Pathogenesis of Clade C HIV Infection

开发有效艾滋病疫苗的经验方法并不成功；事实上，准确的 疫苗的目标是未知的，因为预防感染和疾病进展的相关性 仍有待定义。此外，设计有效的免疫原的一个主要障碍是需要靶向 世界各地遇到的不同的艾滋病毒毒株。为了解决这些问题，我们开发了一种 在夸祖鲁纳塔尔的南非艾滋病流行中心的合作研究计划。这 使我们能够同时检测病毒、宿主遗传和免疫因素 调节急性和慢性艾滋病毒感染，现在允许我们在足够大的范围内扩大这些研究 队列能够控制在人类人群中遇到的不同的人类白细胞抗原类型。是这样的 全面、完整的数据目前还不存在。已从南方生成的初步数据 非洲表明，病毒与宿主的相互作用是高度可预测的，无论是目标表位还是 病毒可以耐受的免疫逃逸途径。建立了超过95%的机制 对这个队列中的人进行了成功的纵向跟踪，我们准备定义准确的表位 针对与最初和持续遏制病毒血症有关的急性和慢性感染，并 确定针对C分支病毒感染的免疫优势表位上出现的首选突变， 这构成了全球病例的大多数。此外，拟议的研究将使我们能够界定 C分支病毒感染中的适应性病毒特异性CD4T+细胞反应，以及这些细胞和 限制II类等位基因在疾病发病机制中的作用。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 功能协作以1)确定C分支患者的CD4+和CD8+T细胞免疫反应 有助于遏制病毒血症的病毒感染，重点关注 南部非洲，以及急性和慢性感染者；2)界定C分支艾滋病毒的演变 细胞免疫选择压力；3)确定免疫选择压力对病毒的影响 C分支HIV感染的复制适合性。

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.