Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo

Pache, Lars; Marsden, Matthew D.; Teriete, Peter; Portillo, Alex J.; Heimann, Dominik; Kim, Jocelyn T.; Soliman, Mohamed S.; Dimapasoc, Melanie; Carmona, Christopher; Celeridad, Maria; Spivak, Adam M.; Planelles, Vicente; Cosford, Nicholas D. P.; Zack, Jerome A.; Chanda, Sumit K.

doi:10.1016/j.xcrm.2020.100037

Cited by 39 publications

(44 citation statements)

References 75 publications

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“…The virus used in this study encodes a reporter gene and barcode in place of Vpr. While we have found that the replacement of Vpr with this reporter does not prevent the establishment of or reactivation from latency in humanized mice, 9,12,32 this particular virus is not suitable for capturing the effects of Vpr on latency. In addition, HIV latency reversal and reservoir cell killing were demonstrated using the LRA SUW133 in BLT mice in a prior study, 12 but those experiments were not repeated here (doing so may provide additional information on reservoir depletion during ART).…”

Section: Limitations Of Studymentioning

confidence: 85%

Tracking HIV Rebound following Latency Reversal Using Barcoded HIV

Marsden

Zhang

et al. 2020

Cell Reports Medicine

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Summary HIV latency prevents cure of infection with antiretroviral therapy (ART) alone. One strategy for eliminating latently infected cells involves the induction of viral protein expression via latency-reversing agents (LRAs), allowing killing of host cells by viral cytopathic effects or immune effector mechanisms. Here, we combine a barcoded HIV approach and a humanized mouse model to study the effects of a designed, synthetic protein kinase C modulating LRA on HIV rebound. We show that administration of this compound during ART results in a delay in rebound once ART is stopped. Furthermore, the rebounding virus appears composed of a smaller number of unique barcoded viruses than occurs in control-treated animals, suggesting that some reservoir cells that would have contributed virus to the rebound process are eliminated by LRA administration. These data support the use of barcoded virus to study rebound and suggest that LRAs may be useful in HIV cure efforts.

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Section: Limitations Of Studymentioning

confidence: 85%

Tracking HIV Rebound following Latency Reversal Using Barcoded HIV

Marsden

Zhang

et al. 2020

Cell Reports Medicine

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“…Our studies have shown that although P-TEFb biogenesis after TCR stimulation is the result of multiple complementary signaling pathways, effective activation can be achieved through the RasGRP1-Raf-ERK1/2 pathway. It therefore seems likely that selectively activating this pathway in combination with activation of a transcription initiation factor, for example using a non-canonical activator of NF-κB [109], provides an optimal strategy for latency reversal in the absence of full T-cell activation – the key missing element in the “shock and kill” HIV eradication strategy.…”

Section: Resultsmentioning

confidence: 99%

Biogenesis of P-TEFb in CD4⁺T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways

Mbonye

Leskov

Shukla

et al. 2021

Preprint

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The switch between HIV latency and productive transcription is regulated by an auto-feedback mechanism initiated by the viral trans-activator Tat, which functions to recruit the host transcription elongation factor P-TEFb to proviral HIV. A heterodimeric complex of CDK9 and one of three cyclin T subunits, P-TEFb is expressed at vanishingly low levels in resting memory CD4 + T cells and cellular mechanisms controlling its availability are central to regulation of the emergence of HIV from latency. Using a well-characterized primary T-cell model of HIV latency alongside healthy donor memory CD4 + T cells, we characterized specific T-cell receptor (TCR) signaling pathways that regulate the generation of transcriptionally active P-TEFb, defined as the coordinate expression of cyclin T1 and phospho-Ser175 CDK9. Protein kinase C (PKC) agonists, such as ingenol and prostratin, stimulated active P-TEFb expression and reactivated latent HIV with minimal cytotoxicity, even in the absence of intracellular calcium mobilization with an ionophore. Unexpectedly, inhibition-based experiments demonstrated that PKC agonists and TCR-mobilized diacylglycerol signal through MAP kinases ERK1/2 rather than through PKC to effect the reactivation of both P-TEFb and latent HIV. Single-cell and bulk RNA-seq analyses revealed that of the four known isoforms of the Ras guanine nucleotide exchange factor RasGRP, RasGRP1 is by far the predominantly expressed diacylglycerol-dependent isoform in CD4 + T cells. RasGRP1 should therefore mediate the activation of ERK1/2 via Ras-Raf signaling upon TCR co-stimulation or PKC agonist challenge. Combined inhibition of the PI3K-mTORC2-AKT-mTORC1 pathway and the ERK1/2 activator MEK prior to TCR co-stimulation abrogated active P-TEFb expression and substantially suppressed latent HIV reactivation. Therefore, contrary to prevailing models, the coordinate reactivation of P-TEFb and latent HIV in primary T cells following either TCR co-stimulation or PKC agonist challenge is independent of PKC but rather involves two complementary signaling arms of the TCR cascade, namely, RasGRP1-Ras-Raf-MEK-ERK1/2 and PI3K-mTORC2-AKT-mTORC1.

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“…IAPi exhibited synergism with HDACis such as vorinostat in vitro , which favors the use of IAPi in conjugation with other LRAs to exploit diverse mechanisms for elimination of latent HIV reservoirs. The structure-activity relationship analysis indicates that bivalent molecule of IAPi is more potent than monovalent compound where its potency may be enhanced by the two binding motifs of BIR domains in cIAP protein [74] ( Fig. 3 ).…”

Section: Understanding the Importance Of Noncanonical Nf-κb In Hiv Cumentioning

confidence: 99%

NF-κB sub-pathways and HIV cure: A revisit

Wong

Jiang

2021

EBioMedicine

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HIV cure is thwarted by the presence of quiescent yet replication competent HIV-1 (HIV). Antiretroviral therapy (ART) is unable to eradicate reservoirs, and upon cessation of ART, HIV will rebound. This review encompasses the curative strategies of HIV in the context of NF-κB sub-pathways that are currently exploited and demonstrate promise in the disruption of latent HIV. Canonical NF-κB signaling has long been established to drive HIV proviral expression while noncanonical NF-κB signaling, a novel and perhaps more desirable mechanism of latency reversal due to its unique characteristics, has recently been shown to also promote HIV expression from latency. Furthermore, we discuss the previously unrecognized upstream signaling of NF-κB as a new avenue for exploration of a functional cure of HIV.

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Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo

Cited by 39 publications

References 75 publications

Tracking HIV Rebound following Latency Reversal Using Barcoded HIV

Tracking HIV Rebound following Latency Reversal Using Barcoded HIV

Biogenesis of P-TEFb in CD4⁺T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways

NF-κB sub-pathways and HIV cure: A revisit

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Pharmacological Activation of Non-canonical NF-κB Signaling Activates Latent HIV-1 Reservoirs In Vivo

Cited by 39 publications

References 75 publications

Tracking HIV Rebound following Latency Reversal Using Barcoded HIV

Tracking HIV Rebound following Latency Reversal Using Barcoded HIV

Biogenesis of P-TEFb in CD4+T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways

NF-κB sub-pathways and HIV cure: A revisit

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Biogenesis of P-TEFb in CD4⁺T cells to reverse HIV latency is mediated by protein kinase C (PKC)-independent signaling pathways