title: Blocking type I interferon signaling enhances T cell recovery and reduces HIV-1 reservoirs.
abstract: Despite the efficient suppression of HIV-1 replication that can be achieved with combined antiretroviral therapy (cART), low levels of type I interferon (IFN-I) signaling persist in some individuals. This sustained signaling may impede immune recovery and foster viral persistence. Here we report studies using a monoclonal antibody to block IFN-α/β receptor (IFNAR) signaling in humanized mice (hu-mice) that were persistently infected with HIV-1. We discovered that effective cART restored the number of human immune cells in HIV-1-infected hu-mice but did not rescue their immune hyperactivation and dysfunction. IFNAR blockade fully reversed HIV-1-induced immune hyperactivation and rescued anti-HIV-1 immune responses in T cells from HIV-1-infected hu-mice. Finally, we found that IFNAR blockade in the presence of cART reduced the size of HIV-1 reservoirs in lymphoid tissues and delayed HIV-1 rebound after cART cessation in the HIV-1-infected hu-mice. We conclude that low levels of IFN-I signaling contribute to HIV-1-associated immune dysfunction and foster HIV-1 persistence in cART-treated hosts. Our results suggest that blocking IFNAR may provide a potential strategy to enhance immune recovery and reduce HIV-1 reservoirs in individuals with sustained elevations in IFN-I signaling during suppressive cART.
authors.forename: Liang
authors.initials: L
authors.lastname: Cheng
authors.forename: Jianping
authors.initials: J
authors.lastname: Ma
authors.forename: Jingyun
authors.initials: J
authors.lastname: Li
authors.forename: Dan
authors.initials: D
authors.lastname: Li
authors.forename: Guangming
authors.initials: G
authors.lastname: Li
authors.forename: Feng
authors.initials: F
authors.lastname: Li
authors.forename: Qing
authors.initials: Q
authors.lastname: Zhang
authors.forename: Haisheng
authors.initials: H
authors.lastname: Yu
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Yasui
authors.forename: Chaobaihui
authors.initials: C
authors.lastname: Ye
authors.forename: Li-Chung
authors.initials: LC
authors.lastname: Tsao
authors.forename: Zhiyuan
authors.initials: Z
authors.lastname: Hu
authors.forename: Lishan
authors.initials: L
authors.lastname: Su
authors.forename: Liguo
authors.initials: L
authors.lastname: Zhang
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000494:pharmacology*; D002908:Chronic Disease; D004195:Disease Models, Animal; D015658:HIV Infections / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007370:Interferon Type I / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008817:Mice, Mutant Strains; D053633:Receptor, Interferon alpha-beta / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D020127:Recovery of Function / Q000187:drug effects* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics / Q000276:immunology
chemical_list: D044966:Anti-Retroviral Agents; D007370:Interferon Type I; D053633:Receptor, Interferon alpha-beta