Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors

• Type of Material: Article
• Authors: Christina Gavegnano, Emory University; Jessica H. Brehm, Case Western Reserve University; Franck P. Dupuy, Research Institute of the MUHC; Aarthi Talla, Case Western Reserve University; Susan Pereira Ribeiro, Case Western Reserve University; Deanna A. Kulpa, Emory University; Cheryl Cameron, Case Western Reserve University; Stephanie Santos, Unconditional Love; Selwyn Hurwitz, Emory University; Vincent Marconi, Emory University; Jean-Pierre Routy, McGill University; Laurent Sabbagh, Université de Montréal; Raymond F Schinazi, Emory University; Rafick Pierre Sekaly, Case Western Reserve University
• Language: English
• Date: 2017-12-21
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2017 Gavegnano et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1371/journal.ppat.1006740
• Title of Journal or Parent Work: PLoS Pathogens
• ISSN: 1553-7366
• Volume: 13
• Issue: 12
• Start Page: e1006740
• End Page: e1006740
• Grant/Funding Information: This work was generously supported by NIH-NIMH grant 1R01MH100999 and NIH-NIAID grant 5P30AI050409 (to RFS); Center for AIDS Research, NIH-NIAID grant 5P01AI076174 and NIH-NIAID grant 5U19AI096109 (to RPS); amfAR fellowship 108261-51-RFRL (to FPD), and the amfAR Impact grant 109222-58-RGRL (to CC).
• Keywords: FAMILY CYTOKINES; SIGNALING PATHWAYS; Phosphorylation; RHEUMATOID-ARTHRITIS; INTERLEUKIN-7 PROMOTES; INFECTED PATIENTS; T cells; Parasitology; T helper cells; Cytokines; Life Sciences & Biomedicine; BLOOD-BRAIN-BARRIER; REGULATORY T-CELLS; IN-VITRO; HIV infections; HIV; Viral replication; Virology; ANTIRETROVIRAL THERAPY; Microbiology; Science & Technology; Memory T cells; TRANSCRIPTION FACTOR
• Research Categories: Biology, Microbiology; Biology, Virology; Health Sciences, Immunology

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.