Clonally expanded HIV-1 proviruses with 5'-leader defects can give rise to nonsuppressible residual viremia
Date:
03/15/2023
Topics:
Citation:
White JA, Wu F, Yasin S, Moskovljevic M, Varriale J, Dragoni F, Camilo-Contreras A, Duan J, Zheng MY, Tadzong NF, Patel HB, Quiambao JMC, Rhodehouse K, Zhang H, Lai J, Beg SA, Delannoy M, Kilcrease C, Hoffmann CJ, Poulin S, Chano F, Tremblay C, Cherian J, Barditch-Crovo P, Chida N, Moore RD, Summers MF, Siliciano RF, Siliciano JD, Simonetti FR. Clonally expanded HIV-1 proviruses with 5'-leader defects can give rise to nonsuppressible residual viremia. J Clin Invest. 2023 Mar 15;133(6):e165245. doi: 10.1172/JCI165245. PMID: 36602866; PMCID: PMC10014112.
Abstract
Background: Antiretroviral therapy (ART) halts HIV-1 replication, decreasing viremia to below the detection limit of clinical assays. However, some individuals experience persistent nonsuppressible viremia (NSV) originating from CD4+ T cell clones carrying infectious proviruses. Defective proviruses represent over 90% of all proviruses persisting during ART and can express viral genes, but whether they can cause NSV and complicate ART management is unknown.
Methods: We undertook an in-depth characterization of proviruses causing NSV in 4 study participants with optimal adherence and no drug resistance. We investigated the impact of the observed defects on 5'-leader RNA properties, virus infectivity, and gene expression. Integration-site specific assays were used to track these proviruses over time and among cell subsets.
Results: Clones carrying proviruses with 5'-leader defects can cause persistent NSV up to approximately 103 copies/mL. These proviruses had small, often identical deletions or point mutations involving the major splicing donor (MSD) site and showed partially reduced RNA dimerization and nucleocapsid binding. Nevertheless, they were inducible and produced noninfectious virions containing viral RNA, but lacking envelope.
Conclusion: These findings show that proviruses with 5'-leader defects in CD4+ T cell clones can give rise to NSV, affecting clinical care. Sequencing of the 5'-leader can help in understanding failure to completely suppress viremia.
Methods: We undertook an in-depth characterization of proviruses causing NSV in 4 study participants with optimal adherence and no drug resistance. We investigated the impact of the observed defects on 5'-leader RNA properties, virus infectivity, and gene expression. Integration-site specific assays were used to track these proviruses over time and among cell subsets.
Results: Clones carrying proviruses with 5'-leader defects can cause persistent NSV up to approximately 103 copies/mL. These proviruses had small, often identical deletions or point mutations involving the major splicing donor (MSD) site and showed partially reduced RNA dimerization and nucleocapsid binding. Nevertheless, they were inducible and produced noninfectious virions containing viral RNA, but lacking envelope.
Conclusion: These findings show that proviruses with 5'-leader defects in CD4+ T cell clones can give rise to NSV, affecting clinical care. Sequencing of the 5'-leader can help in understanding failure to completely suppress viremia.