title: JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope-Mutated HIV-1.
abstract: HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that many of the amino acid changes in Env that are close to the CD4 binding pocket can affect HIV replication. We generated a number of mutant viruses that were unable to infect T cells as cell-free viruses but were nevertheless able to infect certain T cell lines as cell-associated viruses, which was followed by reversion to the wild type. However, the activation of JAK-STAT signaling pathways caused the inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in their abilities to bind to the CD4 receptor. Specifically, two T cell activators, interleukin-2 (IL-2) and phorbol 12-myristate 13-acetate (PMA), both capable of activation of JAK-STAT pathways, were able to inhibit cell-to-cell viral transmission. In contrast, but consistent with the above result, a number of JAK-STAT and mTOR inhibitors actually promoted HIV-1 transmission and reversion. Hence, JAK-STAT signaling pathways may differentially affect the replication of a variety of HIV Env mutants in ways that differ from the role that these pathways play in the replication of wild-type viruses.IMPORTANCESpecific alterations in HIV Env close to the CD4 binding site can differentially change the ability of HIV to mediate infection for cell-free and cell-associated viruses. However, such differences are dependent to some extent on the types of target cells used. JAK-STAT signaling pathways are able to play major roles in these processes. This work sheds new light on factors that can govern HIV infection of target cells.
authors.affiliation: McGill AIDS Centre, Lady Davis Institute at the Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Yudong
authors.initials: Y
authors.lastname: Quan
authors.affiliation: McGill AIDS Centre, Lady Davis Institute at the Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Hongtao
authors.initials: H
authors.lastname: Xu
authors.affiliation: McGill AIDS Centre, Lady Davis Institute at the Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Yingshan
authors.initials: Y
authors.lastname: Han
authors.affiliation: McGill AIDS Centre, Lady Davis Institute at the Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Thibault
authors.initials: T
authors.lastname: Mesplède
authors.affiliation: Department of Microbiology and Immunology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada mark.wainberg@mcgill.ca.|McGill AIDS Centre, Lady Davis Institute at the Jewish General Hospital, Montreal, Quebec, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Wainberg
mesh_terms: D001665:Binding Sites / Q000235:genetics; D015704:CD4 Antigens / Q000378:metabolism*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D015658:HIV Infections / Q000635:transmission* / Q000821:virology; D015497:HIV-1 / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D053612:Janus Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D009570:Nitriles; D010880:Piperidines / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D050791:STAT Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction; D013449:Sulfonamides / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D053586:Virus Internalization; D014779:Virus Replication / Q000235:genetics; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics*; D000096926:Benzenesulfonamides
chemical_list: D015704:CD4 Antigens; D007376:Interleukin-2; D053612:Janus Kinases; D009570:Nitriles; D010880:Piperidines; D011720:Pyrazoles; D011743:Pyrimidines; D011758:Pyrroles; D011759:Pyrrolidines; D050791:STAT Transcription Factors; D013449:Sulfonamides; D058570:TOR Serine-Threonine Kinases; D013755:Tetradecanoylphorbol Acetate; D054299:env Gene Products, Human Immunodeficiency Virus; C508594:IL2 protein, human; C528327:fedratinib; D000096926:Benzenesulfonamides; C540383:ruxolitinib; C479163:tofacitinib; C546842:MTOR protein, human
keywords: Env mutant; HIV-1; cell dependence; cell-associated viruses; reversion