Targeting type I interferon–mediated activation restores immune function in chronic HIV infection

Zhen, Anjie; Rezek, Valerie; Youn, Cindy; Lam, Brianna; Chang, Nelson Y.; Rick, Jonathan W.; Carrillo, Mayra A.; Martin, Heather; Kasparian, Saro; Syed, Philip; Rice, Nicholas; Brooks, David G.; Kitchen, Scott G.

doi:10.1172/jci89488

Cited by 153 publications

(188 citation statements)

References 31 publications

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“…A recent report showed that blockade of IFNAR2 during the chronic phase of HIV-1 infection in hu-mice led to decreased viral replication, diminished HIV-1-driven immune activation, and restored HIV-1-specific CD8 + T cell function (43). The difference between the 2 studies is that Zhen et al used a mAb to block IFNAR2, while we used a mAb to block IFNAR1.…”

Section: Discussionmentioning

confidence: 94%

Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection

Liu¹,

Yu²,

Li³

et al. 2017

JCI Insight

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Section: Discussionmentioning

confidence: 94%

Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection

Liu¹,

Yu²,

Li³

et al. 2017

JCI Insight

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“…The efficacy of dCA in vivo was shown using the BLT humanized mouse model validated for the analysis of HIV latency and persistence (Cheng et al, 2017; Denton et al, 2014; Denton et al, 2012; Garcia, 2016; Melkus et al, 2006; Zhen et al, 2017). Humanized BLT mice are an excellent model for evaluating HIV latency as they allow us to track HIV infection of human cells, in the context of a complex substrate that includes mature T and B lymphocytes, monocytes, macrophages and dendritic cells, as they infiltrate all organs and tissues in a living organism.…”

Section: Discussionmentioning

confidence: 99%

“…Numerous studies have shown BLT mice recapitulate key features of HIV infection, pathogenesis, and latency (Cheng et al, 2017; Denton et al, 2014; Denton et al, 2012; Garcia, 2016; Melkus et al, 2006; Zhen et al, 2017). Administration of dCA to ART suppressed animals for a period of two weeks resulted in a general one log loss of viral RNA in tissues.…”

Section: Introductionmentioning

confidence: 99%

In Vivo Suppression of HIV Rebound by Didehydro-Cortistatin A, a “Block-and-Lock” Strategy for HIV-1 Treatment

et al. 2017

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SUMMARY HIV-1 Tat activates viral transcription and limited Tat-transactivation correlates with latency establishment. We postulated a “block-and-lock” functional cure approach based on properties of the Tat-inhibitor didehydro-Cortistatin A (dCA). HIV-1 transcriptional inhibitors could block ongoing viremia during antiretroviral therapy (ART), locking the HIV promoter in persistent latency. We investigated this hypothesis in human CD4+T cells isolated from aviremic individuals. Combining dCA with ART accelerates HIV-1 suppression and prevents viral rebound after treatment interruption, even during strong cellular activation. We show that dCA mediates epigenetic silencing by increased nucleosomal occupancy at Nucleosome-1, restricting RNAPII recruitment to the HIV-1 promoter. The efficacy of dCA was studied in the bone marrow-liver-thymus (BLT) mouse model of HIV latency and persistence. Adding dCA to ART suppressed mice systemically reduces viral mRNA in tissues. Moreover, dCA significantly delays and reduces viral rebound levels upon treatment interruption. Altogether this work demonstrates the potential of “block-and-lock” cure strategies.

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“…Interestingly, type I IFNs have been shown to cause immunopathology and/or negative effects even in some acute viral infections (e.g., influenza, severe acute respiratory syndrome-associated coronavirus) and in several bacterial infections [1,[10][11][12]. https://doi.org/10.1016/j.cytogfr.2018.03.003 Received 24 January 2018; Received in revised form 23 February 2018; Accepted 8 March 2018 Given the growing evidence of type I IFN involvement in viral disease progression, it is not surprising that the possibility to target either type I IFN or the mechanisms leading to IFN production in HIV-1 disease has been considered a promising new therapeutic approach [13,14]. However, the complexity of both the IFN system and HIV-1 immunopathogenesis make the clinical consequences of manipulating type I IFN signaling difficult to predict in vivo.…”

Section: Introductionmentioning

confidence: 99%

Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome

Scagnolari

Antonelli

2018

Cytokine & Growth Factor Reviews

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Type I interferon (IFN) response initially limits HIV-1 spread and may delay disease progression by stimulating several immune system components. Nonetheless, persistent exposure to type I IFN in the chronic phase of HIV-1 infection is associated with desensitization and/or detrimental immune activation, thereby hindering immune recovery and fostering viral persistence. This review provides a basis for understanding the complexity and function of IFN pleiotropic activity in HIV-1 infection. In particular, the dichotomous role of the IFN response in HIV-1 immunopathogenesis will be discussed, highlighting recent advances in the dynamic modulation of IFN production in acute versus chronic infection, expression signatures of IFN subtypes, and viral and host factors affecting the magnitude of IFN response during HIV-1 infection. Lastly, the review gives a forward-looking perspective on the interplay between microbiome compositions and IFN response.

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Targeting type I interferon–mediated activation restores immune function in chronic HIV infection

Cited by 153 publications

References 31 publications

Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection

Type I interferons suppress viral replication but contribute to T cell depletion and dysfunction during chronic HIV-1 infection

In Vivo Suppression of HIV Rebound by Didehydro-Cortistatin A, a “Block-and-Lock” Strategy for HIV-1 Treatment

Type I interferon and HIV: Subtle balance between antiviral activity, immunopathogenesis and the microbiome

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