High-Resolution Definition of Vaccine-Elicited B Cell Responses Against the HIV Primary Receptor Binding Site

Vaccine-elicited mAbs bind the HIV-1 Env CD4bs differently from broadly neutralizing infection-induced mAbs. Neutralizing HIV A successful vaccine elicits broadly neutralizing antibodies that bind to viruses and prevent infection, but achieving this feat has been a challenge in HIV vaccine development. A prime target for these antibodies is the HIV envelope glycoprotein Env, which binds to CD4 expressed on T cells, resulting in infection. The CD4 binding site on Env is highly conserved, and broadly reactive neutralizing antibodies have been found that selectively bind to this site in HIV-infected individuals. However, when Env is used as an immunogen, the antibodies elicited have only limited neutralization ability. Sundling et al. use a macaque model of HIV infection to tease apart the differences between the infection- and the vaccine-induced antibodies to the CD4 binding site of Env. One limitation for HIV vaccine studies has been the lack of an animal model that mimics human disease. Sundling et al. found that the immunogenetics of the rhesus macaque immunoglobulin locus are similar to those of humans supporting the use of nonhuman primates for preclinical vaccine studies. The authors then immunized these macaques with Env and compared the elicited antibodies with known infection-induced antibodies targeting the CD4 binding site of HIV. They found that the vaccine-induced antibodies are different from broadly neutralizing infection-induced antibodies in the fine specificities targeted within the CD4 binding site as well as in the degree of somatic hypermutation. However, the vaccine-induced antibodies are not very different from non-broadly neutralizing, infection-induced antibodies. These results provide direction for researchers seeking to develop effective HIV vaccine candidates. The high overall genetic homology between humans and rhesus macaques, coupled with the phenotypic conservation of lymphocyte populations, highlights the potential use of nonhuman primates (NHPs) for the preclinical evaluation of vaccine candidates. For HIV-1, experimental models are needed to identify vaccine regimens capable of eliciting desired immune responses, such as broadly neutralizing antibodies (bNAbs). One important neutralization target on the HIV-1 envelope glycoproteins (Envs) is the conserved primary CD4 receptor binding site (CD4bs). The isolation and characterization of CD4bs-specific neutralizing monoclonal Abs (mAbs) from HIV-1–infected individuals have provided insights into how broadly reactive Abs target this conserved epitope. In contrast, and for reasons that are not understood, current Env immunogens elicit CD4bs-directed Abs with limited neutralization breadth. To facilitate the use of the NHP model to address this and other questions relevant to human humoral immunity, we defined features of the rhesus macaque immunoglobulin (Ig) loci and compared these to the human Ig loci. We then studied Env-immunized rhesus macaques, identified single B cells expressing CD4bs-specific Abs, and sequenced and expressed a panel of functional mAbs. Comparison of vaccine-elicited mAbs with HIV-1 infection–induced mAbs revealed differences in the degree of somatic hypermutation of the Abs as well as in the fine specificities targeted within the CD4bs. These data support the use of the preclinical NHP model to characterize vaccine-induced B cell responses at high resolution.