gp120 covalent analogs as candidate HIV vaccines

描述（由申请方提供）：人们普遍认为，有效的HIV-1疫苗接种的一个重要组成部分是能够诱导针对该病毒的广泛中和抗体（Ab）。这种抗体很少在感染个体中或在用病毒包膜蛋白免疫后产生，因为HIV部署了各种免疫逃避机制。常规的HIV-1中和抗体依赖于空间位阻作为它们干扰病毒与宿主细胞受体结合的机制。此外，抗体必须具有高亲和力以与病毒形成持久的复合物。最近，催化env蛋白gp 120裂解的Ab已成为中和HIV的新手段。这些Ab由于切割反应而永久地切割抗原，它们比普通Ab更有效，因为它们能够切割多个抗原分子，并且它们的表位特异性要求比普通Ab不那么严格，因为即使当切割发生在远离蛋白质的受体结合位点的位点时，gp 120的失活也可能发生。随着gp 120的亲电类似物和合成gp 120肽的开发，诱导gp 120的催化Ab的合成已经变得可行。这些类似物的抗体将联合收割机非共价的gp 120识别与丝氨酸蛋白酶样活性结合，导致gp 120的特异性切割。我们建议研究全长gp 120的类似物，整个病毒颗粒和合成的gp 120肽作为免疫原。将以多克隆和单克隆形式研究引发的Ab的催化效率、切割特异性、识别病毒表面上表达的天然gp 120的能力以及中和不同HIV-1分离株的能力。新的疫苗接种策略和HIV-1中和抗体将从这些研究中出现，如果催化抗体合成的生理障碍可以绕过。

DESCRIPTION (provided by applicant): 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.