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

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 由于无法诱导保护性体液反应，HIV-1疫苗的进展受到阻碍。特征良好的中和表位要么免疫原性差，要么在大多数患者分离株上被有效掩蔽。新的证据表明，即使是高度掩蔽的初级分离株也具有敏感的中和靶点，这些靶点可以被自体患者血清识别，有时也可以被异源血清识别。这表明，绘制相关表位图可能会识别能够诱导广泛中和活性的新靶点。 在这个项目中，我们正在鉴定对初级分离株具有广泛中和活性的B和C亚型感染者，并将定位目标表位。我们感兴趣的是抗体中和自体和异源B分支和C分支病毒包膜(Env)糖蛋白的活性。从北美和非洲队列中获得的大量患者样本正在筛选交叉中和活动，并将选择具有感兴趣的中和特性的样本进行详细描述。预计这些研究将确定暴露在典型的抗中和初级分离株上的新靶点。 到目前为止，我们已经对来自赞比亚队列的50多名慢性C型感染者的血浆样本进行了筛选，以对照一组跨分支参考环境来量化交叉中和活性的效力和广度。C亚型感染的患者一般会产生抗体，以低效性中和异源env，尽管这些抗体的靶点和性质尚不清楚。我们已经确定了一个对象，它对异源环境具有广泛和强大的中和活性，正在鉴定该患者的自体病毒环境和抗体中和活性，以及产生单抗。

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.