Longitudinal study of sustainable acceleration of immunosenescence and immunoactivation dependent on SIV replication stress in SIVmac239-infected rhesus macaques

Abstract

It is challenging to trace the variations of host immune features covering the whole process of ‘baseline-infection-treatment-withdrawal’ from HIV-negative to HIV-rebound in HIV-infected patients after discontinuing antiretroviral therapy (ART). Herein, eight monkeys were monitored for 28 days to acquire baseline immune function; infected with 100 TCID50 of SIVmac239 intravenously for 98 days; treated with standard ART for 90 days; followed up for 49 days post withdrawal of ART. Within the 266 days’ longitudinal study, four SIV-dependent stages, SIV-negative (SN, ‘baseline’), SIV-emerged (SE, ‘infection’), SIV-suppressed (SS, ‘treatment’), and SIV-rebounded (SR, ‘withdrawal’), were stratified according to plasma viral RNA quantification. Parallel comparisons of host immune function, including counts of CD4+ T cells, ratios of T-cell subsets and measurement of a panel of cytokines, were performed between SS and SN, and between SR and SE. Compared to the SN stage, an accelerated immunosenescence was found in the SS stage characterized with increased CD38+ HLA-DR− CD4+/CD8+ T-cell subsets, PD-1+ memory CD4+/CD8+ T-cell subsets and elevated cytokines including MIP-1β, IL-8 and IL-10. Compared to the SE stage, the SR phase exhibited an accelerated immune activation against SIV characterized with increased PD-1+ CD4+ TCM cells, decreased PD-1+ CD4+ TEM cells and enhanced pro-inflammatory cytokine levels including TNF-α, IL-6, IL-1β and IFN-γ. This longitudinal study of rhesus macaques demonstrated a sustainable acceleration of immunosenescence/immunoactivation dependent on the stress of SIV replication which may provide insights for future HIV therapies.