Th17 Cells Are Preferentially Infected Very Early after Vaginal Transmission of SIV in Macaques

Abstract

Summary The difficulty in detecting rare infected cells immediately after mucosal HIV transmission has hindered our understanding of the initial cells targeted by the virus. Working with the macaque-simian immunodeficiency virus (SIV) vaginal challenge model, we developed methodology to identify discrete foci of SIV (mac239) infection 48 hours after vaginal inoculation. We find infectious foci throughout the reproductive tract, from labia to ovary. Phenotyping infected cells reveals that SIV has a significant bias for infection of CCR6+ CD4+ T cells. SIV infected cells expressed the transcriptional regulator RORγt confirming that the initial target cells are specifically of the Th17 lineage. Furthermore, we detect host responses to infection, as evidenced by apoptosis, cell lysis, and phagocytosis of infected cells. Thus, our analysis identifies Th17 lineage CCR6+ CD4+ T cells as primary targets of SIV during vaginal transmission. This opens new opportunities for interventions to protect these cells and prevent HIV transmission.

HIV-1 selectively targets gut-homing CCR6+CD4+ T cells via mTOR-dependent mechanisms

“…These two reports (86,87) further support the conclusions of our current study, which reveals the key role played by mTOR in regulating multiple postentry and postintegration HIV replication steps in gut-homing Th17-polarized CCR6 + T cells. In conclusion, our findings point to CCR6 as a "zip code" molecule expressed on the surface of CD4 + T cells transcriptionally programmed to become HIV targets upon recruitment into the intestine and provide a detailed molecular explanation for preferential HIV/SIV replication and persistence in gut-homing CCR6 + CD4 + T cells (24,25,37,42). Most significantly, we reveal the role of the mTOR pathway in regulating effector functions as well as HIV permissiveness in gut-homing CCR6 + Th17 cells at multiple postentry levels.…”

“…The role of ATRA in regulating tolerance and immunity via the modulation of regulatory and effector functions of CD4 + T cells, respectively, is well established (41) Considering the strategic location of Th17 cells at portal sites of HIV/SIV entry (6,24,27,28,63), as well as their important role in maintaining mucosal immunity homeostasis in the context of a complex microbiota (6,64,65), our results point to the potential beneficial use of mTOR inhibitors in preventing HIV infection/ persistence in gut-homing Th17 cells.…”

“…Most recently, CD4 + T cells expressing the Th17 markers CCR6 and RORγt were identified as the first targets of SIV during vaginal transmission (24); in addition, the detrimental role of viral permissive CCR6 + T cell infiltration into the gut was documented (25). The depletion of Th17 cells from the GALT upon HIV infection persists despite viral-suppressive ART (26)(27)(28), even when ART is intensified with integrase and CCR5 inhibitors (29).…”

Identifying species of symbiont bacteria from the human gut that, alone, can induce intestinal Th17 cells in mice

“…Mice devoid of IL-17 signaling manifest alterations in their microbiotas and suffer from increased intestinal permeability and bacterial translocation to systemic sites after infectious insults of the gut (15,16,53). Additionally, loss of Th17 populations during infections by either simian virus or HIV has been associated with intestinal dysbiosis, systemic microbial translocation, and disease progression (53)(54)(55). Moreover, SFB confers heterologous protection from the murine enteropathogen C. rodentium (10).…”

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

“…T H 17 cells appear to be important in the control of opportunistic infections in HIV subjects and appear to be the T cell subset predominately infected by HIV [36]. In HIV-infected individuals, CCR6 + T cells harboured more viral DNA than CCR6 À T cells [35].…”