HIV DISEASE RESEARCH AGENDA

新的抗逆转录病毒药物的快速评价将发生显著变化 通过开发精确的病毒学标记。 我们开发了 血浆HIV病毒血症作为抗逆转录病毒研究标志物的概念。 然而，培养方法是缓慢的，并且通过HIV-RNA PCR检测病毒体 方法可以提供更快速，灵敏和定量的评估， 对治疗的抗病毒反应 我们认为，系统评估 血浆病毒血症和HIV RNA病毒检测是必要的，并提出了一个 一系列研究，目的如下：目的1，进一步发展 血浆病毒血症作为抗逆转录病毒治疗的标志物， 无细胞血浆病毒的感染性与 细胞相关HIV前病毒DNA和细胞游离HIV RNA; AIM 2， 进一步开发直接的离体测定， HIV感染对抗逆转录病毒药物的反应，并提供了一种方法， 靶向随后的体内水平用于进一步的I期研究; AIM 3， 确定基于免疫的病毒阻断艾滋病毒的传染性 中和疗法，如sCD 4和抗逆转录病毒药物，如 糖基化抑制剂脱氧去甲野尻霉素和蛋白酶抑制剂， 降低HIV的细胞相关和无细胞感染滴度， HIV核酸的数量。 我们预计这些方法将证明 对于更快速的评估来说，这是一个特别有用的体外指南 一般抗逆转录病毒药物;特别是那些具有狭窄 口服给药后的治疗指数或生物利用度差。 在 与其他定量病毒学方法如细胞稀释法结合 感染性测定，HIV在各种细胞中的HIV-DNA分布， 在抗逆转录病毒治疗期间， 从而加快这些药物的总体早期I期和II期开发。

The rapid evaluation of new antiretroviral agents will be markedly changed by the development of accurate virologic markers. We have developed the concept of plasma HIV viremia as a marker for antiretroviral studies. However, cultur methods are slow and virion detection by HIV-RNA PCR methods may afford a more rapid, sensitive and quantitative assessment of antiviral response to therapy. We feel that a systematic evaluation of plasma viremia and HIV RNA virus detection is warranted and are proposing a series of investigations with the following aims: AIM 1, to further develop plasma viremia as a marker of antiretroviral therapy by assessing the relationship between infectivity of cell-free plasma virus and presence of both cell-associated HIV proviral DNA and cell-free HIV RNA; AIM 2, to develop further a direct ex vivo assay that will measure the in vivo response of HIV infection to antiretrovirals an provide a method for targeting subsequent in vivo levels for further phase I study; AIM 3, determine if the blocking of HIV infectivity by immune-based viral neutralization therapies, such as sCD4 and antiretrovirals such as the glycosylation inhibitor deoxynorjirimycin and protease inhibitors, will decrease cell-associated and cell-free infectious titers of HIV and quantity of HIV nucleic acid. We anticipate that these methods will prove to be a particularly useful in vitro guide for he more rapid assessment of antiretrovirals in general; particularly those with either a narrow therapeutic index or poor bioavailability following oral dosing. In conjunction with other quantitative virologic methods such as cell-dilution infectivity assays, HIV-DNA distribution of HIV among the various cell- associated and cell-free reservoirs during antiretroviral therapy, and will thus expedite the overall early phase I and II development of these drugs.