PLASMA HIV CHARACTERIZATION PRE & POST HAART

血浆 HIV 特征鉴定前

• 批准号: 6388667
• 负责人: Eric Lorenzo
• 金额: $ 13.54万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-06-01 至 2005-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6388667
• 关键词: AIDS therapy; antiAIDS agent; clinical research; drug resistance; genetic strain; human immunodeficiency virus 1; human subject; molecular cloning; virus genetics; virus load

DESCRIPTION (Adapted from applicant's abstract) Viral resistance is a serious consequence of incomplete suppression of HIV-1 replication. Viral resistance eventually affects from 30% to 50% of all patients undergoing highly active anti-retroviral therapy (HAART). Once HAART resistance is present regaining control of plasma viremia becomes difficult because no clearly effective salvage strategy has been devised. Often, the final result of HAART failure is that a preexistent or generated set of mutations that confer resistance is positively selected. Clearly, this selection is directly applied at the pol gene, reverse transcriptase (RT) and protease coding regions, but the selected pol gene should be linked with the rest of the viral genome, including the highly immunogenic envelope gene. We therefore, expect this genomic linkage to have a genomic restriction effect at the envelope gene. The applicants hypothesize that HAART therapy while effective (viral loads of less than 400 copies/ml, of plasma) will restrict viral genetic variability so that eventual HAART failure, (more than 400 copies/ml of plasma) will result in the initial emergence of a plasma virus population that is more homogeneous genetically than the viral population prior to initiation of therapy. The existence of this "window of homogeneity" and the duration of this window, especially if it is also reflected at the envelope gene, may offer opportunities for therapeutic intervention that may be less effective when the virus is genetically more heterogeneous. Therefore, the applicants propose to sub-clone, sequence and analyze the C2-V3 region of the envelope gene, before HAART initiation and after HAART failure, from the plasma virus of a well-defined cohort of patients. They will also sub-clone, sequence and analyze the appropriate regions of the pol gene, RT and protease. The applicants will conduct these studies with the purpose of characterizing and documenting the development of selection at the pol gene that emerges from HAART failure, and whether it consequently reflects as a restriction of variability at the envelope gene. The applicant also expect to document any prevalent pattern of tropism restriction at the envelope gene. To accomplish these two goals, they will phylogenetically compare HAART failure quasi-species with the quasi-species before HAART and both these groups of quasi-species with the V-3 consensus motif that predicts CCR5 (M-tropic) co-receptor usage. This propose study will focus on genetic evolution and antigenic restriction of HIV in circulating blood of patients undergoing HAART. The applicants believe it is critical to know if this homogeneous (less heterogeneous) window period exists, in which the highly immunogenic envelope gene protein will be a more stable and/or predictable target for future therapeutic approaches.

描述 (摘自申请者的摘要)病毒耐药性是一个严重的后果 对HIV-1复制的不完全抑制。病毒最终产生抗药性 30%至50%的接受高活动度治疗的患者受到影响 抗逆转录病毒疗法(HAART)。一旦HAART抵抗出现，就会重新获得 控制血浆病毒血症变得困难，因为没有明显有效的方法 已经制定了打捞策略。通常，HAART失败的最终结果是 一组预先存在或产生的赋予抗药性的突变是 肯定被选中。显然，此选择直接应用于极点 基因、逆转录酶(RT)和蛋白酶编码区，但选定的 POL基因应该与病毒基因组的其余部分相连，包括 具有高度免疫原性的包膜基因。因此，我们预计这种基因组联系将 对包膜基因有基因组限制作用。申请者 假设HAART治疗有效(病毒载量低于400 拷贝/毫升血浆)将限制病毒的遗传变异性，从而最终 HAART失败，(超过400拷贝/毫升血浆)将导致初始 在遗传上更加同质的血浆病毒群体的出现 比开始治疗前的病毒数量更多。的存在 这一“同质性窗口”和这一窗口的持续时间，特别是如果 也体现在包膜基因上，可以为 当病毒感染时可能不太有效的治疗干预 在基因上更具异质性。因此，申请者建议 对包膜基因的C2-V3区进行亚克隆、测序和分析 HAART启动和HAART失败后，来自一种 明确界定的病人队列。它们还将进行亚克隆、测序和 分析pol基因、RT和蛋白水解酶的适当区域。这个 申请者将进行这些研究，目的是描述和 记录了在POL基因中出现的选择的发展 HAART失败，以及它是否因此反映为对 包膜基因的可变性。申请人还希望记录任何 外膜基因的趋向性限制的流行模式。要完成 这两个目标，他们将从系谱上比较HAART失败 具有HAART之前的准物种的准物种和这两组 具有V-3一致基序的准物种预测CCR5(M嗜性) 共受体的使用。这项拟议的研究将集中在遗传进化和 人类免疫缺陷病毒感染患者外周血中HIV的抗原限制 哈尔特。申请人认为，了解这种同质性是至关重要的 (异质性较低)窗口期，在此期间，高度免疫原性 包膜基因蛋白将成为更稳定和/或更可预测的靶点 未来的治疗方法。