SRA

The development of biomarkers that can predict viral rebound following discontinuation of antiretroviral therapy (ART) in HIV-1-infected humans would be an important advance in HIV-1 cure research. In a prior study, we initiated ART in 20 rhesus macaques on days 0, 1, 2, and 3 following SIVmac251 infection prior to plasma viremia1. Following 6 months of suppressive ART, we discontinued ART and observed viral rebound in 9 of 20 animals. Here we show that transcriptomic and proteomic signatures of inflammation and immune activation in peripheral blood during ART suppression predicted viral rebound following ART discontinuation. Higher levels of proinflammatory and cellular immune activation pathways, including TNF, IL-1, IL-6, monocyte, and T cell activation signaling pathways, correlated with viral rebound following ART discontinuation. Immune modulatory IL-10 and TGF-b signaling also correlated with viral rebound. We then validated these candidate biomarkers of viral rebound in a second cohort of SIV-infected, ART-suppressed macaques. Taken together, these data suggest that persistent upregulation of inflammatory and immune activation pathways despite suppressive ART may represent a peripheral blood biomarker signature of the rebound-competent viral reservoir. The development of interventions that target the viral reservoir and modulate this signature may open new avenues in HIV-1 cure research. Overall design: We evaluated transcriptomic and proteomic features in peripheral blood and lymph nodes prior to ART discontinuation to identify potential biomarkers that predicted rebound viremia following ART discontinuation. We performed transcriptomic profiling in this cohort of 20 macaques at week 24 of ART suppression and showed that signatures in macaques that subsequently exhibited viral rebound following ART discontinuation (9 macaques) were different than signatures in macaques that did not rebound (11 macaques).