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

描述（由申请人提供）：目前大多数HIV疫苗设计都是基于慢性HIV-1亚型B感染的研究。然而，HIV-1亚型C （HIV- 1c）在全球艾滋病流行中普遍占主导地位，以及在急性HIV感染期间有效（尽管是暂时的）遏制病毒，需要对原发性HIV- 1c感染进行全面的疫苗设计分析。假设病毒设定点水平是由病毒-宿主相互作用决定的，我们假设(i)病毒复制动力学、病毒多样性和免疫反应在原发性HIV-1感染之间有所不同；（二）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，（三）急性HIV-1感染中与低病毒设定点相关的病毒学和免疫学参数可以被确定并用于疫苗开发。我们假设，在原发性HIV-1 C感染中，功能性Gag p24特异性T细胞反应和低病毒多样性的结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病毒设定点和nef多样性是高病毒设定点的标志。为了验证这一假设，在博茨瓦纳设计了一项关于急性和早期HIV-1感染的前瞻性研究。本研究有两个具体的目的：1。表征原发性hiv - 1c感染期间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细胞免疫应答、CCR5和CXCR4的表达以及β趋化因子产生水平（MIP-1a、MIP-1B和RANTES）。2. 评估原发hiv - 1c感染的病毒学和免疫学标志物与病毒设定点之间的关系。建立这些因素与病毒设定点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.