Viral Regulation and Evasion of the Host Response

Loo, Yueh–Ming; Gale, Michael

doi:10.1007/978-3-540-71329-6_14

Cited by 48 publications

(54 citation statements)

References 83 publications

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“…Viruses of many families actively inhibit a diverse array of molecular targets to elude immune detection and destruction (reviewed in refs. [29][30][31][32][33][34][35]. Among these, the poxviruses are especially adept at interfering with immune pathways, such as those mediated by NF-B (reviewed by refs.…”

Section: Resultsmentioning

confidence: 99%

Proteomic screening of variola virus reveals a unique NF-κB inhibitor that is highly conserved among pathogenic orthopoxviruses

Mohamed

Rahman

Lanchbury

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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Identification of the binary interactions between viral and host proteins has become a valuable tool for investigating viral tropism and pathogenesis. Here, we present the first systematic protein interaction screening of the unique variola virus proteome by using yeast 2-hybrid screening against a variety of human cDNA libraries. Several protein-protein interactions were identified, including an interaction between variola G1R, an ankryin/F-box containing protein, and human nuclear factor kappa-B1 (NF-B1)/p105. This represents the first direct interaction between a pathogen-encoded protein and NF-B1/p105. Orthologs of G1R are present in a variety of pathogenic orthopoxviruses, but not in vaccinia virus, and expression of any one of these viral proteins blocks NF-B signaling in human cells. Thus, proteomic screening of variola virus has the potential to uncover modulators of the human innate antiviral responses.ankyrin repeats ͉ Skp1 ͉ yeast 2-hybrid

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Section: Resultsmentioning

confidence: 99%

Proteomic screening of variola virus reveals a unique NF-κB inhibitor that is highly conserved among pathogenic orthopoxviruses

Mohamed

Rahman

Lanchbury

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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“…In addition to identifying two cytokines that act as positive regulators of deaminase activity in PBMCs (IFN␣ and, to a lesser extent, IFN␥), we also demonstrated the existence of a negative regulatory pathway. Moreover, because viruses have developed numerous ways to counteract and subvert the type 1 interferon host response (63), it is possible that some viruses have evolved mechanisms for down-regulating A3A deaminase activity, either directly or by co-opting host regulatory pathways.…”

Section: Discussionmentioning

confidence: 99%

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Thielen

McNevin

McElrath

et al. 2010

Journal of Biological Chemistry

105

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In HIV-1-infected individuals, G-to-A hypermutation is found in HIV-1 DNA isolated from peripheral blood mononuclear cells (PBMCs). These mutations are thought to result from editing by one or more host enzymes in the APOBEC3 (A3) family of cytidine deaminases, which act on CC (APOBEC3G) and TC (other A3 proteins) dinucleotide motifs in DNA (edited cytidine underlined). Although many A3 proteins display high levels of deaminase activity in model systems, only low levels of A3 deaminase activity have been found in primary cells examined to date. In contrast, here we report high levels of deaminase activity at TC motifs when whole PBMCs or isolated primary monocyte-derived cells were treated with interferon-␣ (IFN␣) or IFN␣-inducing toll-like receptor ligands. Induction of TC-specific deaminase activity required new transcription and translation and correlated with the appearance of two APOBEC3A (A3A) isoforms. Knockdown of A3A in monocytes with siRNA abolished TC-specific deaminase activity, confirming that A3A isoforms are responsible for all TC-specific deaminase activity observed. Both A3A isoforms appear to be enzymatically active; moreover, our mutational studies raise the possibility that the smaller isoform results from internal translational initiation. In contrast to the high levels of TC-specific activity observed in IFN␣-treated monocytes, CC-specific activity remained low in PBMCs, suggesting that A3G deaminase activity is relatively inhibited, unlike that of A3A. Together, these findings suggest that deaminase activity of A3A isoforms in monocytes and macrophages may play an important role in host defense against viruses. A33 proteins are cytidine deaminases that are capable of inhibiting replication of retroviruses, DNA viruses, and retroelements (reviewed in Refs. 1-3). The seven A3 proteins in the human genome share a strong preference for deaminating cytidines that are in a CC or TC context in single-stranded DNA (edited cytidine underlined). Although APOBEC3G (A3G), the best understood A3 protein, acts preferentially on CC motifs, the six other human A3 proteins display varying degrees of preference for TC motifs (4 -13). Because other cytidine deaminases, such as activation-induced deaminase and APOBEC1, either display a strong preference for editing deoxycytidines in other dinucleotide contexts or act on TC motifs in RNA (4), mutations that arise in a CC or TC context in DNA constitute signatures of editing by A3 proteins.Much headway has been made in understanding how A3 proteins act on HIV-1 DNA, in part through transfection of A3 plasmids into human epithelium-derived cell lines, such as 293T or HeLa cells, which lack significant endogenous expression of most A3 proteins. From such studies, A3G and APOBEC3F (A3F) are known to be packaged into virus particles when the HIV-1 Vif protein is not expressed and to cause a substantial reduction in virus infectivity (5, 12, 14 -16). Reduced virus infectivity results in part from non-enzymatic inhibition of reverse transcription by A3G and A3F (17-2...

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“…3 Receptor ligation results in the activation of signaling pathways leading to the production of type I IFN and inflammatory cytokines (1). Secreted IFN-␣/␤ induces expression of IFN-stimulated genes that are important for the elimination of viruses (2). Additionally, a programmed cell death, apoptosis, is induced in infected cells by yet undefined signaling mechanism to restrict viral infection.…”

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confidence: 99%

Actin and RIG-I/MAVS Signaling Components Translocate to Mitochondria upon Influenza A Virus Infection of Human Primary Macrophages

Öhman

Rintahaka

Kalkkinen

et al. 2009

The Journal of Immunology

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Influenza A virus is one of the most important causes of respiratory infection. During viral infection, multiple cell signaling cascades are activated, resulting in the production of antiviral cytokines and initiation of programmed cell death of virus-infected cells. In the present study, we have used subcellular proteomics to reveal the host response to influenza A infection at the protein level in human macrophages. Macrophages were infected with influenza A virus, after which the cytosolic and mitochondrial cell fractions were prepared and analyzed by using two-dimensional electrophoresis for protein separation and mass spectrometry for protein identification. In cytosolic proteomes, the level of several heat shock proteins and fragments of cytoskeletal proteins was clearly up-regulated during influenza A virus infection. In mitochondrial proteomes, simultaneously with the expression of viral proteins, the level of intact actin and tubulin was highly up-regulated. This was followed by translocation of the components of antiviral RNA recognition machinery, including RIG-I (retinoic acid-inducible protein I), TRADD (TNFR1-associated death domain protein), TRIM25 (tripartite motif protein 25), and IKKε (inducible IκB kinase), onto the mitochondria. Cytochalasin D, a potent inhibitor of actin polymerization, clearly inhibited influenza A virus-induced expression of IFN-β, IL-29, and TNF-α, suggesting that intact actin cytoskeleton structure is crucial for proper activation of antiviral response. At late phases of infection mitochondrial fragmentation of actin was seen, indicating that actin fragments, fractins, are involved in disruption of mitochondrial membranes during apoptosis of virus-infected cells. In conclusion, our results suggest that actin network interacts with mitochondria to regulate both antiviral and cell death signals during influenza A virus infection.

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Viral Regulation and Evasion of the Host Response

Cited by 48 publications

References 83 publications

Proteomic screening of variola virus reveals a unique NF-κB inhibitor that is highly conserved among pathogenic orthopoxviruses

Proteomic screening of variola virus reveals a unique NF-κB inhibitor that is highly conserved among pathogenic orthopoxviruses

Innate Immune Signaling Induces High Levels of TC-specific Deaminase Activity in Primary Monocyte-derived Cells through Expression of APOBEC3A Isoforms

Actin and RIG-I/MAVS Signaling Components Translocate to Mitochondria upon Influenza A Virus Infection of Human Primary Macrophages

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