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. 2009 Dec 18;390(3):404-9.
doi: 10.1016/j.bbrc.2009.09.029. Epub 2009 Sep 11.

Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens

Xiaodong Xiao  1 , Weizao Chen, Yang Feng, Zhongyu Zhu, Ponraj Prabakaran, Yanping Wang, Mei-Yun Zhang, Nancy S Longo, Dimiter S Dimitrov
Affiliations

Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens

Xiaodong Xiao et al. Biochem Biophys Res Commun. .

Abstract

Several human monoclonal antibodies (hmAbs) including b12, 2G12, and 2F5 exhibit relatively potent and broad HIV-1-neutralizing activity. However, their elicitation in vivo by vaccine immunogens based on the HIV-1 envelope glycoprotein (Env) has not been successful. We have hypothesized that HIV-1 has evolved a strategy to reduce or eliminate the immunogenicity of the highly conserved epitopes of such antibodies by using "holes" (absence or very weak binding to these epitopes of germline antibodies that is not sufficient to initiate and/or maintain an efficient immune response) in the human germline B cell receptor (BCR) repertoire. To begin to test this hypothesis we have designed germline-like antibodies corresponding most closely to b12, 2G12, and 2F5 as well as to X5, m44, and m46 which are cross-reactive but with relatively modest neutralizing activity as natively occurring antibodies due to size and/or other effects. The germline-like X5, m44, and m46 bound with relatively high affinity to all tested Envs. In contrast, germline-like b12, 2G12, and 2F5 lacked measurable binding to Envs in an ELISA assay although the corresponding mature antibodies did. These results provide initial evidence that Env structures containing conserved vulnerable epitopes may not initiate humoral responses by binding to germline antibodies. Even if such responses are initiated by very weak binding undetectable in our assay it is likely that they will be outcompeted by responses to structures containing the epitopes of X5, m44, m46, and other antibodies that bind germline BCRs with much higher affinity/avidity. This hypothesis, if further supported by data, could contribute to our understanding of how HIV-1 evades immune responses and offer new concepts for design of effective vaccine immunogens.

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Figures

Fig. 1
Fig. 1
Detectable bindings of germline-like X5, m44, and m46 antibodies in scFv format to Env. Bal gp120-CD4 fusion protein was coated on a 96 well ELISA plate for detection of scFv X5 binding, whereas 89.6 gp140 was coated for detection of scFv m44 and m46 bindings at indicated concentrations. Mature and germline-like antibodies were compared.
Fig. 2
Fig. 2
Lack of binding of germline-like b12, 2G12, and 2F5 antibodies in scFv format. Bal gp120 was coated for detection of b12 binding and 89.6 gp140 was coated for detection of binding by both scFv 2G12 and 2F5. Mature and germline-like formats were compared.
Fig. 3
Fig. 3
Lack of binding of germline-like b12, 2G12, and 2F5 antibodies in Fc fusion protein format to Env. Bal gp120 was coated for detection of mature and germline-like scFv-Fc b12 binding and 89.6 gp140 was coated for detection of binding by mature scFv and germline-like scFv-Fc 2G12 and 2F5.
Fig. 4
Fig. 4
Detectable bindings of germline-like m44 and m46 antibodies in Fc fusion protein format to Env. Env 89.6 gp140 was coated for detection of binding by scFv-Fc m44 and m46 fusion proteins.
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