Systemic HIV/SIV latency reversal via activation of the non-canonical NF-B signaling pathway in vivo
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA593849 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10597323.fastq.gz | Fastqsanger.gz | |||
| SRR10597324.fastq.gz | Fastqsanger.gz | |||
| SRR10597325.fastq.gz | Fastqsanger.gz | |||
| SRR10597326.fastq.gz | Fastqsanger.gz | |||
| SRR10597327.fastq.gz | Fastqsanger.gz |
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Project description:Systemic HIV/SIV latency reversal via non-canonical NF-κB signaling in vivo
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Project description:Molecules mimicking the active N-terminal tetrapeptide of the second mitochondrial-derived activator of caspases (SMACm) potently reverse HIV latency in vitro and ex vivo without the pleotropic cellular effects seen with other LRAs. We verified that SMACm facilitate latency reversal through activation of the non-canonical NFκB pathway as exemplified by rapid degradation of cIAP1, followed by a slower conversion of inactive p100 into active p52. A potent representative of this class, AZD5582, increases cell-associated HIV gag RNA expression in resting CD4+ T cells from ART-suppressed, HIV-infected donors while altering the expression of a restricted number of human genes. These findings represent the first demonstration that SMACm have single agent latency reversal activity in patient-derived cells and support evaluation of SMACm in preclinical animal models.
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Project description:Resting CD4+ T cells that are both persistent and latently infected with HIV represent the most important challenge to HIV eradication. Estimates indicate the need for >70 years of continuous, fully suppressive, antiretroviral therapy (ART) to eliminate the HIV reservoir. Alternatively, induction of HIV from its latent state could accelerate the decline of the reservoir, thereby shortening the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in peripheral blood with minimal focus on tissue reservoirs and had limited effect. We found that activation of the non-canonical NF-B signaling pathway via AZD5582 results in induction of HIV- and SIV-RNA expression in the blood and tissues of ART-suppressed humanized mice and rhesus macaques. Analysis of resting CD4+ T cells from tissues after AZD55852 treatment revealed increased SIV-RNA in lymph nodes in macaques and robust induction of HIV in virtually all tissues analyzed in humanized mice including lymph nodes, thymus, bone marrow, liver, and lung. This promising new approach to latency reversal, in combination with the appropriate tools for systemic clearance of persistent HIV infection, greatly increases opportunities for HIV eradication.
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Project description:Latency reversal and clearance strategies for HIV cure are beginning to employ IAP antagonists (IAPi) to induce unprecedented levels of latent reservoir expression without immunotoxicity during suppressive antiretroviral therapy (ART). However, full targeting of the reservoir may require combinatorial approaches. A Jurkat latency model screen for IAPi combination partners demonstrated synergistic latency reversal with Bromodomain and Extra-Terminal domain protein inhibitors (BETi). Mechanistic investigations using CRISPR-CAS9 and single cell-RNAseq informed comprehensive ex vivo evaluations of IAPi plus pan-BET, bromodomain (BD)-selective BET, or selective BET isoform targeting in CD4 T cells from ART-suppressed donors. IAPi+BETi treatment resulted in striking induction of cell-associated HIV gag RNA but lesser induction of fully elongated and tat-rev RNA, especially compared to T cell activation positive controls. IAPi/BETi resulted in HIV protein induction in bulk cultures of CD4 T cells using an ultrasensitive p24 assay, but did not translate to enhanced viral outgrowth frequency using a standard quantitative viral outgrowth assay. Overall, this study defines HIV transcriptional elongation and splicing as key barriers to latent HIV protein expression following latency reversal, delineates the roles of BET proteins and their bromodomains in HIV latency, and provides rationale for testing of IAPi+BETi in animal models of HIV latency.
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Project description:HIV latency reversal via combined non-canonical NF- B agonism and targeted BET family bromodomain inhibition
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Project description:Long-lasting, latently infected resting CD4+ T cells are the greatest obstacle to obtaining a cure for HIV infection, as these cells can persist despite decades of treatment with antiretroviral therapy (ART). Estimates indicate that more than 70 years of continuous, fully suppressive ART are needed to eliminate the HIV reservoir1. Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Previous attempts to reactivate latent HIV in preclinical animal models and in clinical trials have measured HIV induction in the peripheral blood with minimal focus on tissue reservoirs and have had limited effect2-9. Here we show that activation of the non-canonical NF-κB signalling pathway by AZD5582 results in the induction of HIV and SIV RNA expression in the blood and tissues of ART-suppressed bone-marrow-liver-thymus (BLT) humanized mice and rhesus macaques infected with HIV and SIV, respectively. Analysis of resting CD4+ T cells from tissues after AZD5582 treatment revealed increased SIV RNA expression in the lymph nodes of macaques and robust induction of HIV in almost all tissues analysed in humanized mice, including the lymph nodes, thymus, bone marrow, liver and lung. This promising approach to latency reversal-in combination with appropriate tools for systemic clearance of persistent HIV infection-greatly increases opportunities for HIV eradication.
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Project description:HIV-1 persistence during ART is due to the establishment of long-lived viral reservoirs in resting immune cells. Using an NHP model of barcoded SIVmac239 intravenous infection and therapeutic dosing of the anti-TGFBR1 inhibitor galunisertib (LY2157299), we confirmed the latency reversal properties of in vivo TGF-beta blockade, decreased viral reservoirs and stimulated immune responses. Eight SIV-infected macaques on suppressive ART were treated with 4 2-week cycles of galunisertib. ART was discontinued 3 weeks after the last dose, and macaques euthanized 6 weeks after ART-interruption(ATI). One macaque did not rebound, while the remaining rebounded between week 2 and 6 post-ATI. Galunisertib led to viral reactivation as indicated by plasma viral load and immunoPET/CT with the 64Cu-DOTA-F(ab')2-p7D3-probe. Half to 1 Log decrease in cell-associated (CA-)SIV DNA was detected in lymph nodes, gut and PBMC, while intact pro-virus in PBMC decreased by 3-fold. No systemic increase in inflammatory cytokines was observed. High-dimensions cytometry, bulk and single-cell RNAseq revealed a shift toward an effector phenotype in T and NK cells.
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