CD38 mean fluorescence intensity (MFI) increased not only in CD14+ monocytes that became infected but also in monocytes in the same cultures that remained uninfected (Supporting Information Fig. selleck kinase inhibitor 4). These results indicate that exposure to HIV-1 is sufficient to cause upregulation of CD38 in peripheral blood monocytes in vitro and, taken together

with the observed effects of depleting HIV-specific IL-10+ CD8+ T cells, suggest that the latter could protect monocytes from activation by HIV-1 in vivo. Finally, we investigated whether the effects of HIV-specific IL-10+ CD8+ T cells on monocyte CD38 expression were IL-10-dependent. Treatment of CD8-depleted PBMCs with an IL-10 receptor (IL-10R) blocking antibody prior to co-culture overnight with CD8+ T cells led to a marginal

increase in monocyte CD38 expression, when compared with the effect of depleting HIV-specific IL-10+ CD8+ T cells. This could reflect incomplete receptor blockade on monocytes; alternatively, it could indicate RAD001 ic50 that this population may not mediate its effects solely through IL-10 production (Supporting Information Fig. 5). In this study, we have shown that a distinct subpopulation of HIV-specific CD8+ T cells contributes substantially to IL-10 production by PBMCs in chronic uncontrolled HIV-1 infection. The magnitude of this population was positively correlated with the magnitude of the IFN-γ response to the same HIV-1 antigens and the majority of the CD8+ T-cell subset co-produced IL-10 and IFN-γ upon short-term HIV-1 gag stimulation. However, a shift towards lone IL-10 production was associated with better virological control. Together, these observations suggest that a subset of HIV-1 gag-specific IFN-γ-secreting CD8+ T cells may have acquired the capacity to produce IL-10 in response to chronic viral replication, possibly as Adenosine a protective response to inflammation in the context

of ongoing antigenic stimulation. Their virtual absence in patients treated with an effective ART regimen is consistent with this notion, although this remains to be confirmed in a longitudinal study. Furthermore, their lack of a conventional Treg-cell phenotype contrasted with CMV-specific IL-10+ CD8+ T cells that were detected in some co-infected individuals and suggests that these populations have distinct ontogenies. Co-expression of IL-10 and IFN-γ by tissue-homing virus-specific T cells has been extensively reported in murine viral infection models and in human CD4+ T cells [11, 19, 25-28]. By contrast, human virus-specific CD8+ T-cell populations with dual IL-10-/IFN-γ-secreting capacity appear to be rare: to our knowledge, the only precedent for this is in Epstein-Barr virus (EBV) infected solid organ transplant recipients, in whom CD8+ Treg type 1 cells expressing FoxP3 could be induced in vitro by type-1-polarising DCs [11].