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TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV-infected rhesus macaques on antiretroviral therapy.
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.
Afiliação
  • Lim SY; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Osuna CE; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Hraber PT; Los Alamos National Laboratory, Los Alamos, NM 87545, USA.
  • Hesselgesser J; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Gerold JM; Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA.
  • Barnes TL; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Sanisetty S; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Seaman MS; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
  • Lewis MG; Bioqual, Rockville, MD 20852, USA.
  • Geleziunas R; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Miller MD; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Cihlar T; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Lee WA; Gilead Sciences Inc., Foster City, CA 94404, USA.
  • Hill AL; Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA.
  • Whitney JB; Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. jwhitne2@bidmc.harvard.edu.
Sci Transl Med ; 10(439)2018 05 02.
Article em En | MEDLINE | ID: mdl-29720451
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.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Viremia / Vírus da Imunodeficiência Símia / Antirretrovirais / Receptor 7 Toll-Like Limite: Animals Idioma: En Revista: Sci Transl Med Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Antivirais / Viremia / Vírus da Imunodeficiência Símia / Antirretrovirais / Receptor 7 Toll-Like Limite: Animals Idioma: En Revista: Sci Transl Med Assunto da revista: CIENCIA / MEDICINA Ano de publicação: 2018 Tipo de documento: Article País de afiliação: Estados Unidos País de publicação: Estados Unidos