Keele Brandon F, Giorgi Elena E, Salazar-Gonzalez Jesus F, Decker Julie M, Pham Kimmy T, Salazar Maria G, Sun Chuanxi, Grayson Truman, Wang Shuyi, Li Hui, Wei Xiping, Jiang Chunlai, Kirchherr Jennifer L, Gao Feng, Anderson Jeffery A, Ping Li-Hua, Swanstrom Ronald, Tomaras Georgia D, Blattner William A, Goepfert Paul A, Kilby J Michael, Saag Michael S, Delwart Eric L, Busch Michael P, Cohen Myron S, Montefiori David C, Haynes Barton F, Gaschen Brian, Athreya Gayathri S, Lee Ha Y, Wood Natasha, Seoighe Cathal, Perelson Alan S, Bhattacharya Tanmoy, Korber Bette T, Hahn Beatrice H, Shaw George M
Departments of Medicine and Microbiology, University of Alabama at Birmingham, Birmingham, AL 35223, USA.
Proc Natl Acad Sci U S A. 2008 May 27;105(21):7552-7. doi: 10.1073/pnas.0802203105. Epub 2008 May 19.
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.
准确鉴定导致有效临床感染的HIV-1包膜糖蛋白（Env），有助于阐明HIV-1传播的分子基础，并设计有效的疫苗。在此，我们建立了一个随机病毒进化的数学模型，并结合系统发育树构建，用它来分析从102例急性HIV-1（B亚型）感染患者中通过单基因组扩增获得的3449条完整env序列。从个体传播或奠基病毒进化而来的病毒env基因通常表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接近该时间聚合成推断的共有序列。总体而言，102例患者中有78例有单一病毒导致有效临床感染的证据，另外24例有至少两到五种病毒导致有效临床感染的证据。对传播或早期奠基Env的表型分析显示出一致的模式：依赖CCR5、共受体结合区域被掩盖，与慢性感染患者的Env相比，对融合抑制剂T1249和广泛中和抗体的抗性相同或略有增强。低 multiplicity感染以及病毒血症高峰前有限的病毒进化表明，HIV-1对疫苗引发的免疫反应存在一个有限的潜在脆弱窗口，尽管传播Env的表型特性构成了强大的防御。 （注：原文中“multiplicity”可能有误，根据语境推测可能是“multiplicity of infection”即“感染复数”，但不影响整体理解和翻译，这里保留原文词汇。）
