# The TLR7 agonist vesatolimod does not measurably induce SIV expression in macaques receiving combination antiretroviral therapy initiated during chronic infection

## TL;DR

A study found that a TLR7 agonist did not significantly increase SIV expression in macaques on antiretroviral therapy, contradicting earlier findings.

## Contribution

The study clarifies conflicting results by replicating earlier conditions and using sensitive assays to show no significant virus induction.

## Key findings

- VES treatment did not increase plasma viral load in macaques on cART.
- No measurable reductions in viral DNA were observed in blood or tissues.
- Results align with recent clinical data showing no reliable virus induction by TLR7 agonists.

## Abstract

Lim et al. previously reported that TLR7 agonist (Vesatolimod [VES] or the related compound GS-986) administration to SIVmac251-infected macaques receiving combination antiretroviral therapy (cART) led to transient plasma viral load (PVL) increases, viral DNA (vDNA) reductions in blood and tissues, and, in some animals, extended viral remission after treatment cessation (S. Y. Lim, C. E. Osuna, P. T. Hraber, J. Hesselgesser, et al., Sci Transl Med 10:eaao4521, 2018, https://doi.org/10.1126/scitranslmed.aao4521). However, in multiple subsequent studies, TLR7 agonist administration in SIV or SHIV-infected macaques on cART did not induce measurable virus expression. Notably, these studies utilized earlier cART initiation, lengthier cART treatment before TLR7 agonist administration, different sampling time points, and/or less sensitive virologic assays compared to the Lim study. We hypothesized that study design and assay differences may have led to these apparently discrepant results due to quantitative or qualitative differences in the established viral reservoirs and/or a reduced capacity to detect virus induction. To more closely capture the Lim study conditions, we initiated cART at 65 days post-infection in 10 SIVmac239M-infected rhesus macaques. Six received VES (0.15 mg/kg orally, every 2 weeks for six doses), while four received vehicle control. Although VES treatment induced expected transient increases in interferon-stimulated gene expression and immune cell phenotypic changes, it did not lead to measurable PVL increases in peripheral or hepatic portal vein blood using a highly sensitive PVL assay or increases in cell-associated vRNA:vDNA ratios, nor to measurable reductions in vDNA in blood or tissues. These results align with recent clinical data and confirm that TLR7 agonist treatment does not reliably induce significant virus expression in vivo.