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

Veronica Obregon-Perko,Guido Silvestri,Philip J Santangelo,Stephanie Ehnert,George M Shaw,Genevieve G Fouda,Katharine J Bar,Thomas H Vanderford,Laura Rotolo,Sherrie Jean,Katherine M Bricker,Shan Liang,Amit Kumar,Sallie R Permar,Stella J Berendam,Gloria Mensah,Yesha Desai,Ann Chahroudi,Daryll Vanover,Ferzan Uddin,Fawn Connor-Stroud ,Jennifer Wood

doi:10.1172/jci.insight.152526

Veronica Obregon-Perko, Guido Silvestri + Show 20 more

Open Access

https://doi.org/10.1172/jci.insight.152526

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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.

Highlights

Establishment of the long-lived viral reservoir, which persists on antiretroviral therapy (ART), remains a major obstacle for HIV-1 cure
Using a combination of ImmunoPET imaging, single genome analysis of plasma SHIV RNA and cell-associated SHIV DNA, and tissue-based virus quantification, we demonstrate that the gastrointestinal (GI) tract is a substantial site of viral RNA persistence that is capable of early SHIV.C.CH505 expansion in infant macaques following analytical treatment interruption (ATI) but, as ATI progresses, virus reactivation in other tissues likely contributes to rebound viremia
Greater knowledge of the kinetics and origin of viral rebound after ART cessation is critically needed to develop and evaluate HIV-1 cure strategies. Investigations in this area have largely focused on adults, contributing to a general lack of information on viral recrudescence in children perinatally infected with HIV-1

Summary

Introduction

Establishment of the long-lived viral reservoir, which persists on antiretroviral therapy (ART), remains a major obstacle for HIV-1 cure. Interruption of ART is typically followed by viral rebound and reestablishment of systemic infection, making adherence to ART a lifelong commitment. This is daunting for the nearly 2 million children currently living with HIV-1 [1], who face a lifetime of daily medication that begins decades earlier than individuals infected in adulthood. Blunting the size of the viral reservoir with early ART is challenging to implement in the setting of breastfeeding transmission, where diagnosis can be delayed. There is a critical need to develop alternatives or complements to ART-based measures that can delay or prevent viral rebound in pediatric HIV-1 infection

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