1. Lymphoid tissues contribute to plasma viral clonotypes early after antiretroviral therapy interruption in SIV-infected rhesus macaques.
- Author
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Solis-Leal, Antonio, Boby, Nongthombam, Mallick, Suvadip, Cheng, Yilun, Wu, Fei, De La Torre, Grey, Dufour, Jason, Alvarez, Xavier, Shivanna, Vinay, Liu, Yaozhong, Fennessey, Christine M., Lifson, Jeffrey D., Li, Qingsheng, Keele, Brandon F., and Ling, Binhua
- Subjects
LYMPHOID tissue ,RHESUS monkeys ,ANTIRETROVIRAL agents ,SIMIAN immunodeficiency virus ,LYMPH nodes - Abstract
The rebound-competent viral reservoir, composed of a virus that is able to persist during antiretroviral therapy (ART) and mediate reactivation of systemic viral replication and rebound viremia after ART interruption (ATI), remains the biggest obstacle to treating HIV infection. A better understanding of the cellular and tissue origins and the dynamics of viral populations that initiate rebound upon ATI could help develop therapeutic strategies for reducing the rebound-competent viral reservoir. In this study, barcoded simian immunodeficiency virus (SIV), SIVmac239M, was used to infect rhesus macaques to enable monitoring of viral barcode clonotypes contributing to virus detectable in plasma after ATI. Blood and tissues from secondary lymphoid organs (spleen, mesenteric lymph nodes, and inguinal lymph nodes) and from the colon, ileum, lung, liver, and brain were analyzed using viral barcode sequencing, intact proviral DNA assay, single-cell RNA sequencing, and combined CODEX and RNAscope in situ hybridization. Four of seven animals had viral barcodes detectable by deep sequencing of plasma at necropsy, although plasma viral RNA remained below 22 copies per milliliter. Among the tissues studied, mesenteric lymph nodes, inguinal lymph nodes, and spleen contained viral barcodes detected in plasma. CD4
+ T cells were the main cell type harboring viral RNA after ATI. Furthermore, T cell zones in lymphoid tissues showed higher viral RNA abundance than B cell zones for most animals. These findings are consistent with lymphoid tissues contributing to the virus present in plasma early after ATI. Editor's summary: A major hurdle to treating HIV is the continued presence of the rebound-competent viral reservoir, which persists during antiretroviral therapy (ART) and serves as a source of viremia during ART interruption (ATI). Here, Solis-Leal et al. infected rhesus macaques with a barcoded strain of simian immunodeficiency virus, SIVmac239M, that enabled tracking of viral clonotypes over time and between tissues. The macaques underwent two separate ATIs, and the authors compared barcodes present in the blood and tissues 1 week after ATI. The authors found that the re-emerged viral clonotypes in plasma at ATI-2 mainly overlapped with those found in the secondary lymphoid tissues such as the spleen and lymph nodes; they also found that CD4+ T cells harbored the most viral RNA after ATI. These data suggest that secondary lymphoid organs are likely the primary viral reservoir driving rebound early after ATI. —Courtney Malo [ABSTRACT FROM AUTHOR]- Published
- 2023
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