OA17.03
Background: A better understanding of the cellular targets of HIV in the female genital tract may inform the development of HIV vaccines and microbicides. Proposed correlates of cellular susceptibility include expression of the HIV co-receptor CCR5, mucosal homing integrins, and/or CD69, a marker of early immune activation.
Methods: We used a CCR5-tropic HIV pseudovirus to quantify HIV entry into unstimulated cervical CD4 T cell subsets in a rapid, flow cytometry-based assay. We also assessed the metabolic state of cervical cell subsets based on Ki67 expression, since proliferating cells are more susceptible to productive HIV infection.
Results: HIV entry into cervical T cells was CD4 and CCR5 dependent. Viral entry was approximately three-fold higher into cervical CD4 T cells compared to blood (p=0.0003), although within a given participant, virus entry was strongly correlated between the two compartments (r=0.748, p=0.0002), suggesting shared host determinants of HIV entry. Cervical CD4 T cells that expressed a4b7 (p=0.003), a4b1 (p=0.0002), or CD69 (p=0.0004) were approximately two-fold more susceptible to HIV entry; CCR5 expression was increased at least two-fold on a4b7+(p<0.0001) and CD69+(p<0.0001) CD4 T cells, but only 1.2 fold on a4b1+(p=0.0002) CD4 T cells. Cervical a4b7+CD4 T cells expressed two-fold higher levels of the proliferation marker Ki67 (p=0.003), which was not seen in CCR5+(p=0.95), CD69+(p=0.46) or a4b1+(p=0.24) CD4 T cells.
Conclusions: Preferential HIV entry into immunologically activated and a4b7+cervical CD4 T cells was probably due, at least in part, to increased CCR5 expression. Increased HIV entry into cervical a4b1+CD4 T cells did not correlate with CCR5 overexpression, and the mechanism of enhanced cell entry in this cell subset is unknown. Markers of metabolic activity and proliferation were specifically increased in cervical a4b7+CD4 T cells suggesting that this subset may be particularly suited to sustain productive HIV infection.
