Pathogenesis of Clade C HIV Infection

开发有效艾滋病疫苗的经验性方法并不成功;事实上， 疫苗的目标是未知的，因为它与预防感染和疾病进展有关 仍有待确定。此外，设计有效免疫原的主要障碍是需要靶向 世界各地都有不同的HIV病毒株。为了解决这些问题，我们制定了 这是位于夸祖鲁纳塔尔的南非艾滋病流行中心的一个合作研究项目。这 使我们能够同时检查病毒、宿主遗传和免疫因素， 调节急性和慢性HIV感染，现在使我们能够扩大这些研究的规模， 队列能够控制在人群中遇到的不同HLA类型。等 目前没有全面和综合的数据。初步数据已从南方生成 Africa的研究表明，病毒与宿主的相互作用是高度可预测的，无论是在靶向表位方面，还是在 免疫逃逸的途径。建立机制，95%以上 成功的纵向随访的人在这个队列中，我们准备确定精确的表位 靶向与病毒血症的初始和持续遏制相关的急性和慢性感染， 确定在进化枝C病毒感染中靶向的免疫显性表位处出现的优选突变， 占全球病例的大多数。此外，拟议的研究将使我们能够界定 C支病毒感染中的适应性病毒特异性CD 4 T+细胞应答，以及这些细胞和T细胞的作用。 限制疾病发病机制中的II类等位基因。这些问题对于艾滋病毒疫苗的设计和 了解HIV的发病机制。我们建议建立在我们坚实的初步数据和杰出的 功能合作1）定义C型分化体患者的CD 4+和CD 8 + T细胞免疫应答 病毒感染，有助于遏制病毒血症，重点是最普遍的HLA等位基因， 南部非洲，以及急性和慢性感染者; 2）定义进化枝C艾滋病毒的演变 在细胞免疫选择压力下; 3）确定免疫选择压力对病毒感染的影响。 进化枝C HIV感染的复制适应性。

Empiric approaches to develop an effective AIDS vaccine have not been successful; indeed, the precise goals for a vaccine are unknown as the correlates of protection from infection and disease progression remain to be defined. Moreover, a major obstacle to design of an effective immunogen is the need to target diverse strains of HIV that are encountered worldwide. To address these issues, we have developed a collaborative research program at the center of the South African AIDS epidemic in KwaZulu Natal. This has allowed us to initiate simultaneous examination of viral, host genetic and immunologic factors that modulate acute and chronic HIV infection, and now allows us to expand these studies in large enough cohorts to be able to control for the diverse HLA types encountered in human populations. Such comprehensive and integrated data do not exist currently. Preliminary data already generated from South Africa suggest that the virus-host interaction is highly predictable, both in terms of epitopes targeted and the pathways to immune escape that are tolerated by the virus. With established mechanisms for over 95% successful longitudinal follow up of persons in this cohort, we are poised to define the precise epitopes targeted in acute and chronic infection associated with initial and persistent containment of viremia, and to determine the preferred mutations that arise at immunodominant epitopes targeted in clade C virus infection, which makes up the majority of global cases. Moreover, the proposed studies will allow us to define the adaptive virus-specific CD4 T+ cell response in clade C virus infection, and the role of these cells and the restricting class II alleles in disease pathogenesis. These issues are critical for HIV vaccine design and for understanding HIV pathogenesis. We propose to build on our solid preliminary data and outstanding functional collaborations to 1) Define the CD4+ and CD8+ T cell immune responses in persons with Clade C virus infection that contribute to containment of viremia, focusing on the most prevalent HLA alleles in Southern Africa, and persons with both acute and chronic infection; 2) Define the evolution of clade C HIV under cellular immune selection pressure; 3) Determine the impact of immune selection pressure on viral replicative fitness of clade C HIV infection.