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

描述(由申请人提供)：目前大多数HIV疫苗设计都是基于对慢性HIV-1 B亚型感染的研究。然而，艾滋病毒-1C亚型(HIV-1C)在全球艾滋病流行中的主导地位，以及在急性艾滋病毒感染期间对病毒的有效遏制(尽管是暂时的)，需要在疫苗设计方面对初次艾滋病毒-1C感染进行全面分析。假设病毒设定点的水平由病毒-宿主相互作用决定，我们假设：(I)病毒复制、病毒多样性和免疫反应的动力学在不同的原发HIV-1感染之间不同；(Ii)急性HIV-1感染的病毒学和免疫学决定因素与病毒设定点有关；(Iii)可以确定与低病毒设定点相关的急性HIV-1感染的病毒学和免疫学参数，并将其作为疫苗开发的靶点。我们假设，在初次HIV-1C感染中，功能性Gag p24特异性T细胞反应和TAT和NEF内低病毒多样性的组合与低病毒设定点有关，而缺乏功能性p24特异性免疫反应加上高TAT和NEF多样性是高病毒设定点的标志。为了验证这一假设，设计了一项关于博茨瓦纳急性和早期HIV-1感染的前瞻性研究。1.研究HIV-1C原发感染过程中病毒学和免疫学决定因素的大小、广度和动力学，包括病毒进化和免疫应答的瞬时变化。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CD8T细胞免疫反应、CCR5和CXCR4的表达以及β-趋化因子产生水平(MIP-1a、MIP-1B和RANTES)。2.探讨HIV-1C原发感染的病毒学和免疫学指标与病毒设定点之间的关系。建立这些因素与病毒设定值之间相互关系的多变量模型。

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.