Pathogenesis of Clade C HIV Infection

描述(由申请人提供)：开发有效的艾滋病疫苗的经验方法尚未成功；事实上，疫苗的确切目标尚不清楚，因为预防感染和疾病进展的相关性仍有待确定。此外，设计有效的免疫原的一个主要障碍是需要针对世界各地遇到的各种艾滋病毒毒株。为了解决这些问题，我们在夸祖鲁纳塔尔的南非艾滋病疫情中心制定了一个合作研究计划。这使我们能够启动对调节急性和慢性艾滋病毒感染的病毒、宿主遗传和免疫因素的同时检查，现在允许我们在足够大的队列中扩大这些研究，以便能够控制在人类群体中遇到的不同的人类白细胞抗原类型。这样全面、完整的数据目前还不存在。南非已经产生的初步数据表明，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所耐受的免疫逃逸途径都是如此。有了这个队列中超过95%的成功纵向随访的既定机制，我们准备定义与初始和持续遏制病毒血症相关的急性和慢性感染的精确靶点，并确定在分支C病毒感染的靶点免疫优势表位上出现的首选突变，C分支病毒感染占全球病例的大多数。此外，拟议的研究将使我们能够确定在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性的II类等位基因在疾病发病机制中的作用。这些问题对于HIV疫苗的设计和了解HIV的发病机制至关重要。我们建议以我们坚实的初步数据和出色的功能合作为基础，1)确定有助于遏制病毒血症的Clade C病毒感染者的CD4+和CD8+T细胞免疫反应，重点关注南部非洲最普遍的HLA等位基因以及急性和慢性感染者；2)确定C分支HIV在细胞免疫选择压力下的演变；3)确定免疫选择压力对C分支HIV感染的病毒复制适合性的影响。

DESCRIPTION (provided by applicant): 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.