Assay/Measuring HIV-1 and SIV Antibody Neutralization

描述(申请人提供)：HIV-1疫苗研究的最新进展已经开始确定细胞和体液免疫反应的作用，并重新乐观地认为可以开发出有效的预防性疫苗(Ho和Huang，2002)。预计在不久的将来(2-5年)，几种候选疫苗将准备好在人体上进行大规模评估。很有可能，高效疫苗的开发将是一个迭代的过程，在这个过程中，从早期疫苗试验中吸取的教训将改进未来一代的疫苗。对早期候选者的评估应有助于进一步阐明体液(B细胞抗体)和细胞(细胞毒性T细胞)免疫反应的保护作用，并可能确定其他关键的保护替代标志物。一旦收集到这些信息，就可以用于开发更有效和更定向的免疫原和递送系统。目前，艾滋病毒疫苗领域的装备不足，无法进行必要的全面分析，以支持目前和未来的疫苗工作。总体而言，目前可用于评估艾滋病毒特异性免疫反应的分析方法是为小型研究调查开发的，不适合支持高通量筛选潜在免疫原所需的大量样本测试，或大型临床疗效试验。这样的研究将需要具有高通量测试能力的快速、灵敏和可靠的分析。此外，这种系统必须服从在灵长类模型系统中进行的临床前研究，即SIV/猕猴。最近，病毒学发展了一种新的基于细胞的传染性试验，它能够有三个不同的应用：(A)测量HIV-1对进入抑制剂药物的敏感性，(B)确定共受体的趋向性，(C)检测抗体中和。这项SBIR-AT第一阶段的建议集中在抗体中和应用的进一步发展上。我们打算扩大和提高中和试验的能力，编制一个由HIV-1被膜基因组成的大型多样化样本库，并建立用于常规抗体反应表征的标准病毒面板。

DESCRIPTION (provided by applicant): Recent strides in HIV-1 vaccine research have begun to define the roles of cellular and humoral immune responses and have renewed optimism that an effective prophylactic vaccine can be developed (Ho and Huang, 2002). It is anticipated that several vaccine candidates will be ready for large-scale evaluations in humans in the near future (2-5 years). In all likelihood, the development of a highly efficacious vaccine will be an iterative process in which lessons learned from early vaccine trials improve future generation vaccines. The evaluation of early candidates should help further clarify the protective roles of humoral (B-cell antibody) and cellular (cytotoxic T-cell) immune responses, and possibly identify other critical surrogate markers of protection. Once gleaned, this information can be directed toward the development of more potent and directed immunogens and delivery systems. At present, the HIV vaccine field is inadequately equipped to conduct the comprehensive analyses necessary to support ongoing and future vaccine efforts. In general, assays currently available to evaluate HIV-specific immune responses were developed for small research investigations and are not suited for the high volume sample testing necessary to support high throughput screening of potential immunogens, or large clinical efficacy trials. Such studies will require rapid, sensitive, and reliable assays with high-throughput testing capability. Furthermore, such systems must be amenable to pre-clinical investigations conducted in primate model systems, i.e. SIV/macaque. Recently, ViroLogic developed a novel cell-based infectivity assay that is capable of three distinct applications, (a) measuring the susceptibility of HIV-1 to entry inhibitor drugs, (b) determining co-receptor tropism and (c) detecting antibody neutralization. This SBIR-AT phase I proposal is focused on the further development of the antibody neutralization application. We intend to expand and enhance the capability of the neutralization assay, compile a large diverse specimen library comprised of functional HIV-1 envelope genes, and establish standard virus panels for the routine characterization of antibody responses.