The CNS is a major HIV sanctuary estab lished during the early phases of infection. Recruit ment of Th1Th17 cells into the brain via CCR6, MCAM, and CCR2 Brefeldin A protein transport may significantly contribute to fueling HIV per sistence. CEACAM1 expression is induced by activation and plays a critical role in the regulation of B cell function at intestinal level. The functional role of CEACAM1 Th1Th17 cells in gut associated lymphoid tissues, a major anatomic site for HIV replication, remains to be determined. CXCR6 is co expressed with CCR5 on activated T cells and acts as a minor HIV coreceptor. CXCR6 is also involved in the for mation of the immunological synapse upon interaction with its ligand CXCL16, a membrane bound chemokine expressed by DC. This interaction my lead to effi cient transmission of HIV within the virological synapse.

CXCL16 is also expressed by CD16 monocytes. The pro inflammatory CD16 monocytes are expanded Inhibitors,Modulators,Libraries in HIV Inhibitors,Modulators,Libraries infected subjects, carry integrated HIV DNA in vivo and exhibit the ability to promote viral replica tion in CD4 T cells in vitro. Thus, the interaction of Th1Th17 cells with DC or CD16 monocytes via CXCR6 CXCL16 may contribute significantly to cell to cell transmission of HIV in vivo. Consistent with this prediction, the CXCR6 polymorphism was associated with slow disease progression in HIV infected people. The fact that Th1Th17 cells express receptors regulating both HIV entry and migration into anatomic sites of viral replication place these cells in the first line of HIV targets and provides an explanation for their depletion in HIV infected subjects, including subjects under viral suppressive ART.

The autocrine production of CCR5 binding chemokines protects CD4 T cells from HIV infection. Our microarray studies did not reveal differences Inhibitors,Modulators,Libraries between Th1Th17 and Th1 cells in the expression of these tran scripts, consistent with our previous results. However, the upregulation in Th1 vs. Th1Th17 cells of the PTK2 FAK, a kinase whose activation is linked to CCR5 triggering, suggests that CCR5 binding chemokines act on Th1 cells and may limit this way HIV entry. This scenario is consistent with the finding that differences in HIV DNA integration were marginally significant when cells where exposed to a single round VSV G pseudotyped HIV. Nevertheless, levels of GFP expression, indicative of HIV transcription, were higher in Th1Th17 vs.

Th1 cells suggesting that regulatory mechanisms at both entry and post entry levels control HIV permissiveness in Th1Th17 vs. Th1 cells. Of particular Inhibitors,Modulators,Libraries interest, Th1 cells expressed transcripts corresponding to KLRK1NKG2D, an activating receptor typically expressed on cytotoxic Inhibitors,Modulators,Libraries NK cells and CD8 selleck chemicals Calcitriol T cells. The acquisition of cytotoxic antiviral function was previously reported for CMV specific cells, which exhibit indeed a Th1 polarization profile and are protected from infection.