Primary Infection by a Human Immunodeficiency Virus with Atypical Coreceptor Tropism
Primary Infection by a Human Immunodeficiency Virus with Atypical Coreceptor Tropism
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DOI：
10.1128/jvi.05249-11
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发表时间：
2011-10-01
影响因子：
5.4
通讯作者：
Gao, Feng
中科院分区：
文献类型：
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作者：
Jiang, Chunlai;Parrish, Nicholas F.;Gao, Feng
绝大多数人类免疫缺陷病毒1型（HIV-1）毒株通过与两种辅助受体CCR 5或CXCR 4之一相互作用进入CD 4（+）靶细胞。在这里，我们描述了一种传播/创始者（T/F）病毒（ZP 6248），其利用多种CD 4（+）细胞系以及原代人CD 4（+）T细胞和巨噬细胞上的CCR 5和CXCR 4辅助受体的能力严重受损，但在急性感染个体中复制到非常高的滴度（> 8000万RNA拷贝/ml）。有趣的是，这种进化枝B病毒的包膜（Env）糖蛋白在其第三个可变环（V3）的冠部具有罕见的GPEK序列，而不是共有的GPGR序列。连续血浆样品的广泛测序表明，GPEK序列存在于几乎所有Env中，包括感染后最早时间点的Env。分子克隆的（单个）T/F病毒能够在从ccr 5 Delta 32纯合供体获得的细胞中复制，尽管很差。ZP 6248 T/F病毒还可以感染过表达替代性辅助受体GPR 15、APJ和FPRL-1的细胞系。ZP 6248的V3冠序列中的一个突变（GPEK->GPGK）恢复了其在CCR 5（+）细胞中的感染性，但降低了其在GPR 15（+）细胞中的复制能力，表明V3冠基序在使用这种替代辅助受体中起重要作用。这些结果表明，ZP 6248 T/F病毒通过使用CCR 5或CXCR 4以外的辅助受体建立了急性体内感染，或者CCR 5辅助受体在该个体中以不寻常的构象存在。
The great majority of human immunodeficiency virus type 1 (HIV-1) strains enter CD4(+) target cells by interacting with one of two coreceptors, CCR5 or CXCR4. Here we describe a transmitted/founder (T/F) virus (ZP6248) that was profoundly impaired in its ability to utilize CCR5 and CXCR4 coreceptors on multiple CD4(+) cell lines as well as primary human CD4(+) T cells and macrophages in vitro yet replicated to very high titers (>80 million RNA copies/ml) in an acutely infected individual. Interestingly, the envelope (Env) glycoprotein of this clade B virus had a rare GPEK sequence in the crown of its third variable loop (V3) rather than the consensus GPGR sequence. Extensive sequencing of sequential plasma samples showed that the GPEK sequence was present in virtually all Envs, including those from the earliest time points after infection. The molecularly cloned (single) T/F virus was able to replicate, albeit poorly, in cells obtained from ccr5 Delta 32 homozygous donors. The ZP6248 T/F virus could also infect cell lines overexpressing the alternative coreceptors GPR15, APJ, and FPRL-1. A single mutation in the V3 crown sequence (GPEK->GPGK) of ZP6248 restored its infectivity in CCR5(+) cells but reduced its ability to replicate in GPR15(+) cells, indicating that the V3 crown motif played an important role in usage of this alternative coreceptor. These results suggest that the ZP6248 T/F virus established an acute in vivo infection by using coreceptor(s) other than CCR5 or CXCR4 or that the CCR5 coreceptor existed in an unusual conformation in this individual.