Preventing mucosal HIV transmission with topical microbicides: challenges and opportunities

Abstract

A combination of prevention and treatment modalities will be needed to successfully control the global spread of HIV. Microbicides, drug products topically applied to mucosal surfaces to prevent HIV infection, are one of these biomedical interventions that hold great promise. In order to be efficacious, microbicides must overcome several challenges imposed by the mucosal microenvironment they intend to protect and the mischievous human immunodeficiency virus with its enormous capacity to adapt. Recent data, however, supports the establishment of the primo-infection by only a small number of founder viruses, which are highly vulnerable to microbicidal intervention at the initial stages of mucosal invasion. The biological foundation of these challenges and opportunities in microbicide development is explored in this review. This article forms part of a special supplement on presentations covering HIV transmission and microbicides, based on the symposium "Trends in Microbicide Formulations", held on 25 and 26 January 2010, Arlington, VA.

Keywords: HIV mucosal infection; HIV prevention; HIV transmission; Microbicides; sexually transmitted infections.

Figure 1. Sexual transmission of HIV-1 and topical microbicide targets

Cell-free and cell-associated HIV-1 penetrate the cervicovaginal epithelium through microabrasions and/or intact tissue. They quickly reach Langerhans cells (LC) and intraepithelial CD4+ T lymphocytes (IEL) within the epithelium or dendritic cells (DC) and resting CD4+ T cells in the lamina propria. CD4+ T cells are activated by direct contact with antigen-presenting (AP) LC or DC, or indirectly through cytokine secretion by epithelial and other immune cells. This happens focally at the port(s) of entry. Pre-existing inflammation and chemokine-mediated recruitment of new cells expand the number of activated CD4+ T cells, which fuel the initial infection by a small number of founder viruses. Dissemination of infected T cells, DC, LC and APC/T cell complexes from the initial cervicovaginal infection foci to the draining lymph nodes or directly into systemic circulation leads to an established infection. Microbicide formulations must deliver their active ingredient to all these cells and places if they want to prevent the irrevocable step of systemic dissemination. Modified from Hladik and Hope, 2009, and reproduced with permission.