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

Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Science translational medicine (Impact Factor: 15.84). 07/2012; 4(142):142ra96. DOI: 10.1126/scitranslmed.3003752
Source: PubMed


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.

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    • "Prior to our study, no expressed antibody sequence data existed for lemurs. Even so, previous studies focused on primate evolution and biomedical applications have identified sequence homology among the genes underlying the formation of antibodies (Meek et al. 1991; Helmuth et al. 2000; Link et al. 2002; Sundling et al. 2012). This information motivated us to map lemur transcriptome data to the human heavy-chain locus, a region approximately 1.27 Mb long that encodes the heavy-chain immunoglobulin genes (Matsuda et al. 1998). "
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    • "Compared with mice and other animal species, the homology of the rhesus and human immunoglobulin genes is high. A recent analysis confirmed that the average homology between the corresponding rhesus VH and human VH genes is approximately 92% [14]. In our study, generating a chimeric antibody containing macaque VH and VL combined with human immunoglobulin constant regions, increased the degree of humanness in the full-length antibody to greater than 97%, which is much higher than human-mouse chimeric antibodies. "
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