Differences in immune activation have been identified as the most significant difference between AIDS-susceptible and resistant species. p38 MAPK, activated in HIV and SIV infection, is key to induction of Interferon-stimulated genes (ISG) and cytokine-mediated inflammation and is associated with some of the pathology produced by HIV and SIV infection in AIDS susceptible primates. As small molecule p38 MAPK inhibitors are currently tested in human trials for other inflammatory diseases, we evaluated the effects of treating SIV-infected macaques with a p38 inhibitor in conjunction with ART.
Rhesus macaques were infected with SIVmac251 and after 6 weeks ART and p38 MAPK inhibitor treatment with compound PH-797804 was initiated in one group of animals. Additional groups included ART treatement alone, p38 inhibitor alone, and naive controls. As primary end points we evaluated differences in expression of surface and intracellular molecules linked to immune activation and intracellualr inflammatory cytokine expression in cell subpopulations of blood, lymph node and intestinal tissue, and plasma levels of inflammatory cytokines. As secondary end points, we evaluated the effects that treatments had on viral loads, preservation of central memory CD4+ T cells and anti-SIV immune responses. We also evaluate the treatment impact on protein levels of selected ISG.
ART reduced viremia to 70-80 copies /ml. The p38 inhibitor did not further reduced the viremia, did not affect negatively anti-SIV immune responses and had no side effects. The p38 inhibitor treatment by itself had no significant effect on immune activation. When combined with ART, numerous immune activation markers were significantly reduced compared to the ART alone group. CD38/HLA-DR an Ki67 percentages in blood, lymph node and rectal CD4+ and CD8+ T cells and percentages of IL-6, IL-8, IFN-g and IFN-a producing cells were all significantly reduced. IRF7, pSTAT1 and IP-10 protein accumulation was also reduced in APC. Significant preservation of CD4+/IL22+ and CD4+/IL-17+ T-cells in PBMC, rectal and lymph node mononuclear cells and of central memory CD4+ T cells in blood was also observed in the ART+p38 inhibitor group compared to the ART group.
The p38 MAPK inhibitor used in this studies, already in clinical trials for other inflammatory diseases, significantly reduced immune activation during ART treatment and could be a desirable addition to antiretroviral therapy.