Abstract
HIV/CMV co-infected persons despite prolonged viral suppression often experience persistent immune activation, have an increased frequency of myeloid derived suppressor cells (MDSC) and are at increased risk for cardiovascular disease. We examined how HIV MDSC control CD4+ T cell IFNγ response to a CMVpp65 peptide pool (CMVpp65). We show that HIV/CMV co-infected persons with virologic suppression and recovered CD4+ T cells compared to HIV(−)/CMV(+) controls exhibit an increase in CD4+CX3CR1+IFNγ+ cells in response to CMVpp65; MDSC depletion further augmented CD4+CX3CR1+IFNγ+ cells and IFNγ production. IL-2 and IFNγ in response to CMVpp65 were enhanced with depletion of MDSC expanded in presence of HIV (HIV MDSC), but decreased with culture of HIV MDSC with autologous PBMCs. CMVpp65 specific CD4+CX3CR1+IFNγ+ cells were also decreased in presence of HIV MDSC. HIV MDSC overexpressed B7-H4 and silencing B7-H4 increased the production of IL-2 and IFNγ from autologous cells; a process mediated through increased phosphorylated (p)-Akt upon stimulation with CMVpp65. Additionally, IL-27 regulated the expression of B7-H4 on HIV MDSC, and controlled CMV-specific T cell activity by limiting CMVpp65-IFNγ production and expanding CD4+IL-10+ regulatory T cells. These findings provide new therapeutic targets to control the chronic immune activation and endothelial cell inflammation observed in HIV-infected persons.
Highlights
IL-27 is an immune regulatory cytokine belonging to the IL-12 family that is predominantly produced by antigen presenting cells (APC)
myeloid derived suppressor cells (MDSC) expanded in the presence of HIV, control CMV specific T cell activation and excess IFNγproduction from CD4+CX3CR1+ cells; this is mediated through IL-27 and the inhibitory ligand B7-H4 expressed on HIV MDSC
CMV EOD has been greatly reduced in the ART era, CMV is still implicated in persistent immune activation and increased risk of CVD in persons with sustained HIV suppression[10,31]
Summary
IL-27 is an immune regulatory cytokine belonging to the IL-12 family that is predominantly produced by antigen presenting cells (APC). Subsequent studies have established that IL-27 and IL-27 signaling exert a suppressive effect on CD4+ T cells and limit immune-mediated pathology associated with various pathological conditions[19,20,21]. HIV-infected individuals when compared to uninfected controls demonstrate low plasma IL-27 levels[22], down-regulated expression of IL-27R and suppressed production of cytokines in response to IL-2723. We show that HIV/CMV co-infected individuals with undetectable plasma HIV RNA and recovered CD4+ T cells as compared to HIV-uninfected CMV(+) controls have increased numbers of CMVpp65-specific IFNγproducing activated CD4+CX3CR1+ cells and this further increases with the depletion of MDSC. We further show that IL-27 regulates IFNγand IL-10 production from T cells in response to CMV and induces B7-H4 expression on HIV associated MDSC
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