PLASMA HIV CHARACTERIZATION PRE & POST HAART

血浆 HIV 特征鉴定前

• 批准号: 6760970
• 负责人: Eric Lorenzo
• 金额: $ 12.34万
• 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/6760970
• 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 （改编自申请人摘要）病毒耐药性是一个严重的后果 HIV-1复制的不完全抑制。 病毒耐药性最终 影响了30%到50%的高活性 抗逆转录病毒疗法（HAART）。一旦出现HAART耐药， 血浆病毒血症的控制变得困难，因为没有明确有效的 制定了抢救战略。通常，HAART失败的最终结果是 先前存在的或产生的一组赋予耐药性的突变， 积极选择。显然，这种选择直接应用于极点 基因、逆转录酶（RT）和蛋白酶编码区，但所选的 pol基因应该与病毒基因组的其余部分相连，包括 高免疫原性包膜基因。因此，我们预计这种基因组联系， 在包膜基因上具有基因组限制作用。申请人 假设HAART治疗有效（病毒载量小于400 拷贝/ml血浆）将限制病毒遗传变异性， HAART失败（超过400拷贝/ml血浆）将导致初始 血浆病毒群体的出现在遗传上更加同质 比开始治疗前的病毒群要多。的存在 这种“同质窗口”和这种窗口的持续时间，特别是如果它 也反映在包膜基因上，可能为 治疗干预，可能是不太有效的，当病毒是 基因上更加异质。因此，申请人建议， 亚克隆、测序和分析包膜基因的C2-V3区，然后 HAART启动和HAART失败后，从血浆病毒的一个 明确定义的患者队列。他们还将亚克隆，测序， 分析pol基因、RT和蛋白酶的适当区域。的 申请人将进行这些研究的目的是表征和 记录了pol基因选择的发展， HAART失败，以及它是否因此反映为 基因的变异性。申请人还希望记录任何 在包膜基因的向性限制的普遍模式。完成 这两个目标，他们将从遗传学上比较HAART失败 准物种与HAART前的准物种，这两组 具有预测CCR 5的V-3共有基序的准种（M-嗜性） 辅助受体使用。这项研究将集中在遗传进化和 HIV抗原限制性抗体在循环血液中的应用 HAART。 申请人认为，关键是要知道这种同质的 (less异质性）窗口期存在，其中高度免疫原性的 包膜基因蛋白将是更稳定和/或可预测的靶， 未来的治疗方法。