HIV 1 SEQUENCE DIVERSITY AND PEDIATRIC AIDS

描述（改编自摘要）：遗传的重要性 HIV-1变异对于艾滋病的发病机制尚不清楚。 校长 研究者指出，持续的病毒感染，高病毒载量， 易于出错的复制机制为 进化的力量，以塑造过程中的病毒-宿主的相互作用， 他推测，这一过程可能对病毒感染具有重要意义。 发病机制，无论是通过出现菌株能够占领 新的生态位，如不同的宿主细胞类型，或通过 产生抗原多样性不一致的病毒群体 宿主的免疫系统对它们的控制能力 研究者 和他的同事们最近完成了一项研究， 血浆HIV-1 env C2 V3序列与 HIV-1感染婴儿的疾病进展。 六名婴儿被跟踪 每隔大约六个月取样一次，为期两年。 两 在这段时间内发展成艾滋病。 本研究的结果 表明患有艾滋病的婴儿的核苷酸含量增加 替代，并表现出更大的整体遗传多样性。 婴幼儿 艾滋病也显示出顺序优势谱系，这表明一个过程， 变体的顺序替换，可能是周期性逃逸的结果 由于免疫反应或由于对繁殖宿主的嗜性增加 细胞类型。 推导的氨基酸序列的系统发育分析表明， 在稍后时间点检测到的V3环序列的聚类， 患有艾滋病的婴儿 这些V3环序列共享四个氨基酸， 位置显示为T细胞系向性的遗传决定因素。 的 进化模式表明，来自这些艾滋病婴儿的病毒 独立获得，通过似乎是一个例子， 进化，一个类似的，可能更致命的表型。 的目标 拟议的研究是为了测试这些发现的普遍性。 一百 婴儿将每隔三个月接受一次随访，为期两年。 的 研究者建议从逆转录病毒中采集50个序列 每个患者的每个时间间隔的RNA。 然而，通过使用异源双链体， 分析，他将只需要测序这些序列的一小部分。 的 研究人员建议收集核苷酸序列数据和四个数据 临床表型：（1）病毒载量，（2）CD 4 + T细胞计数，（3）临床 分类;（4）时间。 数据将在 利用种内分支图估计的系统发育框架 邓普顿的程序，这是为重建 种内遗传，并允许嵌套的统计设计， 检验关联假设。 要检验的假设分为两种 类别：（1）与疾病进展相关的遗传多样性;以及 (2)遗传多样性与临床表型的关联。 上 研究人员会问， 与进展缓慢的艾滋病患者相比， 替代，非同义核苷酸与同义核苷酸比例更大 取代，和更大的HIV-1核苷酸多样性，以及是否 前婴儿显示顺序优势谱系和收敛或 V3环中的发散基序。 第二类，他们会问 遗传多样性与病毒载量、CD 4 + T细胞计数，临床分类或时间，如果相关性是 发现，基因型的遗传途径是否与基因型的变化有关， 表型是独立的或趋同的。

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.