Dynamics and origin of rebound viremia in SHIV-infected infant macaques following interruption of long-term ART

• Authors: Guido Silvestri, Emory University; Fawn Connor-Stroud, Emory University; Ann Chahroudi, Emory University; Philip Santangelo, Emory University; Jennifer Wood, Emory University; Thomas Vanderford, Emory University; V Obregon-Perko, Emory University; KM Bricker, Emory University; G Mensah, Emory University; F Uddin, Emory University; L Rotolo, Georgia Institute of Technology; D Vanover, Georgia Institute of Technology; Y Desai, Duke University; S Jean, Emory University; S Ehnert, Emory University; SJ Berendam, Duke University; S Liang, Emory University; KJ Bar, University of Pennsylvania; GM Shaw, University of Pennsylvania; A Kumar, Duke University; GG Fouda, Duke University; SR Permar, Duke University
• Journal Title: JCI INSIGHT
• Volume: Volume 6, Number 23
• Publisher: AMER SOC CLINICAL INVESTIGATION INC | 2021-12-08
• Type of Work: Article
• Publisher DOI: http://doi.org/10.1172/jci.insight.152526
• Keywords: Science & Technology; Life Sciences & Biomedicine; Medicine, Research & Experimental; Research & Experimental Medicine; ANTIRETROVIRAL THERAPY; HIV-INFECTION; PROGRESSION; MUTATIONS; EMERGENCE; RESERVOIR; REVEALS; ESCAPE; BURDEN; MODELS

Abstract

Understanding viral rebound in pediatric HIV-1 infection may inform the development of alternatives to lifelong antiretroviral therapy (ART) to achieve viral remission. We thus investigated viral rebound after analytical treatment interruption (ATI) in 10 infant macaques orally infected with SHIV.C.CH505 and treated with long-term ART. Rebound viremia was detected within 7 to 35 days of ATI in 9 of 10 animals, with posttreatment control of viremia seen in 5 of 5 Mamu-A*01+ macaques. Single-genome sequencing revealed that initial rebound virus was similar to viral DNA present in CD4+ T cells from blood, rectum, and lymph nodes before ATI. We assessed the earliest sites of viral reactivation immediately following ATI using ImmunoPET imaging. The largest increase in signal that preceded detectable viral RNA in plasma was found in the gastrointestinal (GI) tract, a site with relatively high SHIV RNA/DNA ratios in CD4+ T cells before ATI. Thus, the GI tract may be an initial source of rebound virus, but as ATI progresses, viral reactivation in other tissues likely contributes to the composition of plasma virus. Our study provides potentially novel insight into the features of viral rebound in pediatric infection and highlights the application of a noninvasive technique to monitor areas of HIV-1 expression in children.