SIV-specific neutralizing antibody induction following selection of a PI3K drive-attenuated nef variant

• Published in: eLife Vol. 12
• Main Authors: Yamamoto, Hiroyuki, Matano, Tetsuro
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 03.03.2025; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: 1-Phosphatidylinositol 3-kinase; Acquired immune deficiency syndrome; AIDS; Animals; Antibodies; Antibodies, Neutralizing - immunology; Antibodies, Viral - immunology; B-Lymphocytes - immunology; Biological research; Biology, Experimental; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Haplotypes; HIV; Human immunodeficiency virus; Humans; Immune system; Immunology and Inflammation; immunosignaling; Infections; Kinases; Lymphocytes B; Lymphocytes T; Macaca mulatta; Microbiology and Infectious Disease; Mutation; Nef; neutralizing antibody; Phosphatidylinositol 3-Kinases - metabolism; Phosphoinositides; Phosphotransferases; PI3K; Plasma; Rapamycin; Simian Acquired Immunodeficiency Syndrome - immunology; Simian Acquired Immunodeficiency Syndrome - virology; Simian immunodeficiency virus; Simian Immunodeficiency Virus - genetics; Simian Immunodeficiency Virus - immunology; SIV; TOR protein; Viral antibodies; Viral infections; Viral Regulatory and Accessory Proteins - genetics; Viral Regulatory and Accessory Proteins - immunology; Viruses; Japan; SIV; rhesus macaque; viruses; immunosignaling; HIV; PI3K; infectious disease; inflammation; microbiology; neutralizing antibody; immunology; Nef
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.88849

HIV and simian immunodeficiency virus (SIV) infections are known for impaired neutralizing antibody (NAb) responses. While sequential virus–host B cell interaction appears to be basally required for NAb induction, driver molecular signatures predisposing to NAb induction still remain largely unknown. Here we describe SIV-specific NAb induction following a virus–host interplay decreasing aberrant viral drive of phosphoinositide 3-kinase (PI3K). Screening of seventy difficult-to-neutralize SIV mac239 -infected macaques found nine NAb-inducing animals, with seven selecting for a specific CD8 + T-cell escape mutation in viral nef before NAb induction. This Nef-G63E mutation reduced excess Nef interaction-mediated drive of B-cell maturation-limiting PI3K/mammalian target of rapamycin complex 2 (mTORC2). In vivo imaging cytometry depicted preferential Nef perturbation of cognate Envelope-specific B cells, suggestive of polarized contact-dependent Nef transfer and corroborating cognate B-cell maturation post-mutant selection up to NAb induction. Results collectively exemplify a NAb induction pattern extrinsically reciprocal to human PI3K gain-of-function antibody-dysregulating disease and indicate that harnessing the PI3K/mTORC2 axis may facilitate NAb induction against difficult-to-neutralize viruses including HIV/SIV.