# Initial sites of SIV rebound after antiretroviral treatment cessation in rhesus macaques

## TL;DR

This study identifies the gastrointestinal tract and related lymphoid tissues as the main sites where SIV rebounds after stopping antiretroviral treatment in rhesus macaques.

## Contribution

The study reveals specific tissue origins of SIV rebound after ART cessation using barcoded viruses in non-human primates.

## Key findings

- 32 outlier barcodes were identified as potential rebound origins in 11 animals.
- 96% of rebound origins were in the gastrointestinal tract or its associated lymphoid tissues.
- These findings suggest targeted interventions could prevent or control post-ART viral rebound.

## Abstract

The tissue origin(s) and the earliest viral dynamics of HIV rebound after antiretroviral therapy (ART) remain unclear. Here, using barcoded SIVmac239 in rhesus macaques (n = 24), we defined the distribution of barcode-specific viral RNA expression in tissues during ART (n = 6) and then assessed initial clonal rebound 5 and 7 days after ART cessation by identifying barcodes in individual tissues that exceeded the 99th percentile of the on-ART distribution (‘outliers’). In 4 of 11 aviraemic and 6 of 7 viraemic animals, 32 such outlier barcodes were identified. Sixteen of these barcodes were also identified in rebound viraemia, confirming specific tissues as rebound origin and early amplification sites. Overall, 27 of the 32 outlier barcodes were determined to reflect rebound origins, of which 96% were in the gastrointestinal tract (26%) or gastrointestinal tract-associated lymphoid tissues (70%). These results indicate that distinct tissue sites differentially support post-ART viral rebound, with potential therapeutic implications for interventions designed to prevent or control these events.

Using a non-human primate model, the authors identified the tissue sites of initial viral rebound after discontinuation of antiretroviral therapy, demonstrating that such rebound preferentially occurs in the gastrointestinal tract-associated lymphoid tissues.