Peripheral blood CCR4⁺CCR6⁺ and CXCR3 ⁺CCR6⁺ CD4⁺ T cells are highly permissive to HIV-1 infection

There is limited knowledge on the identity of primary CD4⁺ T cell subsets selectively targeted by HIV-1 in vivo. In this study, we established a link between HIV permissiveness, phenotype/homing potential, and lineage commitment in primary CD4⁺ T cells. CCR4⁺CCR6 ⁺, CCR4⁺CCR6^-, CXCR3⁺CCR6 ⁺, and CXCR3⁺CCR6^- T cells expressed cytokines and transcription factors specific for Th17, Th2, Th1Th17, and Th1 lineages, respectively. CCR4⁺CCR6⁺ and CXCR3⁺CCR6 ⁺ T cells expressed the HIV coreceptors CCR5 and CXCR4 and were permissive to R5 and X4 HIV replication. CCR4⁺CCR6^- T cells expressed CXCR4 but not CCR5 and were permissive to X4 HIV only. CXCR3⁺CCR6^- T cells expressed CCR5 and CXCR4 but were relatively resistant to R5 and X4 HIV in vitro. Total CCR6⁺ T cells compared with CCR6^- T cells harbored higher levels of integrated HIV DNA in treatment-naive HIV-infected subjects. The frequency of total CCR6 ⁺ T cells and those of CCR4⁺CCR6⁺ and CXCR3⁺CCR6⁺ T cells were diminished in chronically infected HIV-positive subjects, despite viral-suppressive therapy. A high-throughput analysis of cytokine profiles identified CXCR3 ⁺CCR6⁺ T cells as a major source of TNF-α and CCL20 and demonstrated a decreased TNF-α/IL-10 ratio in CXCR3 ⁺CCR6^- T cells. Finally, CCR4⁺CCR6⁺ and CXCR3⁺CCR6⁺ T cells exhibited gut- and lymph node-homing potential. Thus, we identified CCR4⁺CCR6⁺ and CXCR3⁺CCR6⁺ T cells as highly permissive to HIV replication, with potential to infiltrate and recruit more CCR6⁺ T cells into anatomic sites of viral replication. It is necessary that new therapeutic strategies against HIV interfere with viral replication/persistence in discrete CCR6⁺ T cell subsets.