Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors

PLoS Pathogens

Cheryl Cameron¹  Susan Pereira Ribeiro¹  Jessica H. Brehm¹  Rafick Pierre Sékaly¹  Aarthi Talla¹  Christina Gavegnano²  Raymond F. Schinazi²  Deanna A. Kulpa²  Selwyn J. Hurwitz²  Jean-Pierre Routy³  Vincent C. Marconi⁴  Franck P. Dupuy⁵  Stephanie Santos⁶  Laurent Sabbagh⁷ 

[1] Case Western Reserve University, Dept. of Pathology, Cleveland, OH, United States of America;Center for AIDS Research, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University, Atlanta, GA, United States of America;Chronic Viral Illnesses Service Research Institute, Division of Hematology, McGill University Health Centre, Montréal, QC, Canada;Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA, United States of America;Research Institute of the MUHC, Montréal, QC, Canada;Unconditional Love, Melbourne, FL, United States of America;Université de Montréal, Department of Microbiology, Infectiology, and Immunology, Montreal, QC, Canada

关键词: HIV;    T cells;    Cytokines;    HIV infections;    Viral replication;    Phosphorylation;    T helper cells;    Memory T cells;   

DOI  :  10.1371/journal.ppat.1006740

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

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.

【 授权许可】

CC BY