Identifying correlates of viral rebound timing and viral control in SHIV-infected infant macaques after ART interruption

Evaluation of HIV cure strategies requires antiretroviral therapy (ART) interruption, but ethical and clinical considerations make this difficult in children. Here, we used a pediatric preclinical model of simian-HIV (SHIV) infection to uncover features associated with time to viral rebound (TTR) and posttreatment control (PTC) of rebound viremia after ART interruption to inform the design of studies testing cure interventions. We assessed 141 variables in SHIV-infected infant rhesus macaques in three staggered ART initiation groups and during subsequent analytical treatment interruption (ATI). Viral rebound occurred in 25 of 30 macaques within 7 to 98 days of ATI, with TTR delayed in the early ART group compared with the intermediate and late ART groups. Peak plasma viral load pre-ART was the most important correlate of TTR, with increased model performance through the successive inclusion of six additional viral and immune variables. The odds of PTC were reduced with higher SHIV RNA in rectal CD4⁺ T cells pre-ATI; conversely, higher frequencies of Ki67⁺ effector memory CD8⁺ T cells in lymph nodes increased the likelihood of PTC. RNA sequencing of CD4⁺ T cells pre-ATI revealed a down-regulated metabolic and immune gene signature in macaques with PTC. Analysis of the early ART group alone implicated transforming growth factor–β signaling genes in lack of viral rebound off ART. This comprehensive investigation reveals major determinants of viral rebound dynamics after ART interruption that should be validated and explored as potential biomarkers to screen children with HIV being considered for ATI.