DEVELOPMENT OF IMMUNOREGULATORY PEPTIDES FOR AIDS

需要开发有效的免疫调节和抗病毒试剂， 控制艾滋病毒感染至关重要。在我们研究的过程中 HIV包膜上的CD4附着位点，我们已经确定了一种合成的 肽的特性表明它可能是一个强有力的候选者 治疗剂肽（称为A25D）代表18个氨基酸 来自gp120上推定的CD4附着位点的序列和生物物理 比较表明它含有B和T细胞表位。A25D 在体外阻断HIV传播， 形成试验，然而对HIV感染者进行的研究 表明B和T细胞对肽应答都是最小的。这些 研究结果表明，虽然A25D可能代表了一个关键的表位， 能够诱导组特异性中和的HIV结合位点，这 潜力在大多数人身上都没有实现。我们将这一发现归因于 事实上，包膜的高度免疫显性区域建立了 克隆优势并抑制对附着位点的有效反应。 对于该提案的第一阶段，我们描述了一系列实验， 检查A25D和相关肽用作 促进主动抗HIV免疫的药剂。具体来说，我们将测试 材料在小鼠和兔中诱导抗gp120应答的能力。 此外，我们将使用A25D和相关的合成和重组， 筛选和表征HIV感染者血清的肽 以及SIV感染的猕猴体内的病毒中和抗体。最后，作为 II期研究的前奏，我们建议使用肽作为 增强艾滋病毒感染的试剂，我们将确定的能力， 通过刺激受感染的淋巴细胞来刺激病毒体的产生。

The need to develop effective immunoregulatory ar anti-viral reagents that will control HIV infection is paramount. In the course of our studies of the CD4 attachment site on the HIV envelope we have identified a synthetic peptide with properties that suggest it may be a strong candidate therapeutic agent. The peptide (termed A25D) represents an 18 amino acid sequence from the putative CD4 attachment site on gpl2O and biophysical comparisons suggest that it contains both B and T cell epitopes. A25D blocks HIV transmission in vitro as determined in a standard syncytial formation assay, however studies performed on HIV-infected individuals indicate that both B and T cell responses to the peptide are minimal. These findings suggest that although A25D may represent a critical epitope on the HIV binding site capable of inducing group-specific neutralization, this potential is not realized in most individuals. We attribute this finding to the fact that the highly immunodominant regions of the envelope establish a clonal dominance and suppress effective responses to the attachment site. For Phase I of this proposal we describe a series of experiments which will examine the potential utility of A25D and related peptides to be used as agents to promote active anti-HIV immunity. Specifically, we will test the ability of the material to induce anti-gpl2O responses in mice and rabbits. Furthermore, we will use A25D and related synthetic and recombinant peptides to screen and characterize the sera of HIV-infected individuals and SIV-infected macaques for virus neutralizing antibodies. Finally, as a prelude to Phase II studies in which we propose to use the peptides as boosting reagents for HIV infection,, we will determine the ability to stimulating virion production, by stimulating infected lymphocytes.