Phenotypic properties of transmitted founder HIV-1
Phenotypic properties of transmitted founder HIV-1
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DOI：
10.1073/pnas.1304288110
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发表时间：
2013-04-23
影响因子：
11.1
通讯作者：
Hahn, Beatrice H.
中科院分区：
文献类型：
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作者：
Parrish, Nicholas F.;Gao, Feng;Hahn, Beatrice H.
确定导致HIV-1传播的病毒-宿主相互作用，包括能够建立新生感染的病毒的表型要求，可能对艾滋病疫苗的开发很重要。先前的分析未能确定趋化因子受体5 （CCR5）和CD4+ t细胞趋向性以外的表型特性，这些特性优先与病毒传播相关。然而，这些研究大多局限于检测假病毒背景下的包膜（Env）功能。在这里，我们生成了B亚型（n = 18）和C亚型（n = 23）的传播创始病毒（TF, n = 27）和慢性对照病毒（CC, n = 14）的传染性分子克隆，并在专门设计的检测HIV-1感染早期阶段的检测中比较了它们的表型特性。结果发现，TF病毒粒子的传染性是CC病毒的1.7倍（P = 0.049），每颗粒的Env含量是CC病毒的1.9倍（P = 0.048）。单核细胞来源的树突状细胞捕获TF病毒的效率提高1.7倍（P = 0.035），更容易转移到CD4+ T细胞（P = 0.025）。在原代CD4+ T细胞中，TF和CC病毒的复制动力学相似；然而，当在ifn - α存在下繁殖时，TF病毒比CC病毒复制到更高的滴度。这种差异在B亚型病毒（P = 0.000013）中显著，但在C亚型病毒（P = 0.53）中不显著，这可能反映了各自患者队列的人口统计学差异。综上所述，这些数据表明TF病毒具有更高的Env含量、增强的无细胞感染性、改善的树突状细胞相互作用和相对的ifn - α抗性。在开发和测试艾滋病疫苗时，应考虑到这些可能协同起作用的病毒特性。
Defining the virus-host interactions responsible for HIV-1 transmission, including the phenotypic requirements of viruses capable of establishing de novo infections, could be important for AIDS vaccine development. Previous analyses have failed to identify phenotypic properties other than chemokine receptor 5 (CCR5) and CD4+ T-cell tropism that are preferentially associated with viral transmission. However, most of these studies were limited to examining envelope (Env) function in the context of pseudoviruses. Here, we generated infectious molecular clones of transmitted founder (TF; n = 27) and chronic control (CC; n = 14) viruses of subtypes B (n = 18) and C (n = 23) and compared their phenotypic properties in assays specifically designed to probe the earliest stages of HIV-1 infection. We found that TF virions were 1.7-fold more infectious (P = 0.049) and contained 1.9-fold more Env per particle (P = 0.048) compared with CC viruses. TF viruses were also captured by monocyte-derived dendritic cells 1.7-fold more efficiently (P = 0.035) and more readily transferred to CD4+ T cells (P = 0.025). In primary CD4+ T cells, TF and CC viruses replicated with comparable kinetics; however, when propagated in the presence of IFN-alpha, TF viruses replicated to higher titers than CC viruses. This difference was significant for subtype B (P = 0.000013) but not subtype C (P = 0.53) viruses, possibly reflecting demographic differences of the respective patient cohorts. Together, these data indicate that TF viruses are enriched for higher Env content, enhanced cell-free infectivity, improved dendritic cell interaction, and relative IFN-alpha resistance. These viral properties, which likely act in concert, should be considered in the development and testing of AIDS vaccines.