Origin and Correlates of Viral Rebound in SIV-Infected Rhesus Macaques Following Discontinuation of ART

Abstract

The earliest events of viral rebound following discontinuation of ART in people living with Human Immunodeficiency Virus-1 remain largely unknown. We investigated detailed reservoir characteristics and viral rebound dynamics in 18 Simian Immunodeficiency Virus-infected rhesus macaques treated with antiretroviral therapy for 70 weeks and then necropsied after a 12-day analytical treatment interruption (ATI). Using molecularly barcoded SIVmac239M, we tracked viral clonotypes following ATI in both peripheral blood and tissues at necropsy. Viral rebound appeared to originate by reactivation of a single or a few barcode clonotypes from a limited number of deep lymph nodes or gastrointestinal tissues, followed by rapid virus replication of this clonotype in peripheral blood and tissues as well as serial reactivation of multiple additional barcode clonotypes from different anatomic sites, resulting in oligoclonal plasma viremia. Daily transcriptomic and proteomics profiling in peripheral blood following ATI identified early upregulation of pathways related to T cell signaling, cytokine responses, and metabolism prior to detectable plasma viremia, presumably reflecting initial viral replication in tissues. Taken together, these data provide a detailed anatomic, virologic, and immunologic characterization of viral rebound in SIV-infected macaques following ATI, which provides critical information to inform the development of next generation HIV-1 cure strategies.