Abstract
Vaccine candidates for HIV-1 so far have not been able to elicit broadly neutralizing antibodies (bNAbs) although they express the epitopes recognized by bNAbs to the HIV envelope glycoprotein (Env). To understand whether and how Env immunogens interact with the predicted germline versions of known bNAbs, we screened a large panel (N:56) of recombinant Envs (from clades A, B and C) for binding to the germline predecessors of the broadly neutralizing anti-CD4 binding site antibodies b12, NIH45-46 and 3BNC60. Although the mature antibodies reacted with diverse Envs, the corresponding germline antibodies did not display Env-reactivity. Experiments conducted with engineered chimeric antibodies combining the mature and germline heavy and light chains, respectively and vice-versa, revealed that both antibody chains are important for the known cross-reactivity of these antibodies. Our results also indicate that in order for b12 to display its broad cross-reactivity, multiple somatic mutations within its VH region are required. A consequence of the failure of the germline b12 to bind recombinant soluble Env is that Env-induced B-cell activation through the germline b12 BCR does not take place. Our study provides a new explanation for the difficulties in eliciting bNAbs with recombinant soluble Env immunogens. Our study also highlights the need for intense efforts to identify rare naturally occurring or engineered Envs that may engage the germline BCR versions of bNAbs.
Highlights
Neutralizing anti-HIV antibody responses are generated by approximately 15% of those infected with HIV-1 [1,2,3,4] and monoclonal antibodies (MAbs) with broad and potent anti-HIV neutralizing activities have been isolated from chronically HIV-1infected subjects [5,6,7,8,9,10,11]
We show that recombinant envelope glycoprotein (Env) proteins are inefficient in engaging the predicted germline BCRs of known bnAbs
As a first step in eliciting broadly neutralizing antibodies (bNAbs) by immunization, Env immunogens should be designed that would engage the germline BCR versions of bNAbs
Summary
Neutralizing anti-HIV antibody responses are generated by approximately 15% of those infected with HIV-1 [1,2,3,4] and monoclonal antibodies (MAbs) with broad and potent anti-HIV neutralizing activities have been isolated from chronically HIV-1infected subjects [5,6,7,8,9,10,11]. The presence of epitopes recognized by bNAbs on such Env proteins, these constructs when used as immunogens fail to elicit similar types of broadly neutralizing antibody responses [16,23,24,25,26,27,28,29,30,31,32,33,34,35]. To overcome this major obstacle in HIV vaccine-development, diverse approaches were evaluated over the past two decades, (reviewed in [36]). These approaches were met with very limited success
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