Research ArticleSIV

TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy

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Science Translational Medicine  02 May 2018:
Vol. 10, Issue 439, eaao4521
DOI: 10.1126/scitranslmed.aao4521

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Emptying the reservoir

Antiretroviral therapy can halt HIV-1 replication but cannot clear the hidden reservoirs of latent virus. In new work, Lim et al. treated SIV-infected rhesus macaques on antiretroviral therapy with up to 19 doses of the Toll-like receptor 7 agonists GS-986 or GS-9620. By the third dose, all macaques experienced transient SIV plasma viremia within 48 hours after dosing. Dosing was also associated with activation of lymphocytes (T, NK, and B cells) and reductions in SIV DNA in cells from the peripheral blood, lymph nodes, and gastrointestinal tract. When antiretroviral therapy ceased, 2 of 13 treated macaques did not show rebound of virus and remained virus-free and disease-free for more than 2 years.

Abstract

Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART. In an initial dose-escalation study, and a subsequent dose-optimization study, we found that TLR7 agonists activated multiple innate and adaptive immune cell populations in addition to inducing expression of SIV RNA. We also observed TLR7 agonist–induced reductions in SIV DNA and measured inducible virus from treated animals in ex vivo cell cultures. In a second study, after stopping ART, two of nine treated animals remained aviremic for more than 2 years, even after in vivo CD8+ T cell depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naïve recipient macaques. These findings suggest that TLR7 agonists may facilitate reduction of the viral reservoir in a subset of SIV-infected rhesus macaques.

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