Targeting early infection to prevent HIV-1 mucosal transmission.

Targeting early infection to prevent HIV-1 mucosal transmission.

Measures to prevent sexual mucosal transmission of human immunodeficiency virus (HIV)-1 are urgently needed to curb the growth of the acquired immunodeficiency syndrome (AIDS) pandemic and ultimately bring it to an end. Studies in animal models and acute HIV-1 infection reviewed here reveal potential viral vulnerabilities at the mucosal portal of entry in the earliest stages of infection that might be most effectively targeted by vaccines and microbicides, thereby preventing acquisition and averting systemic infection, CD4 T-cell depletion and pathologies that otherwise rapidly ensue.

Sexual mucosal transmission of HIV is the most common mode of acquisition. This excellent review of what we know now about the events from mucosal exposure to established systemic infection sets out the clear challenges before us and describes the window of opportunity that the earliest stage of infection presents. With vaginal transmission probabilities estimated at 1 in 100 to 1 in 1000, HIV can have a difficult time getting a toehold. Although people with HIV infection generally have several genetically distinct HIV viruses, surprisingly, due to what is called a ‘genetic bottleneck’, only one virus or infected cell initiates productive infection in almost 80% of people who become infected, with the remaining 20% becoming infected with two to five viruses. After exposure, prevention has to start by stopping the establishment of this small founder population in the first week of infection, taking advantage of its vulnerability to reduce its basic reproductive rate below 1. There are only a few days before dissemination and establishment of systemic infection in the second week with massive depletion of memory CD4 T cells in the gut and immune activation providing a new supply of target cells for HIV. Understanding what happens in early infection may not only help explain why male circumcision partially protects heterosexual men and how modest protection occurred in the Thai RV144 vaccine trial, it will lead to the design of targeted biomedical strategies that prevent establishment of HIV infection when HIV exposure occurs at mucosal surfaces.