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Author Notes:

Address correspondence to Raymond F. Schinazi, Email: rschina@emory.edu

Subjects:

Research Funding:

This work was supported in part by NIH grants 8R01-OD011094 (to R.F.S.), 5P30-AI-50409 (to R.F.S.) (Center for AIDS Research), R01-MH100999 (to R.F.S.), and 5-R01-AI087508 (to V.P.) and by the Department of Veterans Affairs (to R.F.S.).

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Microbiology
  • Pharmacology & Pharmacy
  • CD4(+) T-CELLS
  • INFECTED PATIENTS
  • INCB018424 PHOSPHATE
  • HEALTHY-VOLUNTEERS
  • IMMUNE ACTIVATION
  • EXPRESSION
  • PHARMACOKINETICS
  • PHARMACODYNAMICS
  • PROLIFERATION
  • INDUCTION

Ruxolitinib and Tofacitinib Are Potent and Selective Inhibitors of HIV-1 Replication and Virus Reactivation In Vitro

Tools:

Journal Title:

Antimicrobial Agents and Chemotherapy

Volume:

Volume 58, Number 4

Publisher:

, Pages 1977-1986

Type of Work:

Article | Final Publisher PDF

Abstract:

The JAK-STAT pathway is activated in both macrophages and lymphocytes upon human immunodeficiency virus type 1 (HIV-1) infection and thus represents an attractive cellular target to achieve HIV suppression and reduced inflammation, which may impact virus sanctuaries. Ruxolitinib and tofacitinib are JAK1/2 inhibitors that are FDA approved for rheumatoid arthritis and myelofibrosis, respectively, but their therapeutic application for treatment of HIV infection was unexplored. Both drugs demonstrated submicromolar inhibition of infection with HIV-1, HIV-2, and a simian-human immunodeficiency virus, RT-SHIV, across primary human or rhesus macaque lymphocytes and macrophages, with no apparent significant cytotoxicity at 2 to 3 logs above the median effective antiviral concentration. Combination of tofacitinib and ruxolitinib increased the efficacy by 53- to 161-fold versus that observed for monotherapy, respectively, and each drug applied alone to primary human lymphocytes displayed similar efficacy against HIV-1 containing various polymerase substitutions. Both drugs inhibited virus replication in lymphocytes stimulated with phytohemagglutinin (PHA) plus interleukin-2 (IL-2), but not PHA alone, and inhibited reactivation of latent HIV-1 at low-micromolar concentrations across the J-Lat T cell latency model and in primary human central memory lymphocytes. Thus, targeted inhibition of JAK provided a selective, potent, and novel mechanism to inhibit HIV-1 replication in lymphocytes and macrophages, replication of drug-resistant HIV-1, and reactivation of latent HIV-1 and has the potential to reset the immunologic milieu in HIV-infected individuals.

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© 2014, American Society for Microbiology. All Rights Reserved.

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