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

Journal Article · · Science Translational Medicine
ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [2];  [3]; ORCiD logo [4]; ORCiD logo [3]; ORCiD logo [1]; ORCiD logo [1]; ORCiD logo [5];  [3];  [3];  [3];  [3]; ORCiD logo [4]; ORCiD logo [6]
  1. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States)
  2. Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
  3. Gilead Sciences Inc., Foster City, CA (United States)
  4. Harvard Univ., Cambridge, MA (United States)
  5. Bioqual, Rockville, MD (United States)
  6. Brigham and Women's Hospital (Harvard Medical School), Boston, MA (United States); Massachusetts Inst. of Technology (MIT), Cambridge, MA (United States)
+ Show Author Affiliations

Antiretroviral therapy 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 have demonstrably reduced the latent HIV-1 reservoir, or impacted viral rebound following the interruption of antiretroviral therapy. Here, we evaluate orally administered selective tolllike receptor 7 agonists GS-986 and GS-9620 for their ability to induce transient viremia in simian immunodeficiency virus-infected rhesus monkeys on suppressive antiretroviral therapy. In an initial doseescalation study, and a subsequent dose-optimization study, we found that toll-like receptor 7 agonists activate multiple innate and adaptive immune cell populations in addition to inducing SIV RNA. We also observed toll-like receptor 7 agonist-induced reductions in SIV DNA and ex vivo inducible virus from treated animals. In a second study, after stopping antiretroviral therapy, two of nine treated animals have remained aviremic for more than two years, even after in vivo CD8+ lymphocyte depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naive recipient macaques. These findings suggest that toll-like receptor agonists may facilitate reservoir reduction in a subset of individuals.

Research Organization:
Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
Sponsoring Organization:
USDOE
Grant/Contract Number:
AC52-06NA25396
OSTI ID:
1438143
Report Number(s):
LA-UR-16-25422
Journal Information:
Science Translational Medicine, Vol. 10, Issue 439; ISSN 1946-6234
Publisher:
AAASCopyright Statement
Country of Publication:
United States
Language:
English
Citation Metrics:
Cited by: 106 works
Citation information provided by
Web of Science

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  • F., Salazar-Gonzalez, Jesus; P., Busch, Michael; S., Perelson, Alan
  • The University of North Carolina at Chapel Hill University Libraries https://doi.org/10.17615/f6s9-vz03
text January 2008
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Disulfiram Reactivates Latent HIV-1 in a Bcl-2-Transduced Primary CD4+ T Cell Model without Inducing Global T Cell Activation text January 2011

Cited By (20)

Why and where an HIV cure is needed and how it might be achieved journal December 2019
Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells journal January 2020
PD-1 Blockade and TLR7 Activation Lack Therapeutic Benefit in Chronic Simian Immunodeficiency Virus-Infected Macaques on Antiretroviral Therapy journal September 2019
TLR7 agonist administration to SIV-infected macaques receiving early initiated cART does not induce plasma viremia journal June 2019
STING agonists activate latently infected cells and enhance SIV-specific responses ex vivo in naturally SIV controlled cynomolgus macaques journal April 2019
Targeting Cellular and Tissue HIV Reservoirs With Toll-Like Receptor Agonists journal October 2019
Clinical pharmacology in HIV cure research – what impact have we seen? journal December 2018
Dolutegravir Monotherapy of Simian Immunodeficiency Virus-Infected Macaques Selects for Several Patterns of Resistance Mutations with Variable Virological Outcomes journal October 2018
Insight into treatment of HIV infection from viral dynamics models journal August 2018
Evaluating the Intactness of Persistent Viral Genomes in Simian Immunodeficiency Virus-Infected Rhesus Macaques after Initiating Antiretroviral Therapy within One Year of Infection journal October 2019
Combination anti–PD-1 and antiretroviral therapy provides therapeutic benefit against SIV journal September 2018
Robust and persistent reactivation of SIV and HIV by N-803 and depletion of CD8+ cells text January 2020
HIV, HCV and HBV: A Review of Parallels and Differences journal September 2018
HIV-Specific T Cells Can Be Generated against Non-escaped T Cell Epitopes with a GMP-Compliant Manufacturing Platform journal March 2020
STING agonists activate latently infected cells and enhance SIV-specific responses ex vivo in naturally SIV controlled cynomolgus macaques journal April 2019
PD-1 Blockade and TLR7 Activation Lack Therapeutic Benefit in Chronic Simian Immunodeficiency Virus-Infected Macaques on Antiretroviral Therapy journal September 2019
HIV control: Is getting there the same as staying there? journal November 2018
Poly-ICLC, a TLR3 Agonist, Induces Transient Innate Immune Responses in Patients With Treated HIV-Infection: A Randomized Double-Blinded Placebo Controlled Trial journal April 2019
Targeting Cellular and Tissue HIV Reservoirs With Toll-Like Receptor Agonists journal October 2019
Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy journal February 2020

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