The female reproductive tract is one of the most common sites of initial HIV transmission yet we lack a detailed understanding of the cells that are most susceptible to infection. One challenge involves the extensive remodeling of host cells by HIV, rendering it difficult to classify infected cells into traditional T cell subsets.
We exposed specimens of endometrial biopsies and PBMCs from the same donors to a CCR5-tropic transmitted/founder HIV-1 reporter virus, and conducted an extensive phenotypic analysis of uninfected and infected cells using CyTOF. Using bioinformatics analyses of the resultant high-dimensional single-cell datasets, we were able to characterize the subsets of cells that were most susceptible to HIV infection independent of remodeling.
Memory CD4+ T cells were almost exclusively targeted for infection in both the tissue and blood specimens, but those from the endometrium were significantly more susceptible (p<0.01). While a diverse array of endometrial memory CD4+ T cells were targeted for infection, only a small subset of the unstimulated PBMC-derived CD4+ T cells could be infected. In-depth analyses of the features of the endometrial memory CD4+ cells targeted for infection revealed preferential infection of T effector memory (Tem) cells polarized towards the Th1 and Th2 lineages, as well as preferential infection of T resident memory (Trm) and T follicular helper (Tfh) cells. Upon infection, HIV interfered with the TCR signaling apparatus by downregulating CD4, CD45RO, CD28, and ICOS, and upregulated BIRC5 promoting survival of infected cells. Infection also upregulated the chemokine receptors CCR7 and CXCR5 and the tissue retention receptor CD69 while downregulating expression of the CD49d integrin.
These data suggest that unique phenotypic features of memory CD4+ T cells in the genital tract renders these cells highly susceptible to infection by HIV-1, and that upon infection the virus remodels the cell in a manner than undermines TCR signaling while promoting survival and enhancing migration to other lymphoid sites via modulation of homing receptor expression.