Background: The average probability of acquiring HIV during a single unprotected sex act is surprisingly low, but tremendous heterogeneity contributes to the ongoing pandemic. Common mucosal co-infections, including Herpes simplex type 2 (HSV-2) and bacterial vaginosis, may increase HIV susceptibility. Analogous heterogeneity in HIV disease progression and secondary transmission has been described as a "numbers game," with the important predictive number being the HIV viral load in the blood and genital secretions, respectively. Work from our group suggests that heterogeneity in susceptibility may also be predictable, with the number of HIV target cells in the genital mucosa being the important determinant of outcome after unprotected HIV exposure.

Methods: Studies enrolled HIV at-risk and infected participants from Canada and Kenya, and examined the associations of common genital co-infections with alterations in mucosal immunity and HIV transmission. Laboratory parameters studied have included co-infection diagnostics, cytokine /chemokine levels, immune gene expression levels, and flow cytometry-based elucidation of immune cell populations.

Results: HIV acquisition was strongly associated with prevalent HSV-2 infection and "classical" sexually transmitted infections. All co-infections were associated with significant increases in cervical HIV target cells, including activated CD4⁺ T cells and DC-SIGN⁺ dendritic cells. Alterations in vaginal flora—both bacterial vaginosis and intermediate flora—had similar effects in HIV-susceptible women, and in HIV-infected women were associated with reversible increases in HIV shedding and alterations in mucosal immune cell populations.

Conclusions: We conclude that a variety of genital co-infections appears to enhance HIV susceptibility (and secondary transmission), and a common pathway for this effect—as well as for potential increases in HIV susceptibility associated with candidate vaginal microbicides—may be the local recruitment of activated mucosal immune cells. HSV-2 infection and alterations in vaginal flora, due to their high population prevalence and chronic persistence, may be particularly important drivers of HIV transmission.