title: Ruxolitinib and tofacitinib are potent and selective inhibitors of HIV-1 replication and virus reactivation in vitro.
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.
authors.affiliation: Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, USA.
authors.forename: Christina
authors.initials: C
authors.lastname: Gavegnano
authors.forename: Mervi
authors.initials: M
authors.lastname: Detorio
authors.forename: Catherine
authors.initials: C
authors.lastname: Montero
authors.forename: Alberto
authors.initials: A
authors.lastname: Bosque
authors.forename: Vicente
authors.initials: V
authors.lastname: Planelles
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Schinazi
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D015658:HIV Infections / Q000517:prevention & control; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D053613:Janus Kinase 1 / Q000037:antagonists & inhibitors; D053614:Janus Kinase 2 / Q000037:antagonists & inhibitors; D008214:Lymphocytes / Q000821:virology; D008253:Macaca mulatta; D008264:Macrophages / Q000821:virology; D009570:Nitriles; D010880:Piperidines / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D011758:Pyrroles / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D009570:Nitriles; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; C540383:ruxolitinib; C479163:tofacitinib; C507904:JAK1 protein, human; C507924:JAK2 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2