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Systemic HIV and SIV latency reversal via non-canonical NF-?B signalling in vivo.

ABSTRACT: 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-?B 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.

SUBMITTER: Nixon CC

PROVIDER: S-EPMC7111210 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo.

Nixon Christopher C CC Mavigner Maud M Sampey Gavin C GC Brooks Alyssa D AD Spagnuolo Rae Ann RA Irlbeck David M DM Mattingly Cameron C Ho Phong T PT Schoof Nils N Cammon Corinne G CG Tharp Greg K GK Kanke Matthew M Wang Zhang Z Cleary Rachel A RA Upadhyay Amit A AA De Chandrav C Wills Saintedym R SR Falcinelli Shane D SD Galardi Cristin C Walum Hasse H Schramm Nathaniel J NJ Deutsch Jennifer J Lifson Jeffrey D JD Fennessey Christine M CM Keele Brandon F BF Jean Sherrie S Maguire Sean S Liao Baolin B Browne Edward P EP Ferris Robert G RG Brehm Jessica H JH Favre David D Vanderford Thomas H TH Bosinger Steven E SE Jones Corbin D CD Routy Jean-Pierre JP Archin Nancie M NM Margolis David M DM Wahl Angela A Dunham Richard M RM Silvestri Guido G Chahroudi Ann A Garcia J Victor JV

Nature 20200122 7793

Long-lasting, latently infected resting CD4<sup>+</sup> 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 reservoir<sup>1</sup>. Alternatively, induction of HIV from its latent state could accelerate the decrease in the reservoir, thus reducing the time to eradication. Prev ...[more]

PMID: 31969707

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Project description:BackgroundThe NF-κB family of transcription factors and associated signalling pathways are abundant and ubiquitous in human immune responses. Activation of NF-κB transcription factors by viral pathogen-associated molecular patterns, such as viral RNA and DNA, is fundamental to anti-viral innate immune defences and pro-inflammatory cytokine production that steers adaptive immune responses. Diverse non-viral stimuli, such as lipopolysaccharide and cytokines, also activate NF-κB and the same anti-pathogen gene networks. Viruses adapted to human cells often encode multiple proteins targeting the NF-κB pathway to mitigate the anti-viral effects of NF-κB-dependent host immunity.ResultsIn this study we have demonstrated using a variety of assays, in a number of different cell types including primary cells, that plasmid-encoded or virus-delivered simian immunodeficiency virus (SIV) accessory protein Vpx is a broad antagonist of NF-κB signalling active against diverse innate NF-κB agonists. Using targeted Vpx mutagenesis, we showed that this novel Vpx phenotype is independent of known Vpx cofactor DCAF1 and other cellular binding partners, including SAMHD1, STING and the HUSH complex. We found that Vpx co-immunoprecipitated with canonical NF-κB transcription factor p65, but not NF-κB family members p50 or p100, preventing nuclear translocation of p65. We found that broad antagonism of NF-κB activation by Vpx was conserved across distantly related lentiviruses as well as for Vpr from SIV Mona monkey (SIVmon), which has Vpx-like SAMHD1-degradation activity.ConclusionsWe have discovered a novel mechanism by which lentiviruses antagonise NF-κB activation by targeting p65. These findings extend our knowledge of how lentiviruses manipulate universal regulators of immunity to avoid the anti-viral sequelae of pro-inflammatory gene expression stimulated by both viral and extra-viral agonists. Importantly our findings are also relevant to the gene therapy field where virus-like particle associated Vpx is routinely used to enhance vector transduction through antagonism of SAMHD1, and perhaps also through manipulation of NF-κB.

Dataset Information

Systemic HIV and SIV latency reversal via non-canonical NF-?B signalling in vivo.

Publications

Systemic HIV and SIV latency reversal via non-canonical NF-κB signalling in vivo.

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