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

Autor:	Nixon CC; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Mavigner M; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA., Sampey GC; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Qura Therapeutics, Chapel Hill, NC, USA., Brooks AD; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA., Spagnuolo RA; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Irlbeck DM; Qura Therapeutics, Chapel Hill, NC, USA.; HIV Drug Discovery, ViiV Healthcare, Research Triangle Park, NC, USA., Mattingly C; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA., Ho PT; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Schoof N; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA., Cammon CG; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Tharp GK; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA., Kanke M; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Wang Z; GlaxoSmithKline Research and Development, Collegeville, PA, USA., Cleary RA; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Upadhyay AA; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA., De C; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Wills SR; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Qura Therapeutics, Chapel Hill, NC, USA., Falcinelli SD; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Galardi C; Qura Therapeutics, Chapel Hill, NC, USA.; HIV Drug Discovery, ViiV Healthcare, Research Triangle Park, NC, USA., Walum H; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA., Schramm NJ; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Deutsch J; GlaxoSmithKline Research and Development, Collegeville, PA, USA., Lifson JD; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Fennessey CM; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Keele BF; AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA., Jean S; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA., Maguire S; GlaxoSmithKline Research and Development, Collegeville, PA, USA., Liao B; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Infectious Diseases, Guangzhou Eighth People's Hospital, Guangzhou Medical University, Guangzhou, China., Browne EP; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Ferris RG; Qura Therapeutics, Chapel Hill, NC, USA.; HIV Drug Discovery, ViiV Healthcare, Research Triangle Park, NC, USA., Brehm JH; Qura Therapeutics, Chapel Hill, NC, USA.; HIV Drug Discovery, ViiV Healthcare, Research Triangle Park, NC, USA., Favre D; Qura Therapeutics, Chapel Hill, NC, USA.; GlaxoSmithKline Research and Development, Collegeville, PA, USA., Vanderford TH; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA., Bosinger SE; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA., Jones CD; Department of Biology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Routy JP; Chronic Viral Infection Service, McGill University Health Centre, Montreal, Quebec, Canada.; Division of Hematology, McGill University Health Centre, Montreal, Quebec, Canada., Archin NM; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Margolis DM; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Qura Therapeutics, Chapel Hill, NC, USA.; Department of Microbiology and Immunology, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Wahl A; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Dunham RM; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. richard.m.dunham@viivhealthcare.com.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. richard.m.dunham@viivhealthcare.com.; UNC HIV Cure Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. richard.m.dunham@viivhealthcare.com.; Qura Therapeutics, Chapel Hill, NC, USA. richard.m.dunham@viivhealthcare.com.; HIV Drug Discovery, ViiV Healthcare, Research Triangle Park, NC, USA. richard.m.dunham@viivhealthcare.com., Silvestri G; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA.; Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA., Chahroudi A; Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, USA. ann.m.chahroudi@emory.edu.; Yerkes National Primate Research Center, Emory University, Atlanta, GA, USA. ann.m.chahroudi@emory.edu.; Emory + Children's Center for Childhood Infections and Vaccines, Atlanta, GA, USA. ann.m.chahroudi@emory.edu., Garcia JV; International Center for the Advancement of Translational Science, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.; Division of Infectious Diseases, Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.; Center for AIDS Research, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA. victor_garcia@med.unc.edu.
Jazyk:	angličtina
Zdroj:	Nature [Nature] 2020 Feb; Vol. 578 (7793), pp. 160-165. Date of Electronic Publication: 2020 Jan 22.
DOI:	10.1038/s41586-020-1951-3
Abstrakt:	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 reservoir 1 . 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 effect 2-9 . 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.
Databáze:	MEDLINE
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