Evolution of the human immunodeficiency virus type 1 envelope during infection reveals molecular corollaries of specificity for coreceptor utilization and AIDS pathogenesis
Evolution of the human immunodeficiency virus type 1 envelope during infection reveals molecular corollaries of specificity for coreceptor utilization and AIDS pathogenesis
复制标题
DOI：
10.1128/jvi.74.24.11858-11872.2000
复制
发表时间：
2000-12-01
影响因子：
5.4
通讯作者：
Greenberg, ML
中科院分区：
文献类型：
--
作者：
Hu, QX;Barry, AP;Greenberg, ML
人类免疫缺陷病毒1型感染的演变与靶细胞群的变化有关，这是由env多样性导致的辅助受体利用的变异性驱动的。为了阐明这些变化的潜在后果Env介导的融合过程中的艾滋病，我们研究了一系列病毒分离株的生物学特性，并确定辅受体利用的产物的Env克隆从两个人，其次是从检测血清转化的整个过程中，他们的感染。一个有一个典型的过程，另一个有一个加速的进展。早期分离物是非合胞体诱导的，并且相应的Env专门利用CCR 5，而来自感染晚期的Env在两名患者中显示出对CXCR 4的限制性利用。来自具有标准进展的受试者SC24的Env显示出多向性，表现为在干预期间利用CCR 3、CXCR 4和CCR 5。相比之下，来自患者SC 51的Env经历了早期转化为合胞体诱导表型，开发了CCR 5和CXCR 4的双嗜性辅助受体利用。每个分离株的env基因分析显示，具有X4表型的那些在每个受试者内形成不同的亚群。对从患者SC24的R5和多特异性env构建的嵌合体的分析表明，虽然V3结构域在确定辅助受体利用中起主导作用，但V4-V5区域中的序列也有助于后者的表型。免疫沉淀实验证实，杂交Env蛋白以相似的水平表达。这些实验表明，从R5到X4表型的进展可能通过多或双嗜性中间体发生，并且多个结构域有助于该过程。
The evolution of human immunodeficiency virus type 1 infection is associated with a shift in the target cell population, driven by variability in coreceptor utilization resulting from diversity in env. To elucidate the potential consequences of these changes for Env-mediated fusion over the course of AIDS, we examined the biological properties of serial viral isolates and determined coreceptor utilization by the products of env cloned from two individuals, followed from the detection of seroconversion throughout the course of their infection. One had a typical course, and the other had an accelerated progression. Early isolates were non-syncytium inducing, and the corresponding Env exclusively utilized CCR5, whereas Env from late phases of infection showed restricted utilization of CXCR4 in both patients. Env from subject SC24, who had a standard progression, demonstrated multitropism, manifested by utilization of CCR3, CXCR4, and CCR5 in the intervening period. In contrast, Env from patient SC51, who experienced early conversion to the syncytium-inducing phenotype, developed dualtropic coreceptor utilization of CCR5 and CXCR4. Genetic analysis of env from each isolate revealed that those with an X4 phenotype formed a distinct subcluster within each subject. Analysis of chimeras constructed from R5 and multispecific env from patient SC24 demonstrated that while the V3 domain played a dominant role in determining coreceptor utilization, sequences in the V4-V5 region also contributed to the latter phenotype. Immunoprecipitation experiments confirmed that the hybrid Env proteins were expressed at similar levels. These experiments demonstrate that progression from the R5 to X4 phenotype may occur through a multi- or dual-tropic intermediate and that multiple domains contribute to this process.