gp120 covalent analogs as candidate HIV vaccines

gp120 共价类似物作为候选 HIV 疫苗

• 批准号: 6837062
• 负责人: Sudhir Paul
• 金额: $ 34.35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2008-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6837062
• 关键词: AIDS vaccines; HIV envelope protein gp120; abzyme; antibody; antigens; catalyst; human immunodeficiency virus 1; laboratory mouse; monoclonal antibody

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.

描述(由申请人提供)：人们普遍认为，有效接种HIV-1疫苗的一个重要组成部分将是诱导针对病毒的广泛中和抗体(Abs)的能力。由于艾滋病毒的各种免疫逃避机制，这种抗体仅在感染的个体中或在用病毒包膜蛋白免疫后很少产生。传统的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才能与病毒形成持久的复合体。最近，催化包膜蛋白gp120裂解的单抗已经成为一种新的中和HIV的方法。这些抗体由于切割反应而永久地灭活抗原，它们比普通抗体更有效，因为它们能够切割多个抗原分子，而且它们对表位特异性的要求没有普通抗体那么严格，因为即使在远离蛋白质受体结合部位的位置发生切割，也可以发生gp120的失活。随着gp120亲电类似物和人工合成gp120多肽的发展，将催化抗体诱导合成gp120已成为可能。这些类似物的ABS结合了非共价gp120识别和丝氨酸蛋白酶样活性，导致gp120的特异性切割。我们建议将全长gp120的类似物、完整的病毒颗粒和合成的gp120多肽作为免疫原进行研究。将以多克隆和单克隆形式研究其催化效率、切割特异性、识别病毒表面表达的天然gp120的能力以及对不同HIV-1毒株的中和能力。如果能够绕过催化抗体合成的生理障碍，这些研究将产生新的疫苗接种策略和HIV-1中和抗体。