Define the sources of persistent HIV production

项目总结(见说明)： 这个合作实验室的应用集中在最了解的HIV-1的储存库，静息的CD4+T细胞的潜伏储存库。我们的目标是找到针对这个储集层的小分子方法。然而，HLV-1也可能在H/\ART患者的其他宿主中持续存在。因此，根除艾滋病毒-1的全面办法需要确定所有稳定的宿主，并制定战略，以 把每一个都消灭。为此，我们的实验室一直在分析微量残留病毒血症(RV)，这些残留病毒血症(RV)可以通过专门的检测方法在接受HAART的患者中检测到，这些患者的病毒载量通过标准临床检测方法是“无法检测”的。由于血浆中游离病毒的半衰期很短，长期接受HAART的患者中RV的存在表明在有效药物存在的情况下持续产生病毒。 因此，对轮状病毒的分析为了解病毒学抑制状态和阻碍根除的宿主提供了一个独特的窗口。通过对接受HAART的患者中存在的微量RV的序列分析，我们和其他人提供了证据，证明至少有一部分RV来自于不同于静息CD4+T细胞潜伏库的来源。该项目的目标是对独特患者群体中的RV和潜在储存库进行详尽的纵向采样，并比较这两个来源的序列，以验证其他储存库的存在。将在HAART上对感染SIV的猕猴进行平行研究，以努力找到轮状病毒的来源。明确证明存在对房车有贡献的其他水库将 可能需要开发替代治疗方法，而不是针对静息的CD4+T细胞中的潜伏库。在最初的临床试验中评估替代水库对以潜伏水库为目标的战略的反应，可能会提供关于是否需要其他方法来实现根除的关键信息。

PROJECT SUMMARY (See instructions): This Collaboratory application focuses on the best understood reservoir for HIV-1, the latent reservoir in resting CD4+ T cells. Our goal is to find small molecule approaches for targeting this reservoir. However, HlV-1 may also persist in other reservoirs in patients on H/\ART. Therefore a comprehensive approach to HIV-1 eradication requires the identification of all stable reservoirs and the development of strategies to eliminate each one. To this end, our laboratory has been analyzing the trace levels of residual viremia (RV) that can be detected using specialized assays in patients on HAART who have "undetectable" viral loads by standard clinical assays. Because of the short half-life of free virus in the plasma, the presence of RV in patients on long term HAART indicates the ongoing production of virus in the presence of effective drugs. Thus, the analysis of RV provides a unique window into the state of virologic suppression and the reservoirs that stand in the way of eradication. Through sequence analysis of the trace levels of RV present in patients on HAART, our group and others have provided evidence that at least some fraction of the RV is derived from a source distinct from the latent reservoir in resting CD4+ T cells. The goals of the this project are to carry out exhaustive longitudinal sampling of the RV and the latent reservoir in unique patient populations and to compare the sequences from these two sources in order to verify the existence of additional reservoirs. Parallel studies will be carried out in SIV-infected macaques on HAART in a effort to find the source of the RV. Definitave demonstration of the existence of additional reservoirs contributing to RV will may require the development of alternative therapeutic approaches in addition to those targeting the latent reservoir in resting CD4+ T cells. Assessing the response of alternative reservoirs to strategies targeting the latent reservoir in initial clinical trials may provide critical information about the need for additional approaches to achieve eradication.