Identification and characterisation of transmitted and early founder virus envelopes in primary HIV-1 infection
Identification and characterisation of transmitted and early founder virus envelopes in primary HIV-1 infection
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DOI：
10.1073/pnas.0802203105
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发表时间：
2008-05-27
影响因子：
11.1
通讯作者：
Shaw, George M.
中科院分区：
文献类型：
--
作者：
Keele, Brandon F.;Giorgi, Elena E.;Shaw, George M.
精确识别导致临床感染发生的HIV - 1包膜糖蛋白（Env），可能有助于阐明HIV - 1传播的分子基础以及设计有效的疫苗。在此，我们建立了一个随机病毒进化的数学模型，并结合系统发育树的构建，用它分析了从102名急性HIV - 1（B亚型）感染受试者中通过单基因组扩增获得的3449个完整的env序列。从单个传播的或起始的病毒进化而来的病毒env基因通常呈现出突变的泊松分布和星状系统发育，在估计的病毒传播时间或其附近汇聚到一个推断的共有序列。总体而言，102名受试者中有78人有单一病毒导致临床感染发生的证据，另外24人有至少2到5种病毒导致临床感染发生的证据。对传播的或早期起始的Env进行表型分析显示出一种一致的模式，即依赖CCR5、辅助受体结合区域被掩盖，与来自慢性感染受试者的Env相比，对融合抑制剂T1249和广泛中和抗体具有同等或适度增强的抗性。在病毒血症峰值之前的低感染复数和有限的病毒进化表明，HIV - 1对疫苗诱导的免疫反应存在一个潜在的易受攻击的有限窗口期，尽管传播的Env的表型特性构成了强大的防御。
The precise identification of the HIV-1 envelope glycoprotein (Env) responsible for productive clinical infection could be instrumental in elucidating the molecular basis of HIV-1 transmission and in designing effective vaccines. Here, we developed a mathematical model of random viral evolution and, together with phylogenetic tree construction, used it to analyze 3,449 complete env sequences derived by single genome amplification from 102 subjects with acute HIV-1 (clade B) infection. Viral env genes evolving from individual transmitted or founder viruses generally exhibited a Poisson distribution of mutations and star-like phylogeny, which coalesced to an inferred consensus sequence at or near the estimated time of virus transmission. Overall, 78 of 102 subjects had evidence of productive clinical infection by a single virus, and 24 others had evidence of productive clinical infection by a minimum of two to five viruses. Phenotypic analysis of transmitted or early founder Envs revealed a consistent pattern of CCR5 dependence, masking of coreceptor binding regions, and equivalent or modestly enhanced resistance to the fusion inhibitor T1249 and broadly neutralizing antibodies compared with Envs from chronically infected subjects. Low multiplicity infection and limited viral evolution preceding peak viremia suggest a finite window of potential vulnerability of HIV-1 to vaccine-elicited immune responses, although phenotypic properties of transmitted Envs pose a formidable defense.