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JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope Mutated HIV-1.

JAK-STAT Signaling Pathways and Inhibitors Affect Reversion of Envelope Mutated HIV-1.
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Quan Y, Xu H, Han Y, Mesplède T, Wainberg MA,


Quan Y, Xu H, Han Y, Mesplède T, Wainberg MA, (click to view)

Quan Y, Xu H, Han Y, Mesplède T, Wainberg MA,

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Journal of virology 2017 02 15() pii 10.1128/JVI.00075-17

Abstract

HIV can spread by both cell-free and cell-to-cell transmission. Here, we show that numerous 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, followed by reversion to wild type. However, the activation of JAK-STAT signaling pathways caused inhibition of such cell-to-cell infection as well as the reversion of multiple HIV Env mutants that displayed differences in ability to bind to the CD4 receptor. Specifically, two T cell activators, Interleukin-2 (IL2) 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-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.Importance: Specific 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.

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