Mechanisms of Antibody Neutralization Against HIV-1

Beth Israel Deaconess Medical Center, Boston MA

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Abstract

[unreadable] DESCRIPTION (provided by applicant): The functional unit of HIV-1 glycoproteins is a trimer composed of three gp120 and three gp41 subunits. The envelope glycoproteins (Env) are the only viral components exposed on the surface of HIV virions, representing the only legitimate target for vaccines that induce neutralizing antibodies (nAb) to block HIV entry and transmission. It is well recognized that Envs from different HIV-1 strains have very different sensitivities to nAb. On the other hand, many monoclonal antibodies (mAb) can bind to HIV-1 Env, but few of them are capable of potently neutralizing primary HIV-1 strains. The bases for neutralization sensitivity of different HIV-1 stains and potency of different nAbs are poorly understood. Our recent results on the stoichiometry of HIV-1 Env in viral entry and antibody-mediated neutralization indicate that binding one nAb molecule to an Env trimer is sufficient to neutralize the function of the whole trimer. Such a neutralization stoichiometry is not dependent on viral strain variation and specific types of nAb, suggesting that the mechanism of neutralization common to all anti-HIV-1 nAbs is successful binding to the envelope spikes on HIV-1 virions and steric hindrance. In our preliminary results, we have developed that notion by experiments in which a totally unrelated antibody, anti-Flag M2 mAb, can effectively neutralize the function of an HIV-1 Env that carries an exogenous Flag-tag as an artificial epitope. The central goal of the proposed work is to understand the effect of binding affinity and steric hindrance on the efficiency of neutralization, using above model system of HIV-1 Env and anti-Flag M2 antibody. The results will shed light on the mechanistic bases of neutralization resistance of different HIV-1 strains and potency of different nAbs. Conclusions from the proposed studies will have wider implications for general virology, because the hypotheses are germane to the fundamental mechanisms of antibody-mediated neutralization against viruses. [unreadable] [unreadable]