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

Abstract

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 reciprocal to a congenital human antibody-dysregulating disease. Screening of seventy neutralization-resistant SIVmac239-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 mutation reduced aberrant Nef interaction-mediated drive of B-cell maturation-limiting phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin complex 2 (mTORC2). In vivo imaging cytometry depicted preferential Nef perturbation of cognate Envelope-specific B cells, corroborating cognate B-cell maturation post-mutant selection up to NAb induction. Results exemplify a NAb induction pattern extrinsically reciprocal to human PI3K gain-of-function antibody dysregulation, shaped through two-front, sequential virus interaction with both wings of adaptive immunity.