It is widely acknowledged that an important component of effective HIV-1 vaccination will be the ability to induce broadly neutralizing antibodies (Abs) to the virus. Such Abs are made only rarely in infected individuals or following immunization with viral envelope proteins because of various immune evasion mechanisms deployed by HIV. Conventional HIV-1 neutralizing Abs depend on steric hindrance as the mechanism by which they interfere with virus binding to host cell receptors. Moreover, the Abs must possess high affinity to form long-lasting complexes with the virus. Recently, Abs that catalyze the cleavage of the env protein gp120 have emerged as a novel means to neutralize HIV. These Abs inactivate antigens permanently due to the cleavage reaction, they are more potent than ordinary Abs because of their ability to cleave multiple antigen molecules, and their epitope specificity requirements are less strict than ordinary Abs, as inactivation of gp120 can occur even when cleavage occurs at sites remote from the receptor binding sites of the protein. Induction of the synthesis of catalytic Abs to gp120 has become feasible with the development of electrophilic analogs of gp120 and synthetic gp120 peptides. Abs to these analogs combine noncovalent gp120 recognition with a serine protease-like activity, resulting in specific cleavage of gp120. We propose to study as immunogens the analogs of full-length gp120, whole virus particles and a synthetic gp120 peptide. The elicited Abs will be studied in polyclonal and monoclonal form for their catalytic efficiency, cleavage specificity, ability to recognize native gp120 expressed on the viral surface and neutralization of diverse HIV-1 isolates. Novel vaccination strategies and HIV-1 neutralizing Abs will emerge from these studies if the physiological barriers to catalytic Ab synthesis can be bypassed. ? ?
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