Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors.
PLoS Pathog
; 13(12): e1006740, 2017 12.
Article
en En
| MEDLINE
| ID: mdl-29267399
ABSTRACT
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.
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Linfocitos T CD4-Positivos
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Infecciones por VIH
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Latencia del Virus
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Fármacos Anti-VIH
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Inhibidores de las Cinasas Janus
Límite:
Humans
Idioma:
En
Revista:
PLoS Pathog
Año:
2017
Tipo del documento:
Article
País de afiliación:
Estados Unidos