Clade C-specific HIV assay to distinguish true infection from vaccine-induced ser

描述（由申请人提供）：艾滋病毒进化支C在撒哈拉以南非洲和印度次大陆流行，占全球所有艾滋病毒感染的近一半，大多数大规模艾滋病毒疫苗试验都针对C进化支地区。不幸的是，候选艾滋病毒疫苗的开发和试验带来了疫苗诱导的艾滋病毒血清阳性（VISP）的重大风险。VISP被定义为存在针对HIV疫苗抗原的循环抗体，这些抗体与常规HIV免疫测定中使用的同源抗原发生交叉反应，导致假阳性结果。在最近由hvt赞助的艾滋病毒疫苗试验中，41.7%的艾滋病毒疫苗接种者表现出VISP。假阳性检测结果可能对个人造成悲剧性后果，从公共卫生的角度来看，预期的高VISP率将使人们无法监测艾滋病毒疫苗试验或疫苗接种运动的有效性，也无法正确诊断和治疗感染者。RNA检测是目前VISP检测算法的核心，但未能检测出2-3%的已确诊艾滋病毒感染，其高昂的成本是疫苗试验预算的负担，也是资源有限的卫生服务提供者使用的障碍。第一阶段项目的目标是证明一种能够以高灵敏度和特异性区分真正的HIV感染和VISP的进化枝c特异性HIV-1免疫测定（“HIV Selectest”）的可行性。进化支特异性检测背后的基本原理是，它将通过增加进化支C HIV肽序列变异在检测井中可用空间中的数量来提高检测灵敏度。该项目的目标将通过两种创新方法来实现：1)针对检测抗原的进化支特异性靶向，以提高检测灵敏度；2)新使用数据库衍生的肽设计工具，以实现对艾滋病毒变体的最佳覆盖。初步数据表明，通过这些方法可以显著提高对挑战性样本、早期感染和总体样本群体的检测灵敏度。将通过ELISA检测单个抗原肽和肽混合物与特征明确的血清面板来评估进展。通过研究和血液筛查实验室的合作者，我们将获得来自C支系地区的艾滋病毒疫苗试验以及来自特征明确的C支系艾滋病毒阳性和阴性献血者的血清组。在第一阶段，我们期望证明一种能够区分真正的HIV感染和VISP的进化支C HIV选择检测方法的可行性，其敏感性和特异性接近于在相同的目标血清组上测试时获得许可的HIV免疫检测方法。在II期，我们将进一步优化和扩大该检测方法，并进行前瞻性和回顾性临床研究，以获得FDA批准使用Clade C HIV Selectest检测方法，作为解决HIV疫苗接种者因VISP引起的假阳性的成本效益解决方案。

DESCRIPTION (provided by applicant): HIV clade C, endemic in sub-Saharan Africa and the Indian subcontinent, is responsible for nearly half of all global HIV infections, and most large-scale HIV vaccine trials are targeted to clade C regions. Unfortunately, the development and trialing of candidate HIV vaccines brings with it the significant risk of vaccine-induced HIV seropositivity (VISP). VISP is defined as the presence of circulating antibodies to HIV vaccine antigens which cross-react with homologous antigens used in conventional HIV immunoassays, leading to a false positive result. In recent HVTN-sponsored HIV vaccine trials, an overall 41.7% of HIV vaccine recipients exhibited VISP. False positive test results can have tragic personal consequences and, from a public health perspective, the anticipated high rate of VISP would make it impossible to monitor effectiveness of an HIV vaccine trial or vaccination campaign, or to correctly diagnose and treat infected individuals. RNA testing, central to current VISP testing algorithms, fails to detect 2-3% of established HIV infections, and its high cost is a burden to vaccine trial budgets and a barrier to use by resource-limited health providers. The goal of the Phase I project is to demonstrate feasibility of a clade C-specific HIV-1 immunoassay ("HIV Selectest") capable of distinguishing true HIV infection from VISP with high sensitivity and specificity. The rationale behind a clade-specific assay is that it will enable greater detection sensitivity by increasing the number of clade C HIV peptide sequence variants in the space available in the assay well. The project objectives will be achieved through two innovative approaches: 1) clade-specific targeting of assay antigens to improve detection sensitivity and 2) the novel use of database-derived peptide design tools to achieve optimal coverage of HIV variants. Preliminary data have demonstrated that significant gains in detection sensitivity for challenging samples, early infections and overall sample populations are possible through these approaches. Progress will be assessed by ELISA testing of individual antigenic peptides and peptide mixes vs well-characterized serum panels. Through collaborators in research and blood screening laboratories we will acquire panels of sera from HIV vaccine trials in clade C regions as well as from well-characterized clade C HIV-positive and negative donors. In Phase I we expect to demonstrate feasibility of a clade C HIV Selectest assay capable of distinguishing true HIV infection from VISP, with sensitivity and specificity approaching those of licensed HIV immunoassays when tested on the same target serum panels. In Phase II we will further optimize and scale up the assay and perform prospective and retrospective clinical studies aimed at FDA clearance for use of the Clade C HIV Selectest assay as a cost effective solution to resolve false positives due to VISP in HIV vaccine recipients.