational structure of the exposed epithelium. Infected cells can also interact with epithelial cells or susceptible target cells, favoring cell-to cell transmission of the HIV at mucosa (5). Once at the submucosa, the virus can infect intraepithelial cells, or it can bind Langerhans cells or DCs; the first ones can internalize the virions bound to langerin and degrade them, at least in part by induction of autophagy mediated by intracellular Trim5a (6). The second ones can bind the viral particles through DC-SIGN in immature DCs (7) or Siglec-1 in mature DCs (8) once they downregulated DC-SIGN expression. Then, the viral particles are transferred to CD4+ T cells located at the lymphoid nodes, where the activation state of these cells is also crucial for infection. Other recently described cells transferring viral particles are the fibroblast, which are highly ubiquitous and seems to transfer the virus more efficiently than DCs. All these mechanisms have been described in female and male genital mucosa.