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

Gavegnano, Christina; Detorio, Mervi; Montero, Catherine; Bosque, Alberto; Planelles, Vicente; Schinazi, Raymond F.

doi:10.1128/aac.02496-13

Cited by 87 publications

(82 citation statements)

References 35 publications

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“…Gavegnano et al . reported that ruxolitinib and tofacitinib, two inhibitors with selectivity for subtypes JAK1/2 can potently inhibit viral reactivation in vitro [96]. This suggests that in addition to their direct anti-inflammatory effects, these molecules may also directly act on the virus life cycle, and like dCA, may prevent residual levels of viral production from the reservoir.…”

Section: Clinical Interventions: Breaking the Vicious Circlementioning

confidence: 99%

Residual inflammation and viral reservoirs

Massanella

Fromentin

Chomont

2016

Current Opinion in HIV and AIDS

122

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Purpose of review HIV persists in cellular and anatomical reservoirs during antiretroviral therapy (ART). Viral persistence is ensured by a variety of mechanisms including ongoing viral replication and proliferation of latently infected cells. In this review, we summarize recent findings establishing a link between the unresolved levels of inflammation observed in virally suppressed individuals on ART and the mechanisms responsible for HIV persistence. Recent findings Residual levels of viral replication during ART are associated with persistent low levels of immune activation, suggesting that unresolved inflammation can promote the replenishment of the HIV reservoir in tissues. In addition, the recent findings that the latent HIV reservoir is maintained by continuous proliferation of latently infected cells provide another mechanism by which residual inflammation could contribute to HIV persistence. Summary Residual inflammation during ART is likely to be a critical parameter contributing to HIV persistence. Therefore, reducing inflammation may be an efficient way to interfere with the maintenance of the HIV reservoir in virally suppressed individuals on ART.

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Section: Clinical Interventions: Breaking the Vicious Circlementioning

confidence: 99%

Residual inflammation and viral reservoirs

Massanella

Fromentin

Chomont

2016

Current Opinion in HIV and AIDS

122

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“…A prospective clinical trial is being developed to evaluate this concept further. Other drugs that would limit T cell activation, including those that inhibit the JAK/STAT pathway (76), are also being developed. As chronic inflammation may contribute to excess morbidity in ART-suppressed, HIV-1-infected individuals (9), a number of therapies that target the inflammatory pathways are being developed as adjuncts to therapy (e.g., methotrexate, anti-fibrotic drugs, anti-CMV therapy, and a number of agents aimed at gut mucosa and microbial translocation).…”

Section: Immune Modulating Drugsmentioning

confidence: 99%

Immunologic strategies for HIV-1 remission and eradication

Barouch

Deeks

2014

Science

187

151

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Antiretroviral therapy (ART) is able to suppress HIV-1 replication indefinitely in individuals who have access to these medications, are able to tolerate these drugs, and are motivated to take them daily for life. However, ART is not curative. HIV-1 persists indefinitely during ART as quiescent integrated DNA within memory CD4+ T cells and perhaps other long-lived cellular reservoirs. In this review, we discuss the role of the immune system on the establishment and maintenance of this “latent” HIV-1 reservoir. A detailed understanding of how the host immune system shapes the size and distribution of the viral reservoir should lead to the development of a new generation of immune-based therapeutics, which might eventually contribute to a curative intervention.

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“…Thus, inhibition of the JAK-STAT signaling pathway will inhibit HIV replication. In agreement with this, JAK inhibitors were recently reported to inhibit HIV replication in peripheral blood mononuclear cells (PBMCs) and macrophages (54,55). In contrast to many other viral infections, the activation of the immune system cannot easily inhibit HIV spread within a host.…”

Section: Figmentioning

confidence: 65%

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

Quan

Han

et al. 2017

J Virol

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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-tocell 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.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.KEYWORDS HIV-1, Env mutant, cell-associated viruses, cell dependence, reversion H IV-1 infection of cells can be efficiently established by free virus or directly via cell-cell contact, both involving the binding of the HIV gp120 protein to the cellular CD4 receptor and either the CCR5 or CXCR4 coreceptor (1-3). It has been reported that cell-to-cell transmission is more physiologically relevant and efficient although cell-free HIV may be used to initiate new infections in tissue culture (4-7).HIV-1 entry into target cells is believed to be a multistep and complex process initiated by the envelope protein gp120 binding to cell surface CD4, triggering conformational changes of gp120, followed by a second-step interaction between gp120 and either CXCR4 or CCR5, resulting in fusion between the viral envelope and the cellular plasma membrane (8). In addition to viral gp120 and other viral proteins, several host cell components, including intrinsic immune factors (9) and histocompatibility antigens, can influence HIV infectivity (10, 11). However, some viral factors can also counteract innate host defense mechanisms (12). It has also been reported that HIV can under some circumstances enter target cells via a CD4/coreceptor-independent mechanism (13-18), potentially broadening the spectrum of cells that HIV is able to infect.

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

Cited by 87 publications

References 35 publications

Residual inflammation and viral reservoirs

Residual inflammation and viral reservoirs

Immunologic strategies for HIV-1 remission and eradication

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

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