"Tree Shrew Cells Transduced with Human CD4 and CCR5 Support Early Steps of HIV-1 Replication, but Viral Infectivity Is Restricted by APOBEC3"

作者全名："Luo, Meng-Ting; Mu, Dan; Yang, Xiang; Luo, Rong-Hua; Zheng, Hong-Yi; Chen, Min; Guo, Ying-Qi; Zheng, Yong-Tang"

作者地址："[Luo, Meng-Ting; Mu, Dan; Yang, Xiang; Luo, Rong-Hua; Zheng, Hong-Yi; Chen, Min; Zheng, Yong-Tang] Chinese Acad Sci, Key Lab Anim Models & Human Dis Mech, Ctr Biosafety Megasci,KIZ CUHK Joint Lab Bioresou, Kunming Inst Zool,Key Lab Bioact Peptides Yunnan, Kunming, Yunnan, Peoples R China; [Luo, Meng-Ting; Yang, Xiang; Chen, Min; Zheng, Yong-Tang] Univ Chinese Acad Sci, Kunming Coll Life Sci, Kunming, Yunnan, Peoples R China; [Mu, Dan] Chongqing Med Univ, Inst Life Sci, Chongqing, Peoples R China; [Guo, Ying-Qi; Zheng, Yong-Tang] Chinese Acad Sci, Natl Resource Ctr Nonhuman Primates, Kunming Inst Zool, Kunming, Yunnan, Peoples R China; [Guo, Ying-Qi; Zheng, Yong-Tang] Chinese Acad Sci, Natl Res Facil Phenotyp & Genet Anal Model Anim P, Kunming Inst Zool, Kunming, Yunnan, Peoples R China"

通信作者："Zheng, YT (corresponding author), Chinese Acad Sci, Key Lab Anim Models & Human Dis Mech, Ctr Biosafety Megasci,KIZ CUHK Joint Lab Bioresou, Kunming Inst Zool,Key Lab Bioact Peptides Yunnan, Kunming, Yunnan, Peoples R China.; Zheng, YT (corresponding author), Univ Chinese Acad Sci, Kunming Coll Life Sci, Kunming, Yunnan, Peoples R China.; Zheng, YT (corresponding author), Chinese Acad Sci, Natl Resource Ctr Nonhuman Primates, Kunming Inst Zool, Kunming, Yunnan, Peoples R China.; Zheng, YT (corresponding author), Chinese Acad Sci, Natl Res Facil Phenotyp & Genet Anal Model Anim P, Kunming Inst Zool, Kunming, Yunnan, Peoples R China."

来源：JOURNAL OF VIROLOGY

ESI学科分类：MICROBIOLOGY

WOS号：WOS:000708641100009

JCR分区：Q1

影响因子：5.4

年份：2021

卷号：95

期号：16

开始页：　

结束页：　

文献类型：Article

关键词：APOBEC3; HIV-1; restriction factors; tree shrews; Tupaia belangeri chinensis; animal model

摘要："The host range of human immunodeficiency virus type 1 (HIV-1) is narrow. Therefore, using ordinary animal models to study HIV-1 replication, pathogenesis, and therapy is impractical. The lack of applicable animal models for HIV-1 research spurred our investigation on whether tree shrews (Tupaia belangeri chinensis), which are susceptible to many types of human viruses, can act as an animal model for HIV-1. Here, we report that tree shrew primary cells are refractory to wild-type HIV-1 but support the early replication steps of HIV-1 pseudotyped with the vesicular stomatitis virus glycoprotein envelope (VSV-G), which can bypass entry receptors. The exogenous expression of human CD4 renders the tree shrew cell line infectible to X4-tropic HIV1IIIB, suggesting that tree shrew CXCR4 is a functional HIV-1 coreceptor. However, tree shrew cells did not produce infectious HIV-1 progeny virions, even with the human CD4 receptor. Subsequently, we identified tree shrew (ts) apolipoprotein B editing catalytic polypeptide 3 (tsAPOBEC3) proteins as active inhibitors of HIV-1 particle infectivity, with virus infectivity reduced 10-to 1,000-fold. Unlike human APOBEC3G, the tsA3Z2c-Z1b protein was not degraded by the HIV-1 viral infectivity factor (Vif) but markedly restricted HIV-1 replication through mutagenicity and reverse transcription inhibition. The pooled knockout of tsA3Z2c-Z1b partially restored the infectivity of the HIV-1 progeny. This work suggests that tsAPOBEC3 proteins serve as an additional barrier to the development of HIV-1 tree shrew models, even when virus entry is overcome by exogenous expression of human CD4. IMPORTANCE The development of animal models is critical for studying human diseases and their pathogenesis and for evaluating drug and vaccine efficacy. For improved AIDS research, the ideal animal model of HIV-1 infection should be a small laboratory mammal that closely mimics virus replication in humans. Tree shrews exhibit considerable potential as animal models for the study of human diseases and therapeutic responses. Here, we report that human CD4-expressing tree shrew cells support the early steps of HIV-1 replication and that tree shrew CXCR4 is a functional coreceptor of HIV-1. However, tree shrew cells harbor additional restrictions that lead to the production of HIV-1 virions with low infectivity. Thus, the tsAPOBEC3 proteins are partial barriers to developing tree shrews as an HIV-1 model. Our results provide insight into the genetic basis of HIV inhibition in tree shrews and build a foundation for the establishment of gene-edited tree shrew HIV-1-infected models."

基金机构："13th Five-Year Key Scientific and Technological Program of China [2017ZX10304402-002-004]; 863 Program of ChinaNational High Technology Research and Development Program of China [2012AA021801]; Knowledge Innovation Program of the Chinese Academy of SciencesChinese Academy of SciencesKnowledge Innovation Program of the Chinese Academy of Sciences [KSCX2-EW-J-23, KSCX2-EW-R-12]; Chinese Academy of Sciences ""Light of West China"" Program [XBZG-ZDSYS-201909]"

基金资助正文："This work was supported by a grant from the 13th Five-Year Key Scientific and Technological Program of China (2017ZX10304402-002-004) , 863 Program of China (2012AA021801) , Knowledge Innovation Program of the Chinese Academy of Sciences (KSCX2-EW-J-23, KSCX2-EW-R-12) , and Chinese Academy of Sciences ""Light of West China"" Program (XBZG-ZDSYS-201909) ."