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-alpha and CCL20 and demonstrated a decreased TNF-alpha/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.
Gosselin
Annie
A
Department of Microbiology and Immunology, Université de Montréal, Montreal, Quebec, Canada.
Monteiro
Patricia
P
Chomont
Nicolas
N
Diaz-Griffero
Felipe
F
Said
Elias A
EA
Fonseca
Simone
S
Wacleche
Vanessa
V
El-Far
Mohamed
M
Boulassel
Mohamed-Rachid
MR
Routy
Jean-Pierre
JP
Sekaly
Rafick-Pierre
RP
Ancuta
Petronela
P
D044966:Anti-Retroviral Agents / Q000627:therapeutic use; D018791:CD4 Lymphocyte Count; D004198:Disease Susceptibility / Q000276:immunology; D015658:HIV Infections / Q000188:drug therapy / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D007113:Immunity, Innate; D016130:Immunophenotyping; D020381:Interleukin-17 / Q000096:biosynthesis; D054398:Receptors, CCR4 / Q000097:blood*; D054399:Receptors, CCR6 / Q000097:blood*; D054367:Receptors, CXCR3 / Q000097:blood*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology* / Q000821:virology*; D018417:Th1 Cells / Q000276:immunology / Q000821:virology; D018418:Th2 Cells / Q000276:immunology / Q000821:virology; D014779:Virus Replication / Q000187:drug effects / Q000276:immunology
D044966:Anti-Retroviral Agents; C515354:CCR4 protein, human; C106311:CCR6 protein, human; C515187:CXCR3 protein, human; C508717:IL17A protein, human; D020381:Interleukin-17; D054398:Receptors, CCR4; D054399:Receptors, CCR6; D054367:Receptors, CXCR3