A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection.
A cellular trafficking signal in the SIV envelope protein cytoplasmic domain is strongly selected for in pathogenic infection.
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DOI：
10.1371/journal.ppat.1010507
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发表时间：
2022-06
期刊：
影响因子：
6.7
通讯作者：
中科院分区：
文献类型：
--
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HIV/SIV包膜糖蛋白（Env）胞质结构域包含高度保守的基于Tyr的运输信号，其介导网格蛋白依赖性内吞作用和极化分选。尽管进行了广泛的分析，但这些功能在病毒感染和发病机制中的作用尚不清楚。通过缺失Gly-720和Tyr-721（SIVmac 239 Δ戈伊）使该信号失活的SIV分子克隆（SIVmac 239）在猪尾猕猴（PTM）中急性复制至高水平，但被迅速控制。然而，我们先前报道恒河猴和PTM在SIVmac 239 Δ戈伊感染后可进展为AIDS，这与Env胞质结构域中的新氨基酸变化有关。这些包括侧接Δ戈伊缺失的R722 G和与rev和达特开放阅读框重叠的编码氨基酸734-736（ΔQTH）的9个核苷酸缺失。我们发现，含有这些突变的分子克隆重组信号的内吞作用和极化分选。在一个PTM中，选择了一种新的基因型，该基因型产生了用于极化分选但不产生内吞作用的新信号。该基因型与Δ戈伊突变一起，在引入初始PTM时与高病毒载量相关数月。我们的研究结果首次揭示了Env内吞作用的强大选择压力，特别是在体内致病性SIV感染期间的极化分选。在其包膜糖蛋白（Env）的胞质结构域（CD）中，所有人类和猿免疫缺陷病毒（HIV和SIV）都具有酪氨酸依赖性基序，该基序是Env内吞作用和感染细胞中极化分选的有效信号。这种运输信号在发病机制中的作用和相关性尚不清楚。对于致病性SIV，我们已经证明，删除该酪氨酸和前面的甘氨酸，产生一种称为Δ戈伊的病毒，导致猪尾猕猴发病机制的深刻改变。病毒复制被迅速抑制，系统性免疫激活未能发生，CD 4细胞得以幸免。然而，尽管不常见，但Δ GY感染的猕猴可发展高病毒载量和与Env CD中的新突变相关的疾病。在这里，我们表明，这些突变恢复运输功能，显着，在重叠的阅读框架的达特和rev基因的代价。我们量化了这些新信号的影响，并证明了它们能够赋予Δ GY感染动物高病毒载量和/或疾病。这些发现证明了维持Env运输，特别是极化分选的强大体内选择压力。我们提出的假设，为什么这个长期公认的，但知之甚少的Env功能是保守的，HIV/SIV的发病机制是必不可少的。
The HIV/SIV envelope glycoprotein (Env) cytoplasmic domain contains a highly conserved Tyr-based trafficking signal that mediates both clathrin-dependent endocytosis and polarized sorting. Despite extensive analysis, the role of these functions in viral infection and pathogenesis is unclear. An SIV molecular clone (SIVmac239) in which this signal is inactivated by deletion of Gly-720 and Tyr-721 (SIVmac239ΔGY), replicates acutely to high levels in pigtail macaques (PTM) but is rapidly controlled. However, we previously reported that rhesus macaques and PTM can progress to AIDS following SIVmac239ΔGY infection in association with novel amino acid changes in the Env cytoplasmic domain. These included an R722G flanking the ΔGY deletion and a nine nucleotide deletion encoding amino acids 734–736 (ΔQTH) that overlaps the rev and tat open reading frames. We show that molecular clones containing these mutations reconstitute signals for both endocytosis and polarized sorting. In one PTM, a novel genotype was selected that generated a new signal for polarized sorting but not endocytosis. This genotype, together with the ΔGY mutation, was conserved in association with high viral loads for several months when introduced into naïve PTMs. For the first time, our findings reveal strong selection pressure for Env endocytosis and particularly for polarized sorting during pathogenic SIV infection in vivo. In the cytoplasmic domain (CD) of their envelope glycoproteins (Env), all human and simian immunodeficiency viruses (HIV and SIV) have a tyrosine-dependent motif that is a potent signal for Env endocytosis and polarized sorting in infected cells. The role and relevance of this trafficking signal in pathogenesis is unknown. For a pathogenic SIV, we have shown that deletion of this tyrosine and a preceding glycine, creating a virus termed ΔGY, results in profoundly altered pathogenesis in pigtail macaques. Viral replication is rapidly suppressed, systemic immune activation fails to occur, and CD4 cells are spared. However, although uncommon, ΔGY-infected macaques can develop high viral loads and disease in association with novel mutations in the Env CD. Here we show that these mutations restore trafficking functions, remarkably, at the expense of tat and rev genes in overlapping reading frames. We quantified the effects of these new signals and demonstrated their ability to confer high viral loads and/or disease to ΔGY-infected animals. These findings demonstrate strong in vivo selection pressures to maintain Env trafficking, in particular, polarized sorting. We present hypotheses for why this long recognized, but poorly understood Env function is conserved and essential for HIV/SIV pathogenesis.
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影响因子：
5.4
作者：
Berlioz-Torrent, C;Shacklett, BL;Benarous, R
通讯作者：
Benarous, R
DOI：
10.1083/jcb.201310021
发表时间：
2014-01-06
期刊：
The Journal of cell biology
影响因子：
--
作者：
Bonifacino JS
通讯作者：
Bonifacino JS
DOI：
10.3109/15419069809004468
发表时间：
1998-01-01
期刊：
CELL ADHESION AND COMMUNICATION
影响因子：
--
作者：
del Pozo, MA;Nieto, M;Sánchez-Madrid, F
通讯作者：
Sánchez-Madrid, F
影响因子：
1.5
作者：
Ball, JM;Mulligan, MJ;Compans, RW
通讯作者：
Compans, RW
影响因子：
5.4
作者：
Day, JR;Münk, C;Guatelli, JC
通讯作者：
Guatelli, JC