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

描述（由申请方提供）：目前大多数HIV疫苗设计是基于慢性HIV-1亚型B感染的研究。然而，HIV-1亚型C（HIV-1 C）在世界范围内的艾滋病流行中占主导地位，以及在急性HIV感染期间对病毒的有效（尽管是暂时的）遏制，需要对原发性HIV-1 C感染的疫苗设计进行全面分析。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）病毒复制的动力学、病毒多样性和免疫应答在原发性HIV-1感染之间变化;（ii）急性HIV-1感染中的病毒学和免疫决定因素与病毒设定点有关，和（iii）与低病毒设定点相关的急性HIV-1感染中的病毒学和免疫学参数可以被识别并作为疫苗开发的目标。我们假设，在原发性HIV-1C感染中，功能性Gag p24特异性T细胞应答和达特和nef内的低病毒多样性的组合与低病毒设定点相关，而缺乏功能性p24特异性免疫应答加上高达特和nef多样性是高病毒设定点的标志。为了检验这一假设，在博茨瓦纳的急性和早期HIV-1感染的前瞻性研究已经设计。本研究有两个具体目的：1.描述原发性HIV-1 C感染期间病毒学和免疫学决定因素的幅度、广度和动力学，包括病毒进化和免疫应答的短暂变化。将分析病毒载量（RNA和DNA）、病毒多样性（p24、达特、env和nef）、病毒特异性CD 4+和CD 8 + T细胞免疫应答、CCR 5和CXCR 4的表达以及β-趋化因子产生水平（MIP-1a、MIP-1B和RANTES）。2.评估原发性HIV-1C感染者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.