SYNTHETIC HIV-1 ENV PROTEIN ANALOGS FOR FUTURE VACCINES

描述：(改编自申请者的摘要)这一目标 一项建议是设计免疫原以防止感染人类 免疫缺陷病毒(HIV-1)。这种免疫原料有望引发 清除HIV-1和HIV感染细胞的免疫反应，这两者都可以 传播疾病。这种回应的组成部分包括：(1) 抗体：(A)是病毒中和抗体(VNAb)和(B)参与 抗体和补体介导的细胞毒性(ADCC和ACC， 其产生依赖于特定辅助T(Th)的世代 细胞；(2)细胞毒性T(TC)细胞。 HIV-1囊膜糖蛋白gp120序列的高度变异性 和gp41在不同的HIV-1分离株之间的差异和亚型特异性 早期的VNAb反应表明，产生广泛的保护性 HIV-1免疫原可能很难。他们建议设计多组件 合成多肽免疫原可诱导广泛的VNAb、ADCC、ACC和 HIV-1特异性的Th和Tc细胞反应。要选择适当的 对于这种免疫原的多肽，他们建议对 选定的B细胞和T细胞表位之间的免疫化学交叉反应 HIV-1糖蛋白gp120/gp41的序列变异 在这些病毒蛋白和人类白细胞抗原免疫反应性的限制 这些表位。建议的免疫原的成分包括： 与gp120序列的(A)高变环对应的多肽 (对应于分离物IIIB中的残基303-338) 数量有限的HIV-1的免疫交叉反应基础 分离株；(B)主要辅助性T细胞决定簇；和(C)一个或两个 其他诱导病毒中和和/或细胞毒性的多肽 抗体。

DESCRIPTION: (Adapted from the applicant's abstract) The goal of this proposal is to design immunogens for preventing infections with the human immunodeficiency virus (HIV-1). Such immunogens are expected to elicit immune responses eliminating HIV-1 and HIV-infected cells both of which can transmit disease. The components of such a response include: (1) antibodies which: (a) are virus-neutralizing (VNAb) and (b) participate in antibody- and complement-mediated cytotoxicity (ADCC and ACC, the production of which is dependent on generations of specific helper T (Th) cells; and (2) cytotoxic T (Tc) cells. The high variability in the sequence of HIV-1 envelope glycoproteins gp120 and gp41 between distinct HIV-1 isolates and the subtype specificity of early VNAb responses suggested that the production of broadly protective HIV-1 immunogens may be difficult. They propose to design multicomponent synthetic peptide immunogens eliciting broad VNAb, ADCC, ACC and HIV-1-specific Th and Tc cell responses. To select the appropriate peptides for such immunogens, they propose to carry out detailed studies on the immunochemical cross-reactivity between selected B- and T-cell epitopes of HIV-1 glycoproteins gp120/gp41 considering both the sequence variability in these viral proteins and the HLA restriction of immune responsiveness to these epitopes. The components of the proposed immunogens include: peptides corresponding to (a) hypervariable loops of the gp120 sequence (corresponding to residues 303-338 in the isolate IIIB) selected on the basis of immunological cross-reactivity from a limited number of HIV-1 isolates; (b) major T helper cell determinants; and (c) one or two additional peptides eliciting virus-neutralizing and/or cytotoxic antibodies.