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

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, alpha(4)beta(7), or alpha(4)beta(1) were preferential HIV targets; this enhanced susceptibility was strongly correlated with increased CCR5 expression in alpha(4)beta(+)(7) and CD69(+) CD4(+) T cells, and to a lesser extent in alpha(4)beta(+)(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 a4b7 still demonstrated enhanced entry into alpha(4)beta(+)(1) cells. In summary, a rapid and sensitive HIV entry assay demonstrated enhanced susceptibility of activated endocervical CD4(+) T cells, and those expressing alpha(4 beta 7) or alpha(4 beta 1). This may relate to increased CCR5 expression by these cell subsets, but did not appear to be due to direct interaction of alpha 4 beta(7) or alpha 4 beta(1) with HIV envelope.