fedratinib and HIV-Infections

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.

Topics: Binding Sites; CD4 Antigens; CD4-Positive T-Lymphocytes; env Gene Products, Human Immunodeficiency Virus; HIV Infections; HIV-1; Humans; Interleukin-2; Janus Kinases; Nitriles; Piperidines; Pyrazoles; Pyrimidines; Pyrroles; Pyrrolidines; Signal Transduction; STAT Transcription Factors; Sulfonamides; Tetradecanoylphorbol Acetate; TOR Serine-Threonine Kinases; Virus Internalization; Virus Replication