CRISPR-Cas Targeting of Host Genes as an Antiviral Strategy

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Abstract

Currently, a new gene editing tool—the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) associated (Cas) system—is becoming a promising approach for genetic manipulation at the genomic level. This simple method, originating from the adaptive immune defense system in prokaryotes, has been developed and applied to antiviral research in humans. Based on the characteristics of virus-host interactions and the basic rules of nucleic acid cleavage or gene activation of the CRISPR-Cas system, it can be used to target both the virus genome and host factors to clear viral reservoirs and prohibit virus infection or replication. Here, we summarize recent progress of the CRISPR-Cas technology in editing host genes as an antiviral strategy.

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Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.

Trinity Zang, Stuart J D Neil, Paul D. Bieniasz (2008)

Human cells possess an antiviral activity that inhibits the release of retrovirus particles, and other enveloped virus particles, and is antagonized by the HIV-1 accessory protein, Vpu. This antiviral activity can be constitutively expressed or induced by interferon-alpha, and it consists of protein-based tethers, which we term 'tetherins', that cause retention of fully formed virions on infected cell surfaces. Using deductive constraints and gene expression analyses, we identify CD317 (also called BST2 or HM1.24), a membrane protein of previously unknown function, as a tetherin. Specifically, CD317 expression correlated with, and induced, a requirement for Vpu during HIV-1 and murine leukaemia virus particle release. Furthermore, in cells where HIV-1 virion release requires Vpu expression, depletion of CD317 abolished this requirement. CD317 caused retention of virions on cell surfaces and, after endocytosis, in CD317-positive compartments. Vpu co-localized with CD317 and inhibited these effects. Inhibition of Vpu function and consequent mobilization of tetherin's antiviral activity is a potential therapeutic strategy in HIV/AIDS.

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Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

Huan Yan, Guocai Zhong, Guangwei Xu … (2012)

Human hepatitis B virus (HBV) infection and HBV-related diseases remain a major public health problem. Individuals coinfected with its satellite hepatitis D virus (HDV) have more severe disease. Cellular entry of both viruses is mediated by HBV envelope proteins. The pre-S1 domain of the large envelope protein is a key determinant for receptor(s) binding. However, the identity of the receptor(s) is unknown. Here, by using near zero distance photo-cross-linking and tandem affinity purification, we revealed that the receptor-binding region of pre-S1 specifically interacts with sodium taurocholate cotransporting polypeptide (NTCP), a multiple transmembrane transporter predominantly expressed in the liver. Silencing NTCP inhibited HBV and HDV infection, while exogenous NTCP expression rendered nonsusceptible hepatocarcinoma cells susceptible to these viral infections. Moreover, replacing amino acids 157–165 of nonfunctional monkey NTCP with the human counterpart conferred its ability in supporting both viral infections. Our results demonstrate that NTCP is a functional receptor for HBV and HDV. DOI: http://dx.doi.org/10.7554/eLife.00049.001

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The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein.

Nanette Van Damme, Daniel Goff, Chris Katsura … (2008)

The HIV-1 accessory protein Vpu counteracts a host factor that restricts virion release from infected cells. Here we show that the interferon-induced cellular protein BST-2/HM1.24/CD317 is such a factor. BST-2 is downregulated from the cell surface by Vpu, and BST-2 is specifically expressed in cells that support the vpu phenotype. Exogenous expression of BST-2 inhibits HIV-1 virion release, while suppression of BST-2 relieves the requirement for Vpu. Downregulation of BST-2 requires both the transmembrane/ion channel domain and conserved serines in the cytoplasmic domain of Vpu. Endogenous BST-2 colocalizes with the HIV-1 structural protein Gag in endosomes and at the plasma membrane, suggesting that BST-2 traps virions within and on infected cells. The unusual structure of BST-2, which includes a transmembrane domain and a lumenal GPI anchor, may allow it to retain nascent enveloped virions on cellular membranes, providing a mechanism of viral restriction counteracted by a specific viral accessory protein.

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Author and article information

Journal

Journal ID (nlm-ta): Viruses

Journal ID (iso-abbrev): Viruses

Journal ID (publisher-id): viruses

Title: Viruses

Publisher: MDPI

ISSN (Electronic): 1999-4915

Publication date (Electronic): 16 January 2018

Publication date Collection: January 2018

Volume: 10

Issue: 1

Affiliations

[1 ]School of Basic Medical Sciences, Wuhan University, Wuhan 430071, China; Chen-shuliang@ 123456whu.edu.cn

[2 ]Institute of Health Inspection and Testing, Hubei Provincial Center for Disease Control and Prevention, Wuhan 430079, China; fish-yuxiao@ 123456hotmail.com

[3 ]School of Medicine (Shenzhen), Sun Yat-sen University, Guangzhou 510080, China

Author notes

[* ]Correspondence: guodeyin@ 123456mail.sysu.edu.cn ; Tel./Fax: +86-20-8733-5130

Article

Publisher ID: viruses-10-00040

DOI: 10.3390/v10010040

PMC ID: 5795453

PubMed ID: 29337866

License:

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

CRISPR-Cas Targeting of Host Genes as an Antiviral Strategy

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Abstract

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MDPI: Coronavirus

Most cited references 127

Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu.

Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus

The interferon-induced protein BST-2 restricts HIV-1 release and is downregulated from the cell surface by the viral Vpu protein.

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