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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]
+ Show Author Affiliations
  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. doi:10.1126/scitranslmed.aao4521.
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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
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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.
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@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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Works referenced in this record:

The general stochastic model of nucleotide substitution
journal, February 1990

Roles for CXC Chemokine Ligands 10 and 11 in Recruiting CD4 + T Cells to HIV-1-Infected Monocyte-Derived Macrophages, Dendritic Cells, and Lymph Nodes
journal, April 2005

Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys
journal, May 2011

Latent HIV in primary T lymphocytes is unresponsive to histone deacetylase inhibitors
journal, August 2011

Combinatorial Latency Reactivation for HIV-1 Subtypes and Variants
journal, March 2010

  • Burnett, John C.; Lim, Kwang-il; Calafi, Arash
  • Journal of Virology, Vol. 84, Issue 12
  • DOI: 10.1128/jvi.00161-10

Genital Tract Sequestration of SIV following Acute Infection
journal, February 2011

T-Cell Vaccination Reduces Simian Immunodeficiency Virus Levels in Semen
journal, July 2009

  • Whitney, James B.; Luedemann, Corinne; Hraber, Peter
  • Journal of Virology, Vol. 83, Issue 20
  • DOI: 10.1128/jvi.01202-09

Sustained efficacy and seroconversion with the Toll-like receptor 7 agonist GS-9620 in the Woodchuck model of chronic hepatitis B
journal, June 2015

Primary Isolate Neutralization by HIV Type 1-Infected Patient Sera in the Era of Highly Active Antiretroviral Therapy
journal, November 1999

  • Dreyer, Kimberly; Kallas, Esper G.; Planelles, Vicente
  • AIDS Research and Human Retroviruses, Vol. 15, Issue 17
  • DOI: 10.1089/088922299309856

Delineation of multiple subpopulations of natural killer cells in rhesus macaques
journal, June 2005

Development and Homeostasis of T Cell Memory in Rhesus Macaque
journal, January 2002

  • Pitcher, Christine J.; Hagen, Shoko I.; Walker, Joshua M.
  • The Journal of Immunology, Vol. 168, Issue 1
  • DOI: 10.4049/jimmunol.168.1.29

GS-9620, an Oral Agonist of Toll-Like Receptor-7, Induces Prolonged Suppression of Hepatitis B Virus in Chronically Infected Chimpanzees
journal, June 2013

Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection
journal, May 2008

  • Keele, B. F.; Giorgi, E. E.; Salazar-Gonzalez, J. F.
  • Proceedings of the National Academy of Sciences, Vol. 105, Issue 21
  • DOI: 10.1073/pnas.0802203105

Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid
journal, February 2009

  • Archin, Nancie M.; Espeseth, Amy; Parker, Daniel
  • AIDS Research and Human Retroviruses, Vol. 25, Issue 2
  • DOI: 10.1089/aid.2008.0191

Immune and Genetic Correlates of Vaccine Protection Against Mucosal Infection by SIV in Monkeys
text, January 2011

  • V., Mach, L.; S., Keating,; M., Asmal,
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/8yyj-xk28

Mechanisms of HIV Latency: an Emerging Picture of Complexity
journal, January 2010

Histone Deacetylase Inhibitors for Purging HIV-1 from the Latent Reservoir
journal, March 2011

  • Matalon, Shay; Rasmussen, Thomas A.; Dinarello, Charles A.
  • Molecular Medicine, Vol. 17, Issue 5-6
  • DOI: 10.2119/molmed.2011.00076

Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection
journal, March 2005

  • Mattapallil, Joseph J.; Douek, Daniel C.; Hill, Brenna
  • Nature, Vol. 434, Issue 7037
  • DOI: 10.1038/nature03501

Control of Viremia in Simian Immunodeficiency Virus Infection by CD8+ Lymphocytes
journal, February 1999

A Limited Group of Class I Histone Deacetylases Acts To Repress Human Immunodeficiency Virus Type 1 Expression
journal, March 2009

  • Keedy, Kara S.; Archin, Nancie M.; Gates, Adam T.
  • Journal of Virology, Vol. 83, Issue 10
  • DOI: 10.1128/jvi.02585-08

Pharmacokinetic and Pharmacodynamic Properties of GS-9620, a Novel Toll-Like Receptor 7 Agonist, Demonstrate Interferon-Stimulated Gene Induction without Detectable Serum Interferon at Low Oral Doses
journal, October 2013

  • Fosdick, Abigail; Zheng, Jim; Pflanz, Stefan
  • Journal of Pharmacology and Experimental Therapeutics, Vol. 348, Issue 1
  • DOI: 10.1124/jpet.113.207878

Expression of Latent HIV Induced by the Potent HDAC Inhibitor Suberoylanilide Hydroxamic Acid
text, January 2009

  • Amy, Espeseth,; Daria, Hazuda,; Manzoor, Cheema,
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/86nj-jr45

Rapid seeding of the viral reservoir prior to SIV viraemia in rhesus monkeys
journal, July 2014

  • Whitney, James B.; Hill, Alison L.; Sanisetty, Srisowmya
  • Nature, Vol. 512, Issue 7512
  • DOI: 10.1038/nature13594

Eradication Therapies for HIV Infection: Time to Begin Again
text, January 2011

  • M., Margolis, David
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/r6y6-tg81

Inhibitors of Histone Deacetylases: CORRELATION BETWEEN ISOFORM SPECIFICITY AND REACTIVATION OF HIV TYPE 1 (HIV-1) FROM LATENTLY INFECTED CELLS
journal, April 2011

  • Huber, Kelly; Doyon, Geneviève; Plaks, Joseph
  • Journal of Biological Chemistry, Vol. 286, Issue 25
  • DOI: 10.1074/jbc.m110.180224

Eradication Therapies for HIV Infection: Time to Begin Again
journal, April 2011

Estimating time since infection in early homogeneous HIV-1 samples using a poisson model
journal, October 2010

  • Giorgi, Elena E.; Funkhouser, Bob; Athreya, Gayathri
  • BMC Bioinformatics, Vol. 11, Issue 1
  • DOI: 10.1186/1471-2105-11-532

Latent infection of CD4+ T cells provides a mechanism for lifelong persistence of HIV-1, even in patients on effective combination therapy
journal, May 1999

  • Finzi, Diana; Blankson, Joel; Siliciano, Janet D.
  • Nature Medicine, Vol. 5, Issue 5
  • DOI: 10.1038/8394

Vaccine protection against acquisition of neutralization-resistant SIV challenges in rhesus monkeys
journal, January 2012

  • Barouch, Dan H.; Liu, Jinyan; Li, Hualin
  • Nature, Vol. 482, Issue 7383
  • DOI: 10.1038/nature10766

Antiretroviral Intensification and Valproic Acid Lack Sustained Effect on Residual HIV-1 Viremia or Resting CD4+ Cell Infection
journal, February 2010

Naïve and memory B cells in the rhesus macaque can be differentiated by surface expression of CD27 and have differential responses to CD40 ligation
journal, January 2011

  • Kuhrt, David; Faith, Seth; Hattemer, Angela
  • Journal of Immunological Methods, Vol. 363, Issue 2
  • DOI: 10.1016/j.jim.2010.09.017

Type I interferon responses in rhesus macaques prevent SIV infection and slow disease progression
journal, July 2014

  • Sandler, Netanya G.; Bosinger, Steven E.; Estes, Jacob D.
  • Nature, Vol. 511, Issue 7511
  • DOI: 10.1038/nature13554

Histone Deacetylase Inhibitors Impair the Elimination of HIV-Infected Cells by Cytotoxic T-Lymphocytes
journal, August 2014

Mamu-B*08-Positive Macaques Control Simian Immunodeficiency Virus Replication
journal, May 2007

  • Loffredo, John T.; Maxwell, Jess; Qi, Ying
  • Journal of Virology, Vol. 81, Issue 16
  • DOI: 10.1128/jvi.00895-07

Safety, pharmacokinetics and pharmacodynamics of GS-9620, an oral Toll-like receptor 7 agonist
journal, January 2013

  • Lopatin, Uri; Wolfgang, Grushenka; Tumas, Daniel
  • Antiviral Therapy, Vol. 18, Issue 3
  • DOI: 10.3851/imp2548

The Effect of Raltegravir Intensification on Low-level Residual Viremia in HIV-Infected Patients on Antiretroviral Therapy: A Randomized Controlled Trial
text, January 2010

  • M., Jacobson, Jeffrey; T., Gandhi, Rajesh; Sarah, Palmer,
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/tvqk-k182

Optimization and qualification of an 8-color intracellular cytokine staining assay for quantifying T cell responses in rhesus macaques for pre-clinical vaccine studies
journal, December 2012

  • Donaldson, Mitzi M.; Kao, Shing-Fen; Eslamizar, Leila
  • Journal of Immunological Methods, Vol. 386, Issue 1-2
  • DOI: 10.1016/j.jim.2012.08.011

Valproic acid without intensified antiviral therapy has limited impact on persistent HIV infection of resting CD4+ T cells
journal, January 2008

Disulfiram Reactivates Latent HIV-1 in a Bcl-2-Transduced Primary CD4+ T Cell Model without Inducing Global T Cell Activation
journal, April 2011

  • Xing, S.; Bullen, C. K.; Shroff, N. S.
  • Journal of Virology, Vol. 85, Issue 12
  • DOI: 10.1128/JVI.02033-10

Maximum likelihood phylogenetic estimation from DNA sequences with variable rates over sites: Approximate methods
journal, September 1994

A Nonhuman Primate Model for the Selective Elimination of CD8+ Lymphocytes Using a Mouse-Human Chimeric Monoclonal Antibody
journal, June 1999

  • Schmitz, Jörn E.; Simon, Meredith A.; Kuroda, Marcelo J.
  • The American Journal of Pathology, Vol. 154, Issue 6
  • DOI: 10.1016/S0002-9440(10)65450-8

Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection
text, January 2008

  • F., Salazar-Gonzalez, Jesus; P., Busch, Michael; S., Perelson, Alan
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/f6s9-vz03

A Limited Group of Class I Histone Deacetylases Acts To Repress Human Immunodeficiency Virus Type 1 Expression
text, January 2009

  • J., Hazuda, D.; S., Keedy, K.; A., Espeseth,
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/pb48-db96

Disulfiram Reactivates Latent HIV-1 in a Bcl-2-Transduced Primary CD4+ T Cell Model without Inducing Global T Cell Activation
text, January 2011

  • C., Quinn, T.; S., Bhat,; H. -C., Yang,
  • The University of North Carolina at Chapel Hill University Libraries
  • DOI: 10.17615/h8w8-wr34
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    journal, August 2018

    • Hill, Alison L.; Rosenbloom, Daniel I. S.; Nowak, Martin A.
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