Markers of Viral Set Point in Primary HIV-1C Infection

原发性 HIV-1C 感染的病毒设定点标志物

• 批准号: 7422344
• 负责人: VLADIMIR A NOVITSKY
• 金额: $ 43.07万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7422344
• 关键词: Acquired Immunodeficiency Syndrome; Acute; Area; Botswana; CCR5 gene; CD8B1 gene; CXCR4 gene; Chronic; Containment; Coupled; DNA; Epidemic; Evolution; Gagging; HIV Infections; HIV vaccine; HIV-1; Immune response; Immunologic Markers; Immunologics; Infection; Kinetics; Macrophage Inflammatory Proteins; Modeling; Monitor; Monkeys; Pattern; Phenotype; Phylogenetic Analysis; Plasma; Production; Prospective Studies; RANTES; RNA; Research; Risk; Small Inducible Cytokine A3; Staging; Study Subject; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Vaccine Design; Viral; Viral Genes; Viral Load result; Viral Markers; Virus; base; beta-Chemokines; design; research study; response; vaccine development; viral DNA; virus host interaction

DESCRIPTION (provided by applicant): Most HIV vaccine designs are currently based on studies of chronic HIV-1 subtype B infection. However, the prevailing dominance of HIV-1 subtype C (HIV-1 C) in the worldwide AIDS epidemic, and the efficient, albeit temporary, containment of the virus during acute HIV infection necessitates a comprehensive analysis of primary HIV-1 C infection with regard to vaccine design. Assuming that the level of viral set point is dictated by virus-host interactions, we postulated that (i) the kinetics of viral replication, viral diversity, and immune responses vary between primary HIV-1 infections; (ii) virological and immunological determinants in acute HIV-1 infection are related to viral set point, and (iii) virological and immunological parameters in acute HIV-1 infection associated with low viral set point could be identified and targeted for vaccine development. We hypothesize that a combination of functional Gag p24-specific T cell responses and low viral diversity within tat and nef in primary HIV-1 C infection is associated with low viral set point, while lack of functional p24-specific immune response coupled with high tat and nef diversity are markers of high viral set point. To test this hypothesis a prospective study on acute and early HIV-1 infection in Botswana has been designed. There are two Specific Aims in the study: 1. To characterize the magnitude, breadth and kinetics of virological and immunological determinants during primary HIV-1 C infection including transient changes in viral evolution and immune responses. Viral load (RNA and DNA), viral diversity (p24, tat, env, and nef), virus-specific CD4+ and CD8+ T cell immune responses, expression of CCR5 and CXCR4, and levels of beta-chemokine production (MIP-1a, MIP-1B and RANTES) will be analyzed. 2. To assess the association between virological and immunological markers in primary HIV-1 C infection with viral set point. To develop a multivariate model of the inter-relationship of these factors with viral set point.

描述（由申请人提供）：大多数HIV疫苗设计目前基于慢性HIV-1亚型B感染的研究。然而，在全球范围内，HIV-1亚型C（HIV-1 C）的主要优势有助于流行病，尽管在急性HIV感染期间，病毒在疫苗设计中对原发性HIV-1感染进行了全面的分析，但在疫苗设计中的原发性HIV-1感染中有效地遏制了该病毒。假设病毒设定点的水平取决于病毒宿主相互作用，我们假设（i）原发性HIV-1感染之间的病毒复制，病毒多样性和免疫反应的动力学不同； （ii）急性HIV-1感染中的病毒学和免疫学决定因素与病毒设定点有关，并且（iii）急性HIV-1感染的病毒学和免疫学参数可以鉴定出与低病毒设定点相关的感染，并靶向疫苗发育。我们假设在原发性HIV-1 C感染中，功能性GAG P24特异性T细胞反应与TAT和NEF内的病毒多样性的组合与低病毒设定点有关，而缺乏功能性p24特异性免疫反应，与高TAT和NEF多样性相结合，是高病毒设定点的标记。为了检验这一假设，已经设计了有关博茨瓦纳急性和早期HIV-1感染的前瞻性研究。研究中有两个具体的目的：1。表征原发性HIV-1 C感染期间病毒学和免疫决定因素的大小，广度和动力学，包括病毒进化和免疫反应的短暂变化。将分析病毒载量（RNA和DNA），病毒多样性（P24，TAT，ENV和NEF），病毒特异性CD4+和CD8+ T细胞免疫反应，CCR5和CXCR4的表达以及β-变性的生产水平（MIP-1A，MIP-1A，MIP-1B和RANTES）。 2。评估原发性HIV-1 C感染中病毒学和免疫学标记与病毒设定点之间的关联。为了开发这些因素与病毒设定点的相互关系的多元模型。