SIV-Specific Neutralizing Antibody Induction Following Selection of a T-Cell Escape nef Mutation

HIV and simian immunodeficiency virus (SIV) infections are known for impaired neutralizing antibody (NAb) responses. While sequential virus-host B cell interaction has been indicated to be a baseline requisite for NAb induction, what events may further drive NAb induction has remained largely unknown. Here we describe anti-SIV NAb induction triggered after selection of a T-cell escape nef variant. Screening of seventy neutralization-resistant SIVmac239-infected macaques found seven animals inducing NAbs in the chronic phase. These selected for a CD8+ T-cell escape mutation in viral nef before NAb induction. This mutation reduces Nef-mediated hyperactivation of Akt, a canonical negative regulator of B-cell maturation, in Nef-invaded B cells, explanatory for amelioration in Nef/Akt-mediated suppression of B-cell maturation. Indeed, SIV Env-specific B-cell responses were elevated following the mutant selection. These results highlight Nef-mediated B-cell perturbation in HIV/SIV infection and provide an understanding of sequential virus interaction with both wings of adaptive immune responses.