Identification of preferential CD4+ T-cell targets for HIV infection in the cervix

Abstract

A better understanding of the cellular targets of HIV infection in the female genital tract may inform HIV prevention efforts. Proposed correlates of cellular susceptibility include the HIV co-receptor CCR5, peripheral homing integrins, and immune activation. We used a CCR5-tropic pseudovirus to quantify HIV entry into unstimulated endocervical CD4+ T cells collected by cytobrush. Virus entry was threefold higher into cervix-derived CD4+ T cells than blood, but was strongly correlated between these two compartments. Cervix-derived CD4+ T cells expressing CD69, α 4 β 7, or α 4 β 1 were preferential HIV targets; this enhanced susceptibility was strongly correlated with increased CCR5 expression in α 4 β 7+ and CD69+ CD4+ T cells, and to a lesser extent in α 4 β 1+ CD4+ T cells. Direct binding of gp140 to integrins was not observed, integrin inhibitors had no effect on virus entry, and pseudotypes with an env that preferentially binds α 4 β 7 still demonstrated enhanced entry into α 4 β 1+ cells. In summary, a rapid and sensitive HIV entry assay demonstrated enhanced susceptibility of activated endocervical CD4+ T cells, and those expressing α 4 β 7 or α 4 β 1. This may relate to increased CCR5 expression by these cell subsets, but did not appear to be due to direct interaction of α 4 β 7 or α 4 β 1 with HIV envelope.