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

Abstract

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.

Authors:
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)
Publication Date:
Research Org.:
Los Alamos National Lab. (LANL), Los Alamos, NM (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
1438143
Report Number(s):
LA-UR-16-25422
Journal ID: ISSN 1946-6234
Grant/Contract Number:  
AC52-06NA25396
Resource Type:
Accepted Manuscript
Journal Name:
Science Translational Medicine
Additional Journal Information:
Journal Volume: 10; Journal Issue: 439; Journal ID: ISSN 1946-6234
Publisher:
AAAS
Country of Publication:
United States
Language:
English
Subject:
60 APPLIED LIFE SCIENCES; Biological Science

Citation Formats

Lim, So-Yon, Osuna, Christa E., Hraber, Peter T., Hesselgesser, Joe, Gerold, Jeffrey M., Barnes, Tiffany L., Sanisetty, Srisowmya, Seaman, Michael S., Lewis, Mark G., Geleziunas, Romas, Miller, Michael D., Cihlar, Tomas, Lee, William A., Hill, Alison L., and Whitney, James B. TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy. United States: N. p., 2018. Web. https://doi.org/10.1126/scitranslmed.aao4521.
Lim, So-Yon, Osuna, Christa E., Hraber, Peter T., Hesselgesser, Joe, Gerold, Jeffrey M., Barnes, Tiffany L., Sanisetty, Srisowmya, Seaman, Michael S., Lewis, Mark G., Geleziunas, Romas, Miller, Michael D., Cihlar, Tomas, Lee, William A., Hill, Alison L., & Whitney, James B. TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy. United States. https://doi.org/10.1126/scitranslmed.aao4521
Lim, So-Yon, Osuna, Christa E., Hraber, Peter T., Hesselgesser, Joe, Gerold, Jeffrey M., Barnes, Tiffany L., Sanisetty, Srisowmya, Seaman, Michael S., Lewis, Mark G., Geleziunas, Romas, Miller, Michael D., Cihlar, Tomas, Lee, William A., Hill, Alison L., and Whitney, James B. Wed . "TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy". United States. https://doi.org/10.1126/scitranslmed.aao4521. https://www.osti.gov/servlets/purl/1438143.
@article{osti_1438143,
title = {TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy},
author = {Lim, So-Yon and Osuna, Christa E. and Hraber, Peter T. and Hesselgesser, Joe and Gerold, Jeffrey M. and Barnes, Tiffany L. and Sanisetty, Srisowmya and Seaman, Michael S. and Lewis, Mark G. and Geleziunas, Romas and Miller, Michael D. and Cihlar, Tomas and Lee, William A. and Hill, Alison L. and Whitney, James B.},
abstractNote = {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.},
doi = {10.1126/scitranslmed.aao4521},
journal = {Science Translational Medicine},
number = 439,
volume = 10,
place = {United States},
year = {2018},
month = {5}
}

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