HIV 1 SEQUENCE DIVERSITY AND PEDIATRIC AIDS

描述(改编自摘要)：基因的重要性 HIV-1变异在艾滋病发病机制中的作用尚不清楚。《校长》 研究人员指出，持续的病毒感染，高病毒载量，以及 易于出错的复制机制为以下方面提供了理想的条件 在病毒-宿主相互作用过程中塑造病毒-宿主相互作用的进化力量 感染；他推测这一过程可能对病毒具有重要意义 致病机制要么是通过出现能够占据 新的生态位，例如不同的宿主细胞类型，或者通过 抗原性多样性压倒一切的病毒群体的产生 宿主免疫系统控制它们的能力。《调查者》 他的同事们最近完成了一项研究，旨在描述 血浆HIV-1包膜蛋白C2V3基因序列在体内的进化 L感染艾滋病毒的婴儿的疾病进展情况。对六名婴儿进行了跟踪调查 抽样间隔约为六个月，为期两年。二 在这段时间内发展为艾滋病。这项研究的结果 表明患上艾滋病的婴儿有更高的核苷酸比率 并表现出较大的总体遗传多样性。婴儿患有 艾滋病也显示出连续的显性血统，表明 变种的顺序替换，可能是周期性逃逸的结果 来自免疫反应或由于增加了对高产宿主的趋向性 单元类型。对推导出的氨基酸序列的系统发育分析表明 在后面的时间点检测到的V3环序列的聚类 患有艾滋病的婴儿。这些V3环序列共有四个氨基酸 显示的位置是T细胞系趋向性的遗传决定因素。这个 进化模式表明，这些患有艾滋病的婴儿的病毒 独立获得，通过一个似乎是融合的例子 进化，一种类似的，可能更致命的表型。该计划的目标是 拟议的研究是为了检验这些发现的普遍性。一百 婴儿将每隔三个月接受一次为期两年的随访。这个 研究人员建议从逆转录病毒中提取50个序列 每个患者在每个时间间隔的RNA。然而，通过使用异质双工 分析后，他只需要对这些序列中的一小部分进行测序。这个 研究人员建议收集核苷酸序列数据和四个 临床表型：(1)病毒载量，(2)CD4+T细胞计数，(3)临床 分类；(4)时间。这些数据将在一个 基于种内分支图估计的系统发育框架 Templeton程序，该程序是为重建 种内系统发育，并允许嵌套统计设计来 检验关联性的假设。要检验的假设分为两个 类别：(1)与疾病进展有关的遗传多样性；以及 (2)遗传多样性与临床表型的相关性。在第一个 研究人员会问，婴儿是否会迅速发展到 与进展缓慢的人相比，艾滋病患者的核苷酸比率更高 代换，非同义核苷酸与同义核苷酸的比例更大 替换，以及更大的艾滋病毒-L核苷酸多样性，以及 以前的婴儿表现出顺序的显性血统和汇聚性或 V3环中的发散模体。在第二类中，他们会问 基因多样性和病毒载量、CD4+之间是否存在关联 T细胞计数、临床分类或时间，如果关联是 发现，基因途径是否与该基因的改变有关 表型独立或趋同。

DESCRIPTION (adapted from the Abstract): The importance of genetic variation of HIV-1 for the pathogenesis of AIDS is unclear. The Principal Investigator notes that a persistent viral infection, a high viral load, and an error-prone replication mechanism provide ideal conditions for evolutionary forces to shape the virus-host interaction during the course of infection; he speculates that this process may have importance for viral pathogenesis either through the emergence of strains capable of occupying new ecological niches, such as different host cell types, or through the generation of a population of viruses whose antigenic diversity overwhelms the capacity of the host's immune system to contain them. The Investigator and his associates have completed recently a study aimed at characterizing the in vivo evolution of plasma HIV-1 env C2V3 sequences in relation to disease progression in HIV-l infected infants. Six infants were followed with sampling at approximately six-month intervals for two years. Two progressed to AIDS within this time frame. The results from this study indicate that infants who developed AIDS had an increased rate of nucleotide substitution and showed a greater overall genetic diversity. Infants with AIDS also showed sequentially dominant lineages, suggesting a process of sequential replacement of variants, perhaps as a result of periodic escape from the immune response or due to increasing tropism for a productive host cell type. Phylogenetic analysis of deduced amino acid sequences showed a clustering of V3 loop sequences detected at later time points from the two infants with AIDS. These V3 loop sequences shared four amino acids in positions shown to be genetic determinants of T-cell line tropism. The evolutionary pattern suggests that viruses from these infants with AIDS have acquired independently, through what appears to be an example of convergent evolution, a similar and possibly more virulent phenotype. The aims of the proposed research are to test the generality of these findings. One hundred infants will be followed at three-month intervals for two years. The Investigator proposes to sample 50 sequences from reverse transcribed viral RNA at each time interval for each patient. However, by using heteroduplex analysis, he will need to sequence only a fraction of these sequences. The Investigator proposes to collect nucleotide sequence data and data for four clinical phenotypes: (1) viral load, (2) CD4+ T-cell count, (3) clinical classification, and (4) time. The data will be analyzed within a phylogenetic framework using the intraspecific cladogram estimation procedure of Templeton, which was developed for reconstruction of within-species phylogenies and allows for a nested statistical design to test hypotheses of association. The hypotheses to be tested fall into two categories: (1) genetic diversity associated with disease progression; and (2) association of genetic diversity with clinical phenotypes. In the first category the researchers will ask whether infants who rapidly progress to AIDS as compared to slow progressors have an increased rate of nucleotide substitution, a greater proportion of nonsynonymous to synonymous nucleotide substitutions, and greater HIV-l nucleotide diversity, and whether the former infants show sequentially dominant lineages and convergent or divergent motifs in the V3 loop. In the second category they will ask whether an association exists between genetic diversity and viral load, CD4+ T cell count, clinical classification or time and, if an association is found, whether the genetic avenues to the genotype related to the change in phenotype are independent or convergent.