Polyfunctional Tier 2–Neutralizing Antibodies Cloned following HIV-1 Env Macaque Immunization Mirror Native Antibodies in a Human Donor

Abstract

Vaccine efforts to combat HIV are challenged by the global diversity of viral strains and shielding of neutralization epitopes on the viral envelope glycoprotein trimer. Even so, the isolation of broadly neutralizing Abs from infected individuals suggests the potential for eliciting protective Abs through vaccination. This study reports a panel of 58 mAbs cloned from a rhesus macaque (Macaca mulatta) immunized with envelope glycoprotein immunogens curated from an HIV-1 clade C–infected volunteer. Twenty mAbs showed neutralizing activity, and the strongest neutralizer displayed 92% breadth with a median IC50 of 1.35 μg/ml against a 13-virus panel. Neutralizing mAbs predominantly targeted linear epitopes in the V3 region in the cradle orientation (V3C) with others targeting the V3 ladle orientation (V3L), the CD4 binding site (CD4bs), C1, C4, or gp41. Nonneutralizing mAbs bound C1, C5, or undetermined conformational epitopes. Neutralization potency strongly correlated with the magnitude of binding to infected primary macaque splenocytes and to the level of Ab-dependent cellular cytotoxicity, but did not predict the degree of Ab-dependent cellular phagocytosis. Using an individualized germline gene database, mAbs were traced to 23 of 72 functional IgHV alleles. Neutralizing V3C Abs displayed minimal nucleotide somatic hypermutation in the H chain V region (3.77%), indicating that relatively little affinity maturation was needed to achieve in-clade neutralization breadth. Overall, this study underscores the polyfunctional nature of vaccine-elicited tier 2–neutralizing V3 Abs and demonstrates partial reproduction of the human donor’s humoral immune response through nonhuman primate vaccination.

A neutralizing antibody target in early HIV-1 infection was recapitulated in rhesus macaques immunized with the transmitted/founder envelope sequence

“…Our study provides evidence that the nAb outcomes we observed were imprinted on the Z1800M and R66M T/F Envs to some extent, a concept that has been supported by other studies in RM and in HIV transmission pairs [6,[59][60][61]. Our approach also highlights the complexity of generating soluble HIV trimers in the context of diverse variants.…”

VDJ Gene Usage in IgM Repertoires of Rhesus and Cynomolgus Macaques

“…The use of computational inference methods, such as IgDiscover (6), partis (17) and TIgGER (18), provides a means to define VDJ genotypes in individuals in a more time-efficient manner (6,17,18). This approach has been used successfully for studies of antibody diversity, affinity maturation and B cell lineage tracing in immunized macaques (19)(20)(21)(22)(23).…”

CD4+ T Cells Are Dispensable for Induction of Broad Heterologous HIV Neutralizing Antibodies in Rhesus Macaques

“…The VC10014 immunogen platform has consistently demonstrated the induction of Tier 2 heterologous NAbs ( 20 , 21 , 39 ). Although modest, the Imm group showed a trend toward enhanced protection from repeated heterologous challenge, as well as conferring decreased viral burden upon infection.…”

“…In this study, we utilized the VC10014 DNA-protein co-immunization vaccine platform consisting of gp160 plasmids and trimeric gp140 proteins derived from a clade B HIV-1 infected subject who developed broadly neutralizing plasma Abs, which previously induced Tier 2 heterologous neutralizing Abs in rabbits and rhesus macaques ( 19 – 21 ). We evaluated the influence of CD4+ T cell depletion during the vaccination regimen on the characteristics of the Env-specific humoral response in rhesus macaques.…”