当培养来自HIV感染者的免疫细胞时，研究人员发现抗炎药物托法替尼（tofacitinib）和鲁索替尼（ruxolitinib）可阻断被感染的细胞产生HIV，从而将这种病毒传播给邻近的细胞，并清除这种病毒库。相关研究结果于2017年12月21日发表在PLoS Pathogens期刊上，论文标题为“Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors”。
作者: ipsvirus 时间: 2017-12-26 20:34 Novel mechanisms to inhibit HIV reservoir seeding using Jak inhibitors
Christina Gavegnano , Jessica H. Brehm , Franck P. Dupuy , Aarthi Talla, Susan Pereira Ribeiro, Deanna A. Kulpa, Cheryl Cameron, Stephanie Santos, Selwyn J. Hurwitz, Vincent C. Marconi, Jean-Pierre Routy, Laurent Sabbagh, Raymond F. Schinazi , Rafick Pierre Sékaly
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.
