Viral rebound in SHIV-infected infant macaques is predicted by immunovirologic features measured before and after antiretroviral therapy
Evaluation of HIV cure strategies requires antiretroviral therapy (ART) interruption, but ethical and clinical considerations make this difficult in children. Uncovering predictors of time to viral rebound (TTR) and post-treatment control (PTC) of rebound viremia in a pediatric preclinical model may inform the design of studies testing novel cure interventions in these populations. We thus assessed 141 variables in SHIV-infected infant rhesus macaques (RMs) where ART initiation was staggered then followed by analytical treatment interruption (ATI). Viral rebound occurred in 25/30 RMs within 7-98 d of ATI, with TTR significantly delayed in the Early ART group compared to the Intermediate and Late ART groups (median TTR  84, 18, and 17 d, respectively; p<0.001). Peak plasma viral load pre-ART best described TTR, with increased predictive strength through the successive inclusion of six additional variables. Increased peak viral load pre-ART decreased the odds of no rebound and elevated Ki67+ effector memory CD8+ T cells in lymph nodes pre-ATI increased the odds of PTC. RNA sequencing of CD4+ T cells pre-ATI showed heme metabolism and IFNg response pathways were most upregulated in RMs with sustained suppression of viremia during ATI. Analysis of only the Early ART group also implicated TGFb pathway genes in lack of viral rebound off ART. This comprehensive investigation reveals major determinants of viral rebound dynamics following ART interruption that should be validated and explored as biomarkers to screen children with HIV being considered for ATI. Overall design: 18 infant Indian rhesus macaques infected with SHIV.C.CH505.375H.dCT at 4 weeks of age divided into three groups (n=6) differing in timing of antiretroviral therapy (ART) initiation following infection: 8 wpi for Late ART, 2 wpi for Intermediate ART, and 4 or 7 dpi for Early ART. Animals were maintained on daily ART for a minimum of 52 weeks prior to treatment interruption. RNA sequencing was perfomed on CD4+ T cells isolated from blood and lymph nodes prior to treatment interruption.