Viral evolution in a pediatric rhesus macaque model of HIV therapy and rebound

Abstract

In 2017, approximately 180,000 infants were infected with HIV and 1.8 million children were living with HIV globally. While lifelong combination antiretroviral therapy (ART) can effectively suppress virus replication, ART is not curative due to the establishment of stable latent viral reservoirs immediately after infection. A functional cure able to achieve sustained viral remission will be required to attain an ART-free life. Our study goal was to characterize the kinetics of Simian-Human Immunodeficiency Virus (SHIV) evolution and viral rebound in infant and adult preclinical models of HIV reservoir on ART. In this study, 6 infant and adult rhesus macaques (RMs) were infected with Simian-Human Immunodeficiency Virus (SHIV).C.CH0505.375H.dCT virus via oral and intravenous challenge, respectively. Twelve weeks post infection (wpi), infant and adult RMs were placed on ART for 8 and 12 weeks, respectively. ART was then interrupted and kinetics of viral rebound was measured using qRT-PCR. Viral diversity was measured pre- and post-ART using single genome amplification and sequencing of the HIV env gene. Plasma viral RNA (vRNA) in infants and adults displayed similar kinetics until ART initiation, peaking at 2 wpi. Upon ART initiation, plasma vRNA load was suppressed in infants and adults to undetectable levels within 2-4 weeks. Post-ART, 5/6 infant and 3/6 adult RMs rebounded to >150 vRNA copies/ml of plasma within 1-3 weeks. Pre-ART and post-ART, HIV env sequence diversity was greater in adult plasma viruses than in infant plasma viruses, with average pairwise distance values of 0.007 and 0.005, respectively. Post-ART, infant plasma viruses are more closely related to pre-ART viruses than are adult plasma viruses, perhaps due to less immune pressure in infants. These findings further delineate the clinically relevant differences in HIV env genetic diversity between infants and adults and emphasize the clear need for highly relevant, preclinical models for the development of pediatric-specific therapeutic and curative strategies to achieve an HIV-free generation.