NOVEL EPITOPES THAT MEDIATE BROAD NEUTRALIZATION OF CLADE B AND C HIV-1 ISOLATES

介导 B 型和 C 型 HIV-1 分离株广泛中和的新表位

• 批准号: 8172428
• 负责人: Cynthia Ann Derdeyn
• 金额: $ 2.74万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172428
• 关键词: African American; Antibodies; Autologous; Computer Retrieval of Information on Scientific Projects Database; Epitope Mapping; Epitopes; Funding; Glycoproteins; Grant; HIV-1 vaccine; Institution; Masks; Mediating; Monoclonal Antibodies; Patients; Plasma; Process; Property; Research; Research Personnel; Resistance; Resources; Sampling; Serum; Source; United States National Institutes of Health; Viral; cohort; immunogenic; interest; neutralizing antibody; novel; response

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Progress towards an HIV-1 vaccine has been stymied by the inability to induce a protective humoral response. Well-characterized neutralization epitopes are either poorly immunogenic or effectively masked on the majority of patient isolates. Newer evidence suggests that even highly masked primary isolates possess sensitive neutralization targets that are recognized by autologous patient sera and occasionally by heterologous sera. This suggests that mapping the epitopes involved may identify novel targets that are capable of inducing broadly neutralizing activities. In this project, we are identifying subtype B and C infected patients that possess broadly neutralizing activities for primary isolates, and will localize the target epitopes. We are interesting in antibody activities that mediate neutralization of both autologous and heterologous clade B and clade C viral envelope (Env) glycoproteins. A large number of patient samples obtained from both North-American and African cohorts are being screened for cross-neutralizing activities, and samples with interesting neutralizing properties will be selected for detailed characterization. It is anticipated that these studies will define novel targets that are exposed on typical neutralization-resistant primary isolates. To date, we have screened over 50 plasma samples from chronically subtype C infected subjects from a Zambian cohort against a panel of cross-clade reference Envs to quantify the potency and breadth of cross-neutralizing activity. Subtype C infected patients in general produce antibodies that can neutralize heterologous Envs with low potency, although the targets and properties of these antibodies are not yet known. We have identified one subject that possesses both broad and potent neutralizing activity against heterologous Envs and are in the process of characterizing the autologous viral Env and antibody neutralizing activity in this patient, as well as generating monoclonal antibodies.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 由于无法诱导保护性体液反应，HIV-1疫苗的进展受到阻碍。充分表征的中和表位在大多数患者分离株上的免疫原性差或被有效掩盖。较新的证据表明，即使是高度掩蔽的原代分离株也具有敏感的中和靶标，这些靶标可被自体患者血清识别，偶尔也可被异源血清识别。这表明，映射所涉及的表位可以鉴定能够诱导广泛中和活性的新靶标。 在这个项目中，我们正在确定亚型B和C感染的患者，具有广泛的中和活性的主要分离物，并将定位的目标表位。我们感兴趣的是介导自体和异源进化枝B和进化枝C病毒包膜（Env）糖蛋白中和的抗体活性。正在对从北美和非洲队列中获得的大量患者样本进行交叉中和活性筛选，并将选择具有有趣中和特性的样本进行详细表征。预计这些研究将确定暴露于典型耐中和原代分离株的新靶标。 迄今为止，我们已经针对一组交叉进化枝参考Envs筛选了来自赞比亚队列的慢性亚型C感染受试者的50多个血浆样品，以量化交叉中和活性的效力和广度。亚型C感染的患者通常产生可以以低效力中和异源Env的抗体，尽管这些抗体的靶点和性质尚不清楚。我们已经鉴定了一个对异源Env具有广泛和有效中和活性的受试者，并且正在表征该患者中的自体病毒Env和抗体中和活性，以及产生单克隆抗体。