Peripheral Blood CCR4+CCR6+ and CXCR3+CCR6+ CD4+ T Cells Are Highly Permissive to HIV-1 Infection

Abstract

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.

CCR5/CD4/CXCR4 oligomerization prevents HIV-1 gp120IIIBbinding to the cell surface

“…This discrepancy is probably due to differences in the cell types analyzed. We determined viral infection by using the entire population of CCR5-transfected CD4 + primary T or Jurkat CD4 + cells (40% transfection efficiency), whose expression of CCR5 resembled that of activated primary T cells and Th1 cells (54,55), whereas our analysis of the mechanism involving actin polymerization was restricted to CCR5 + cells. Our data concur with a report that, in NIH 3T3 cells coexpressing CD4, CXCR4, and CCR5, the T-tropic HIV-1 isolate HCF was less infective than in CCR5-negative cells (56); another study showed lower infectivity of primary X4 viruses (ELI 1 and K4) in HeLa-CD4 cells when CCR5 was coexpressed (57).…”

CCR6/CCL20 chemokine axis in human immunodeficiency virus immunity and pathogenesis

“…The X4 HIV strain infected mainly T H 1T H 17, T H 17 and, to a lesser degree, T H 2 cells. Because a similar surface expression of CXCR4 was observed on all four cell types, this suggests that there are additional post-entry mechanisms that permit viral replication [35]. Similarly, CCR5 expression on T cell subsets correlated poorly with levels of integration of the R5 HIV strain.…”

“…In HIV-infected individuals, CCR6 + T cells harboured more viral DNA than CCR6 À T cells [35]. The X4 HIV strain infected mainly T H 1T H 17, T H 17 and, to a lesser degree, T H 2 cells.…”

“…T H 17 cells are specialized CD4 + T cells characterized by the master transcription factor RORgt/RORC2 and the chemokine receptor CCR6 [34]. Because of their CCR6/CCL20 profile, T H 17 cells are attracted to key immunological sites in HIV infection, such as the gut and lymph nodes (LNs) [35].…”

“…In treatment-naive patients, some researchers established that peripheral T H 17 cells, contrary to the gastrointestinal tract, are not reduced [35,42,44], whereas others confirm a reduction in these cells [45][46][47]. Antiretroviral therapy (ART)-treated patients have lower peripheral blood T H 17 cells than untreated patients [35,44,48].…”