Nef defect attenuates HIV viremia and immune dysregulation in the bone marrow-liver-thymus-spleen (BLTS) humanized mouse model

• Published in: Virology (New York, N.Y.) Vol. 598; p. 110192
• Main Authors: Biradar, Shivkumar, Agarwal, Yash, Das, Antu, Shu, Sherry T., Samal, Jasmine, Ho, Sara, Kelly, Nickolas, Mahesh, Deepika, Teredesai, Shreya, Castronova, Isabella, Mussina, London, Mailliard, Robbie B., Smithgall, Thomas E., Bility, Moses T.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.10.2024
• Subjects: Animals; BLTS-Humanized mice; Bone Marrow - immunology; Bone Marrow - virology; Disease Models, Animal; HIV Infections - immunology; HIV Infections - virology; HIV nef; HIV-1 - genetics; HIV-1 - immunology; HIV-1 - physiology; Humans; Immune dysregulation; Immunity, Innate; Liver - immunology; Liver - pathology; Liver - virology; Mice; nef Gene Products, Human Immunodeficiency Virus - genetics; nef Gene Products, Human Immunodeficiency Virus - immunology; Spleen - immunology; Spleen - virology; Thymus Gland - immunology; Thymus Gland - virology; Viremia - immunology; Virus Replication; Immune dysregulation; BLTS-Humanized mice; HIV nef
• ISSN: 0042-6822; 1096-0341; 1096-0341
• DOI: 10.1016/j.virol.2024.110192

In vitro studies have shown that deletion of nef and deleterious mutation in the Nef dimerization interface attenuates HIV replication and associated pathogenesis. Humanized rodents with human immune cells and lymphoid tissues are robust in vivo models for investigating the interactions between HIV and the human immune system. Here, we demonstrate that nef deletion impairs HIV replication and HIV-induced immune dysregulation in the blood and human secondary lymphoid tissue (human spleen) in bone marrow-liver-thymus-spleen (BLTS) humanized mice. Furthermore, we also show that nef defects (via deleterious mutations in the dimerization interface) impair HIV replication and HIV-induced immune dysregulation in the blood and human spleen in BLTS-humanized mice. We demonstrate that the reduced replication of nef-deleted and nef-defective HIV is associated with robust antiviral innate immune response, and T helper 1 response. Our results support the proposition that Nef may be a therapeutic target for adjuvants in HIV cure strategies. [Display omitted] •The human immune system in the BLTS-humanized mice controls nef-defective HIV viremia.•HIV nef defect abrogates HIV-induced CD4+ T cell depletion in BLTS-humanized mice.•HIV nef defect abrogates HIV-induced T cell-checkpoint inhibitor expression in the human spleen.•Nef dimerization defect abrogates HIV-induced immune dysregulation in the human spleen.