患者来源的HIV-1 Vpu和Nef等位基因对自然杀伤细胞配体的细胞表面下调作用

Cell Surface Downregulation of NK Cell Ligands by Patient-Derived HIV-1 Vpu and Nef Alleles.

作者信息

Galaski Johanna, Ahmad Fareed, Tibroni Nadine, Pujol Francois M, Müller Birthe, Schmidt Reinhold E, Fackler Oliver T

机构信息

*Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, Heidelberg, Germany; †German Center for Infection Research, Heidelberg University, Heidelberg, Germany; ‡Department of Clinical Immunology and Rheumatology, Hannover Medical School, Hannover, Germany; and §German Center for Infection Research, Hannover Medical School, Hannover, Germany.

出版信息

J Acquir Immune Defic Syndr. 2016 May 1;72(1):1-10. doi: 10.1097/QAI.0000000000000917.

DOI:10.1097/QAI.0000000000000917

PMID:26656785

Abstract

OBJECTIVE

HIV-1 Vpu and Nef proteins downregulate cell surface levels of natural killer (NK) cell ligands but functional consequences of individual downregulation events are unclear. We tested how well-conserved NK cell ligand downregulation is among Vpu and Nef variants isolated from chronic HIV patients.

METHODS

Proviral vpu and nef sequences were amplified from 27 chronic HIV patients, subcloned, and tested for their ability to downregulate cell surface receptors.

RESULTS

Cell surface downregulation of CD4, CD317/tetherin, and major histocompatibility complex class 1 that exert biological functions other than NK cell activation were well conserved among patient-derived Vpu and Nef variants. Among NK cell ligands, NK-T-B-antigen, poliovirus receptor, and UL16-binding protein were identified as main targets for Vpu and Nef, the downregulation of which by at least 1 viral protein was highly conserved. NK cell ligands displayed specific sensitivity to Vpu (NK-T-B-antigen) or Nef (poliovirus receptor), and downregulation of cell surface UL16-binding protein was identified as a novel and highly conserved activity of HIV-1 Vpu but not Nef.

CONCLUSIONS

The conservation of downregulation of major NK cell ligands by either HIV-1 Vpu or Nef suggests an important pathophysiological role of this activity, which may impact the acute but not the chronic phase of HIV infection.

摘要

目的

HIV-1 Vpu和Nef蛋白可下调自然杀伤（NK）细胞配体的细胞表面水平，但单个下调事件的功能后果尚不清楚。我们测试了从慢性HIV患者中分离出的Vpu和Nef变体之间NK细胞配体下调的保守程度。

方法

从27例慢性HIV患者中扩增前病毒vpu和nef序列，进行亚克隆，并测试其下调细胞表面受体的能力。

结果

在患者来源的Vpu和Nef变体中，CD4、CD317/连接蛋白以及主要组织相容性复合体I类分子的细胞表面下调在发挥除NK细胞激活以外生物学功能方面具有高度保守性。在NK细胞配体中，NK-T-B抗原、脊髓灰质炎病毒受体和UL16结合蛋白被确定为Vpu和Nef的主要靶点，至少一种病毒蛋白对其下调具有高度保守性。NK细胞配体对Vpu（NK-T-B抗原）或Nef（脊髓灰质炎病毒受体）表现出特异性敏感性，细胞表面UL16结合蛋白的下调被确定为HIV-1 Vpu而非Nef的一种新的高度保守活性。