Division of Infectious Disease, Department of Medicine, Icahn School of Medicine at Mount Sinai, 1 Gustave L. Levy Place, New York, NY 10029, USA.
Viruses. 2022 Apr 13;14(4):808. doi: 10.3390/v14040808.
HIV-1 Env signal peptide (SP) is an important contributor to Env functions. Env is generated from Vpu/Env encoded bicistronic mRNA such that the 5' end of Env-N-terminus, that encodes for Env-SP overlaps with 3' end of Vpu. Env SP displays high sequence diversity, which translates into high variability in Vpu sequence. This study aimed to understand the effect of sequence polymorphism in the Vpu-Env overlapping region (VEOR) on the functions of two vital viral proteins: Vpu and Env. We used infectious molecular clone pNL4.3-CMU06 and swapped its SP (or VEOR) with that from other HIV-1 isolates. Swapping VEOR did not affect virus production in the absence of tetherin however, presence of tetherin significantly altered the release of virus progeny. VEOR also altered Vpu's ability to downregulate CD4 and tetherin. We next tested the effect of these swaps on Env functions. Analyzing the binding of monoclonal antibodies to membrane embedded Env revealed changes in the antigenic landscape of swapped Envs. These swaps affected the oligosaccharide composition of Env-N-glycans as shown by changes in DC-SIGN-mediated virus transmission. Our study suggests that genetic diversity in VEOR plays an important role in the differential pathogenesis and also assist in immune evasion by altering Env epitope exposure.
HIV-1 包膜信号肽（SP）是包膜功能的重要贡献者。包膜由 Vpu/Env 编码的双顺反子 mRNA 产生，使得包膜-N 端的 5' 端，即编码包膜 SP 的区域，与 Vpu 的 3' 端重叠。包膜 SP 显示出高度的序列多样性，这转化为 Vpu 序列的高度变异性。本研究旨在了解 Vpu-Env 重叠区（VEOR）中序列多态性对两种重要病毒蛋白：Vpu 和 Env 的功能的影响。我们使用感染性分子克隆 pNL4.3-CMU06，并将其 SP（或 VEOR）与来自其他 HIV-1 分离株的 SP 进行交换。然而，在没有 tetherin 的情况下，VEOR 的交换并不影响病毒的产生，但是 tetherin 的存在显著改变了病毒产物的释放。VEOR 还改变了 Vpu 下调 CD4 和 tetherin 的能力。我们接下来测试了这些交换对 Env 功能的影响。分析单克隆抗体与膜嵌入的 Env 的结合揭示了交换后的 Env 的抗原景观发生了变化。这些交换影响了 Env-N-聚糖的寡糖组成，如 DC-SIGN 介导的病毒传播变化所示。我们的研究表明，VEOR 中的遗传多样性在差异发病机制中起着重要作用，并且通过改变包膜表位暴露来协助免疫逃逸。
