Memory CCR6+CD4+ T Cells Are Preferential Targets for Productive HIV Type 1 Infection Regardless of Their Expression of Integrin β7

Abstract

HIV type 1 infection is associated with a rapid depletion of Th17 cells from the GALT. The chemokine receptor CCR6 is a marker for Th17 lineage polarization and HIV permissiveness in memory CD4+ T cells. CCR6+ T cells have the potential to migrate into the GALT via the gut-homing integrin α4β7, a newly identified HIV-gp120 binding receptor. In this study, we investigated whether memory T cells coexpressing CCR6 and integrin β7 are selective HIV targets and whether retinoic acid (RA)-induced imprinting for gut-homing selectively increases CCR6+ T cell permissiveness to infection. We demonstrated that β7−R6+ and β7+R6+ compared with β7−R6− and β7+R6− T cells were highly permissive to HIV, produced Th17 cytokines, and their frequency was decreased in the peripheral blood of HIV-infected subjects. RA upregulated integrin α4 and β7 coexpression in both CCR6+ and CCR6− T cells, but increased HIV permissiveness selectively in CCR6+ T cells via entry (CCR5 upregulation) and postentry mechanisms. In conclusion, these results demonstrate that CCR6, but not the integrin β7, is a discriminative marker for memory T cells imprinted with a transcriptional program favorable to HIV replication. Nevertheless, given the ability of integrin β7 to regulate cell migration into the GALT and bind HIV-gp120, CCR6+ T cells coexpressing integrin β7 and CCR5 might have an extraordinary ability to disseminate HIV from the portal sites of entry. Understanding the molecular mechanisms of memory CCR6+ T cell differentiation is critical for the design of new therapeutic strategies that should interfere with viral permissiveness but not Th17 lineage commitment and gut-homing potential in CCR6+ T cells.

Role of Semen in Modulating the Female Genital Tract Microenvironment – Implications for HIV Transmission

“…CD4 + Th17 cells are among the earliest HIV/SIV preferential targets and play a crucial role in HIV pathogenesis. 86,[94][95][96][97] In contrast to the significant semen-induced increase in DCs and LCs in the female genital epithelium, no or modest increases in FRT CD4 + T cell density have been detected following semen exposure. 23,38 At the same time, due to CCL20, a small number of these highly susceptible to HIV-1 CD4 + Th 17 cells can infiltrate the mucosal epithelium or migrate to local lymph nodes.…”

“…CCL20 is the only chemokine ligand for the CCR6 receptor, expressed by subsets of DCs, particularly precursors of LCs, and memory T cells including CD4 + Th17 T cells. 74,86,87 LCs, present in cervicovaginal mucosa, are among the primary targets of HIV-1/SIV. 30,31,88,89 LCs are able to capture HIV-1 virions and transport them to the draining lymph nodes where the virions can be transmitted to T cells for productive infection, 27,[88][89][90] although there is some evidence to suggest viral particles captured by LCs are internalized and rendered incapable of infection.…”

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

“…Others have found that increased CCR5 surface expression could be correlated with the susceptibility of early differentiated IL-17 + CD4 T cells, leading the authors to postulate that this may be a possible mechanism for viral permissiveness [39]. One earlier study [40] used all-trans-retinoic acid (ATRA) (a compound that upregulates a4b7 integrin expression) to study the mechanisms of the preference of the R5-HIV strain to infect CCR6 + memory T cells over CCR6 À cells. Indeed, pseudotyped HIV that enter host cells independently of chemokine co-receptors showed a preference for infection of ATRA-treated CCR6 + cells (over untreated CCR6 + cells, and compared with treated and untreated CCR6 À/À cells), suggesting that the mechanism by which HIV is selective towards ATRA-treated CCR6 + cells is likely through post-entry mechanisms such as integration and transcription [40].…”

“…One earlier study [40] used all-trans-retinoic acid (ATRA) (a compound that upregulates a4b7 integrin expression) to study the mechanisms of the preference of the R5-HIV strain to infect CCR6 + memory T cells over CCR6 À cells. Indeed, pseudotyped HIV that enter host cells independently of chemokine co-receptors showed a preference for infection of ATRA-treated CCR6 + cells (over untreated CCR6 + cells, and compared with treated and untreated CCR6 À/À cells), suggesting that the mechanism by which HIV is selective towards ATRA-treated CCR6 + cells is likely through post-entry mechanisms such as integration and transcription [40]. Subtle molecular differences in T H 17 cells may also be responsible for their increased permissiveness to HIV infection with genome-wide transcriptional profiles of T H 17 versus T H 1 cells (as 'controls') revealing an increased expression of molecules responsible for promoting TCR signalling that are essential for HIV transmission (e.g.…”

HIV Without AIDS: The Immunological Secrets of Natural Hosts

“…To understand how natural hosts preserve Th17 cells and mucosal immunity might be central to the development of therapeutic interventions aimed at improving mucosal immunity in HIV-infected individuals. While the exact cause accounting for this phenotype is still unclear, several non-mutually exclusive mechanisms have been proposed, including the increased susceptibility to HIV/SIV infection of Th17 cells and its CD4+CCR6+ and CD4+CD161+ T cell precursors (Gosselin et al, 2010;Kader et al, 2009;Monteiro et al, 2011;Prendergast et al, 2010) and the defective generation of Th17 cells in nonnatural versus natural hosts. Very recent and unpublished observations suggest that loss of CD4+IL-21+ T cells and CD103+ dendritic cells, with reduced availability of IL-21 or retinoic acid, respectively, may significantly contribute to Th17 cell depletion in SIV-infected rhesus macaques (Cervasi B et al, CROI 2011;Klatt N et al, Keystone 2011).…”