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[PMID]:29267399
[Au] Autor:Gavegnano C; Brehm JH; Dupuy FP; Talla A; Ribeiro SP; Kulpa DA; Cameron C; Santos S; Hurwitz SJ; Marconi VC; Routy JP; Sabbagh L; Schinazi RF; Sékaly RP
[Ad] Endereço:Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA, United States of America.
[Ti] Título:Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.
[So] Source:PLoS Pathog;13(12):e1006740, 2017 12.
[Is] ISSN:1553-7374
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Despite advances in the treatment of HIV infection with ART, elucidating strategies to overcome HIV persistence, including blockade of viral reservoir establishment, maintenance, and expansion, remains a challenge. T cell homeostasis is a major driver of HIV persistence. Cytokines involved in regulating homeostasis of memory T cells, the major hub of the HIV reservoir, trigger the Jak-STAT pathway. We evaluated the ability of tofacitinib and ruxolitinib, two FDA-approved Jak inhibitors, to block seeding and maintenance of the HIV reservoir in vitro. We provide direct demonstration for involvement of the Jak-STAT pathway in HIV persistence in vivo, ex vivo, and in vitro; pSTAT5 strongly correlates with increased levels of integrated viral DNA in vivo, and in vitro Jak inhibitors reduce the frequency of CD4+ T cells harboring integrated HIV DNA. We show that Jak inhibitors block viral production from infected cells, inhibit γ-C receptor cytokine (IL-15)-induced viral reactivation from latent stores thereby preventing transmission of infectious particles to bystander activated T cells. These results show that dysregulation of the Jak-STAT pathway is associated with viral persistence in vivo, and that Jak inhibitors target key events downstream of γ-C cytokine (IL-2, IL-7 and IL-15) ligation to their receptors, impacting the magnitude of the HIV reservoir in all memory CD4 T cell subsets in vitro and ex vivo. Jak inhibitors represent a therapeutic modality to prevent key events of T cell activation that regulate HIV persistence and together, specific, potent blockade of these events may be integrated to future curative strategies.
[Mh] Termos MeSH primário: Fármacos Anti-HIV/farmacologia
Linfócitos T CD4-Positivos/virologia
Infecções por HIV/virologia
Inibidores de Janus Quinases/farmacologia
Latência Viral/efeitos dos fármacos
[Mh] Termos MeSH secundário: Linfócitos T CD4-Positivos/efeitos dos fármacos
Células Cultivadas
HIV-1/efeitos dos fármacos
HIV-1/fisiologia
Seres Humanos
Piperidinas/farmacologia
Pirazóis/farmacologia
Pirimidinas/farmacologia
Pirróis/farmacologia
Replicação Viral/efeitos dos fármacos
[Pt] Tipo de publicação:JOURNAL ARTICLE; RESEARCH SUPPORT, N.I.H., EXTRAMURAL; RESEARCH SUPPORT, NON-U.S. GOV'T
[Nm] Nome de substância:
0 (Anti-HIV Agents); 0 (INCB018424); 0 (Janus Kinase Inhibitors); 0 (Piperidines); 0 (Pyrazoles); 0 (Pyrimidines); 0 (Pyrroles); 87LA6FU830 (tofacitinib)
[Em] Mês de entrada:1801
[Cu] Atualização por classe:180111
[Lr] Data última revisão:
180111
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171222
[St] Status:MEDLINE
[do] DOI:10.1371/journal.ppat.1006740



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