High-resolution definition of vaccine-elicited B cell responses against the HIV primary receptor binding site.
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.
Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Christopher
C
Sundling
Yuxing
Y
Li
Nick
N
Huynh
Christian
C
Poulsen
Richard
R
Wilson
Sijy
S
O'Dell
Yu
Y
Feng
John R
JR
Mascola
Richard T
RT
Wyatt
Gunilla B
GB
Karlsson Hedestam
D016915:AIDS Vaccines / Q000276:immunology*; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D057134:Antibodies, Neutralizing / Q000276:immunology; D000915:Antibody Affinity / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology* / Q000821:virology*; D001665:Binding Sites; D015704:CD4 Antigens / Q000276:immunology*; D002469:Cell Separation; D000939:Epitopes / Q000276:immunology; D056426:Genetic Loci / Q000235:genetics; D014644:Genetic Variation; D015483:HIV Antibodies / Q000737:chemistry; D015699:HIV Envelope Protein gp120 / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology*; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000276:immunology; D007156:Immunologic Memory / Q000276:immunology; D008024:Ligands; D008253:Macaca mulatta / Q000276:immunology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D012689:Sequence Homology, Nucleic Acid; D059010:Single-Cell Analysis
D016915:AIDS Vaccines; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D015704:CD4 Antigens; D000939:Epitopes; D015483:HIV Antibodies; D015699:HIV Envelope Protein gp120; D007143:Immunoglobulin Heavy Chains; D008024:Ligands