HIV Therapeutic Vaccine Concept

描述（由申请人提供）：HIV-1 gp120中的桥接片连接了gp120的内域和外域。桥接片的一半（¿2/3）由来自V2和V3结构域的可变片段的氨基酸组成，而桥接片的另一半（称为¿20/21）由来自C4结构域的高度保守的氨基酸组成。¿20/21是gp120中CD4结合位点（CD4bs）的主要组成部分，当它不被CD4占据时，结合抗体似乎可以接近。在艾滋病毒感染的前3至4个月内，不会产生针对构象受限的¿20/21的抗体，因此¿20/21可能成为早期治疗性疫苗干预的目标。我们已经成功地设计和合成了一种来自¿20/21氨基酸序列的免疫原，称为CDC4，并免疫了实验动物，以评估靶向抗体与来自各种病毒株的gp120结合的有效性。其目的是开发CDC4作为抑制HIV体内传播的治疗性疫苗的组成部分。这项提议的目标是用抗体标记在hiv感染细胞表面表达的桥接片的¿20/21部分。将进行体外中和试验和能够激活抗体依赖性细胞毒性（ADCC）的抗体的测试，作为体内中和的可能相关。简单地将抗20/21抗体与gp120结合，然后激活adcc样机制，可能会起到控制病毒传播的作用，并可能推迟感染患者服用抗HIV-1药物的需要。公共卫生相关性：该项目旨在针对HIV-1表面的保守位点创建一种新的治疗性疫苗。这种新的免疫治疗方法应该有助于帮助感染艾滋病毒的患者控制病毒。

DESCRIPTION (provided by applicant): The bridging sheet in HIV-1 gp120 connects the inner domain with the outer domain of gp120. Half of the bridging sheet (¿2/3) is composed of amino acids from the variable segments from the V2 and V3 domains whereas the second half of the bridging sheet, referred to as ¿20/21, is composed of highly conserved amino acids from the C4 domain. ¿20/21 is a major component of the CD4 binding site (CD4bs) in gp120 and, when it is not occupied by CD4, appears to be accessible to binding antibodies. Within the first 3 to 4 months of HIV infection, antibodies to the conformationally constrained ¿20/21 are not produced, making ¿20/21 a possible target for early stage therapeutic vaccine intervention. We have successfully designed and synthesized an immunogen from the ¿20/21 amino acid sequence, called CDC4, and immunized test animals to evaluate the targeted antibodies for effectiveness in binding to gp120 from various strains of the virus. The aim is to develop CDC4 as a component of a therapeutic vaccine for suppressing the spread of HIV in vivo. The goal of this proposal is to tag with antibodies the ¿20/21 portion of the bridging sheet expressed on the surface of HIV-infected cells. In vitro neutralization assays and tests with the antibodies capable of activating antibody-dependent cellular cytotoxicity (ADCC) as a possible correlate of in vivo neutralization will be performed. Simple binding of anti- ¿20/21 antibodies to gp120 and activating ADCC-like mechanisms then might act to control viral spread and perhaps delay the need of an infected patient having to take anti HIV-1 drugs. PUBLIC HEALTH RELEVANCE: This project is geared toward creating a novel therapeutic vaccine against a conserved sites on the surface of HIV-1. Such a novel immunotherapeutic should be useful in assisting patients suffering from HIV infection with keeping the virus under control.