|
1
|
Mutations in the E2-PePHD region of hepatitis C virus genotype-3a and correlation with response to interferon and ribavirin combination therapy in Pakistani patients. Virol J 2010; 7:377. [PMID: 21194456 PMCID: PMC3019161 DOI: 10.1186/1743-422x-7-377] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2010] [Accepted: 12/31/2010] [Indexed: 12/26/2022] Open
Abstract
Hepatitis C is a major health problem affecting more than 200 million individuals in the world. Current treatment regimen consisting of interferon alpha and ribavirin does not always succeed in eliminating the virus completely from patient's body. One of the mechanisms by which virus evades the antiviral effect of interferon alpha involves protein kinase (PKR) eukaryotic initiation factor 2 alpha (eIF2a) phosphorylation homology domain (PePHD). This domain in genotype 1 strains is reportedly homologous to PKR and its target eIF2a. By binding to PKR, PePHD inhibits its activity and therefore cause virus to evade antiviral activity of interferon (IFN). Many studies have correlated substitutions in this domain to the treatment response and lead to inconclusive results. Some studies suggested that substitutions favor response while others emphasized that no correlation exists. In the present study we therefore compared sequences of PePHD domain of thirty one variants of six hepatitis C virus patients of genotype 3. Three of our HCV 3a infected patients showed rapid virological response to interferon alpha and ribavirin combination therapy whereas the remaining three had breakthrough to the same combination therapy. It is found that PePHD domain is not entirely conserved and has substitutions in some isolates irrespective of the treatment response. However substitution of glutamine (Q) with Leucine (L) in one of the breakthrough responders made it more identical to HCV genotype 1a. These substitutions in the breakthrough responders also tended to increase average hydrophilic activity thus making binding of PePHD to PKR and inhibition of PKR more favorable.
Collapse
|
|
2
|
Malta FDM, Medeiros-Filho JEMD, Azevedo RSD, Gonçalves L, Silva LCD, Carrilho FJ, Pinho JRR. Sequencing of E2 and NS5A regions of HCV genotype 3a in Brazilian patients with chronic hepatitis. Mem Inst Oswaldo Cruz 2010; 105:92-8. [PMID: 20209336 DOI: 10.1590/s0074-02762010000100014] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2009] [Accepted: 11/05/2009] [Indexed: 01/17/2023] Open
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease throughout the world. The NS5A and E2 proteins of HCV genotype 1 were reported to inhibit the double-stranded (ds) RNA-dependent protein kinase (PKR), which is involved in the cellular antiviral response induced by interferon (IFN). The response to IFN therapy is quite different between genotypes, with response rates among patients infected with types 2 and 3 that are two-three-fold higher than in patients infected with type 1. Interestingly, a significant percentage of HCV genotype 3-infected patients do not respond to treatment at all. The aim of this paper was to analyse the sequences of fragments of the E2 and NS5A regions from 33 outpatients infected with genotype 3a, including patients that have responded (SVR) or not responded (NR) to treatment. HCV RNA was extracted and amplified with specific primers for the NS5A and E2 regions and the PCR products were then sequenced. The sequences obtained covered amino acids (aa) 636-708 in E2 and in NS5A [including the IFN sensitivity determining region (ISDR), PKR-binding domain and extended V3 region)]. In the E2 and NS5A regions, we did observe aa changes among patients, but these changes were not statistically significant between the SVR and NR groups. In conclusion, our results suggest that the ISDR domain is not predictive of treatment success in patients infected with HCV genotype 3a.
Collapse
Affiliation(s)
- Fernanda de Mello Malta
- Departamento de Gastroenterologia, Laboratório de Gastroenterologia e Hepatologia Tropical, Instituto de Medicina Tropical, Universidade de São Paulo, São Paulo, SP, Brasil.
| | | | | | | | | | | | | |
Collapse
|
|
3
|
Zou MN, Huang YX, Li Z, Ma LN, Lin ZH, Guo XH, Cao ZH, Chen XY. Association between single nucleotide polymorphism of IFN-induced antiviral protein genes and curative effect of antiviral treatment in chronic hepatitis C patients. Shijie Huaren Xiaohua Zazhi 2008; 16:2175-2180. [DOI: 10.11569/wcjd.v16.i19.2175] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate effects of single nucleotide polymorphism (SNP) of interferon-induced antiviral protein on therapeutic effects of antiviral therapy for hepatitis C.
METHODS: A total of 168 chronic hepatitis C (CHC) patients were enrolled into the randomized trail of both interferon and pegylated interferon in combination with ribavirin antiviral treatments for 52 wk, with a 26-week follow-up. Sustained virological response (SVR) was evaluated then. Peripheral blood samples were collected at base line. Viral genotype was determined using PCR and viral load was determined using fluorescent quantitative PCR. And SNP in antiviral protein MxA gene promoter at nt-88, nt-123 and PKR-activated eIF-2α-reg2 sites were examined by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP).
RESULTS: There were significant differences in curative effect between CHC patients with GT or TT genotype and those with GG genotype (c2 = 6.862, P = 0.012; c2 = 12.941, P = 0.001, respectively). No significant difference was found between GT and TT genotypes. The curative effect in CHC patients with either CA genotype or AA genotype was better than those with CC genotype (c2 = 5.818, P = 0.020; c2 = 4.498, P = 0.046). No significant difference was found between CA and AA genotypes. Statistic analysis revealed no significant difference in curative effect between genotype of regulatory region 2 of the eIF-2α gene (A/G) and AG or GG genotypes.
CONCLUSION: Patients who carry MxA gene with TT or GT genotype at promoter nt-88 have better curative effect than those with GG genotype when treated with IFN. AA or AC genotype at MxA -123 is better than CC genotype. Genotype at of eIF-2α-reg2 site is not correlated with IFN treatment response in CHC patients.
Collapse
|
|
4
|
Bode JG, Brenndörfer ED, Häussinger D. Subversion of innate host antiviral strategies by the hepatitis C virus. Arch Biochem Biophys 2007; 462:254-65. [PMID: 17467654 DOI: 10.1016/j.abb.2007.03.033] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2007] [Accepted: 03/21/2007] [Indexed: 01/14/2023]
Abstract
Since its discovery in 1989, Hepatitis C Virus (HCV) has been recognized as a major cause of chronic hepatitis, end-stage cirrhosis and hepatocellular carcinoma affecting world wide more than 210 million people. The fact that 80% of newly infected patients fail to control infection, the slow development of overt disease and immune-response as well as the unsatisfying results of current IFN/ribavirin combination therapy suggests that the hepatitis C virus developed powerful strategies to evade and to antagonize the immune response of the host and to resist the antiviral actions of interferons. During the last 10 years several viral strategies have been uncovered for control and evasion from cellular antiviral host response initiated by the pathogen-associated molecular pattern recognizing receptors RIG1 and TLR3 and mediated by the release of type I interferon and subsequent induction of interferon stimulated genes. This review highlights recent results providing an idea of how the hepatitis C virus interferes with the different steps of initial antiviral host-response and establishes persistent infection.
Collapse
Affiliation(s)
- Johannes G Bode
- Department of Gastroenterology, Hepatology and Infectiology, Heinrich-Heine-University, Düsseldorf, Germany.
| | | | | |
Collapse
|
|
5
|
Sallie R. Replicative homeostasis III: implications for antiviral therapy and mechanisms of response and non-response. Virol J 2007; 4:29. [PMID: 17355620 PMCID: PMC1847443 DOI: 10.1186/1743-422x-4-29] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2007] [Accepted: 03/13/2007] [Indexed: 12/27/2022] Open
Abstract
While improved drug regimens have greatly enhanced outcomes for patients with chronic viral infection, antiviral therapy is still not ideal due to drug toxicities, treatment costs, primary drug failure and emergent resistance. New antiviral agents, alternative treatment strategies and a better understanding of viral pathobiology, host responses and drug action are desperately needed. Interferon (IFN) and ribavirin, are effective drugs used to treat hepatitis C (HCV), but the mechanism(s) of their action are uncertain. Error catastrophe (EC), or precipitous loss of replicative fitness caused by genomic mutation, is postulated to mediate ribavirin action, but is a deeply flawed hypothesis lacking empirical confirmation. Paradoxically ribavirin, a proven RNA mutagen, has no impact on HCV viraemia long term, suggesting real viruses, replicating in-vitro, as opposed to mathematical models, replicating in-silico, are likely to resist EC by highly selective replication of fit (~consensus sequence) genomes mediated, in part, by replicative homeostasis (RH), an epicyclic mechanism that dynamically links RNApol fidelity and processivity and other viral protein functions. Replicative homeostasis provides a rational explanation for the various responses seen during treatment of HCV, including genotype-specific and viral load-dependent differential response rates, as well as otherwise unexplained phenomena like the transient inhibition and rebound of HCV viraemia seen during ribavirin monotherapy. Replicative homeostasis also suggests a primarily non-immunological mechanism that mediates increased immune responsiveness during treatment with ribavirin (and other nucleos(t)ide analogues), explicating the enhanced second-phase clearance of HCV ribavirin promotes and, thus, the apparent immunomodulatory action of ribavirin. More importantly, RH suggests specific new antiviral therapeutic strategies.
Collapse
|
|
6
|
Ukai K, Ishigami M, Yoshioka K, Kawabe N, Katano Y, Hayashi K, Honda T, Yano M, Goto H. Mutations in carboxy-terminal part of E2 including PKR/eIF2alpha phosphorylation homology domain and interferon sensitivity determining region of nonstructural 5A of hepatitis C virus 1b: their correlation with response to interferon monotherapy and viral load. World J Gastroenterol 2006; 12:3722-3728. [PMID: 16773689 PMCID: PMC4087465 DOI: 10.3748/wjg.v12.i23.3722] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/25/2006] [Revised: 01/28/2006] [Accepted: 02/28/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To study the amino acid substitutions in the carboxy (C)-terminal part of E2 protein and in the interferon (IFN) sensitivity determining region (ISDR) and their correlation with response to IFN and viral load in 85 hepatitis C virus (HCV)-1b-infected patients treated with IFN. METHODS The C-terminal part of E2 (codons 617-711) including PKR/eIF2alpha phosphorylation homology domain (PePHD) and ISDR was sequenced in 85 HCV-1b-infected patients treated by IFN monotherapy. RESULTS The amino acid substitutions in PePHD detected only in 4 of 85 patients were not correlated either with response to IFN or with viral load. The presence of substitutions in a N-terminal variable region (codons 617-641) in the C-terminal part of E2 was significantly correlated with both small viral load (33.9% vs 13.8%, P = 0.0394) and sustained response to IFN (25.0% vs 6.9%, P = 0.0429). Four or more substitutions in ISDR were significantly correlated with both small viral load (78.6% vs 16.2%, P < 0.0001) and sustained response to IFN (85.7% vs 2.9%, P < 0.0001). In multivariate analysis, ISDR in nonstructural (NS) 5A (OR = 0.39, P < 0.0001) and N-terminal variable region (OR = 0.51, P = 0.039) was selected as the independent predictors for small viral load, and ISDR (OR = 39.0, P < 0.0001) was selected as the only independent predictor for sustained response. CONCLUSION The N-terminal variable region in the C-terminal part of E2 correlates with both response to IFN monotherapy and viral load and is one of the factors independently associated with a small viral load.
Collapse
Affiliation(s)
- Koji Ukai
- Division of Liver and Biliary Diseases, Department of Internal Medicine, Fujita Health University School of Medicine, Kutsukake, Toyoake, Aichi, Japan
| | | | | | | | | | | | | | | | | |
Collapse
|
|
7
|
Gaudy C, Lambelé M, Moreau A, Veillon P, Lunel F, Goudeau A. Mutations within the hepatitis C virus genotype 1b E2-PePHD domain do not correlate with treatment outcome. J Clin Microbiol 2005; 43:750-4. [PMID: 15695675 PMCID: PMC548054 DOI: 10.1128/jcm.43.2.750-754.2005] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The hepatitis C virus (HCV) envelope protein 2 (E2) interacts in vitro with the interferon alpha (IFN-alpha)-inducible double-stranded RNA-activated protein kinase, suggesting a possible mechanism by which HCV may evade the antiviral effects of IFN-alpha. Variability in the part of the HCV E2 gene encoding the carboxy-terminal part of the protein, which includes the interaction domain (E2-PePHD), was explored in 25 patients infected with HCV genotype 1b and receiving IFN-alpha therapy. PCR products were generated and sequenced for 15 patients with a sustained response and for 10 patients with no virological response after treatment with IFN-alpha and ribavirin. PePHD amino acid sequences were obtained for isolates from serum collected before and during treatment, after 2 months in responders, and after 6 months in nonresponders. Quasispecies analysis of the pretreatment PePHD region was performed for isolates from patients displaying amino acid substitutions in this domain on direct sequencing. The E2-PePHD sequence was highly conserved in both resistant and susceptible genotype 1b strains and was identical to the prototype HCV type J sequence. No significant emergence of PePHD mutants during therapy was observed in our clonal analysis, and sporadic mutations and treatment outcomes were not found to be correlated. The PePHD sequence before or during treatment cannot be used to predict reliably the outcome of treatment in HCV type 1b-infected patients.
Collapse
Affiliation(s)
- Catherine Gaudy
- Département de Microbiologie Médicale et Moléculaire EA 3856, Faculté de Médecine, 2, bis Boulevard Tonnellé, F37044 Tours Cedex, France
| | | | | | | | | | | |
Collapse
|
|
8
|
Wang LY, Lin HH, Lee TD, Wu YF, Hu CT, Cheng ML, Lo SY. Human leukocyte antigen phenotypes and hepatitis C viral load. J Clin Virol 2005; 32:144-50. [PMID: 15653417 DOI: 10.1016/j.jcv.2004.05.011] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Revised: 04/26/2004] [Accepted: 05/18/2004] [Indexed: 12/25/2022]
Abstract
BACKGROUND After hepatitis C virus (HCV) infection, 55% to 85% of patients become chronic carriers. HCV-RNA could be detected in the sera of these patients though the viral load varies. Various factors may be involved in determining the viral load. OBJECTIVES In this study, we want to investigate the relationship between human leukocyte antigen phenotypes and hepatitis C viral load. STUDY DESIGN One hundred and sixty HCV-RNA positive subjects were investigated in this study. RESULTS We have analyzed 160 HCV-RNA positive subjects and found that lower HCV viral load is significantly associated with HBsAg-positivity (P = 0.017) but not age, gender, or mixed infection (infection with different HCV genotypes). One hundred and fifty-four HBsAg-negative subjects were further analyzed to explore the relationship between human leukocyte antigen (HLA) phenotypes and HCV viral load. Subjects with certain HLA alleles (A*34, B*56, DRB1*1502) have significantly lower viral load than those without these alleles (P = 0.0074, 0.0039 and 0.016, respectively) while those with HLA-B*4001 have significantly higher viral load (P = 0.0026). Furthermore, lower viral load was significantly associated with HLA-DRB1 heterozygosity in subjects with HLA-B heterozygosity (P = 0.048). CONCLUSIONS Our data suggests a role for host immunogenetic factors in determining viral load during HCV infection.
Collapse
Affiliation(s)
- Li-Yu Wang
- Graduate Institute of Aboriginal Health, Tzu Chi University, Hualien, Taiwan
| | | | | | | | | | | | | |
Collapse
|
|
9
|
Vuillermoz I, Khattab E, Sablon E, Ottevaere I, Durantel D, Vieux C, Trepo C, Zoulim F. Genetic variability of hepatitis C virus in chronically infected patients with viral breakthrough during interferon-ribavirin therapy. J Med Virol 2005; 74:41-53. [PMID: 15258967 DOI: 10.1002/jmv.20144] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Little is known about hepatitis C virus (HCV) breakthrough during antiviral therapy, although it would help in understanding HCV resistance to current antiviral treatments. To analyse the implication of virological factors and the vigour of humoral immune responses in this phenomenon, we studied nine chronic hepatitis C patients with a viral breakthrough during IFN/ribavirin combination therapy, as well as five responders and five non-responders. The IRES and regions coding for the capsid protein, the PePHD domain of envelope glycoprotein E2 and the NS5A and 5B proteins were amplified by RT-PCR before treatment, before and during breakthrough, and after treatment. The major variant sequence was obtained by direct sequencing. The heterogeneity of quasispecies was studied by SSCP in all patients and sequencing after cloning in seven genotype 1b-infected patients. Humoral responses against HCV epitopes were also analysed. The major sequences of IRES, PePHD, and NS5B remained stable during treatment, regardless of the treatment response. However, the capsid protein and the regions flanking PePHD showed sequence variations in breakthrough patients, although no specific mutation was identified. The variable V3 region of NS5A, but not the PKR-binding domain and the ISDR, seemed to be associated with differences in response to treatment. The analysis of HCV quasispecies revealed no characteristic pattern during treatment in breakthrough patients, whose HCV genome profiles looked most similar to that of non-responders. The humoral response was similar between groups. In conclusion, viral breakthrough does not seem to be due to selection of resistant strains with signature mutations.
Collapse
Affiliation(s)
- I Vuillermoz
- INSERM UNIT 271, 151 Cours Albert Thomas, Lyon, France
| | | | | | | | | | | | | | | |
Collapse
|
|
10
|
Yang SS, Lai MY, Chen DS, Chen GH, Kao JH. Mutations in the NS5A and E2-PePHD regions of hepatitis C virus genotype 1b and response to combination therapy of interferon plus ribavirin. Liver Int 2003; 23:426-33. [PMID: 14986817 DOI: 10.1111/j.1478-3231.2003.00875.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/13/2023]
Abstract
BACKGROUND/AIMS Combination therapy with interferon (IFN) and ribavirin is the current standard treatment for chronic hepatitis C, but the efficacy is still not satisfactory, especially for genotype 1b. NS5A and E2 proteins of hepatitis C virus (HCV) may repress the IFN-induced RNA-dependent protein kinase (PKR), and thus have the potential to influence the response of HCV to IFN therapy; however, this issue remains controversial. METHODS Nucleotide sequences of the PKR-eIF2alpha phosphorylation homology domain (E2-PePHD) and PKR-binding domain (NS5A-PKR bd) of the HCV genome were analyzed by amplification and direct sequencing in 30 HCV genotype 1b patients who had been treated with IFN and ribavirin. RESULTS Nine (30%) patients achieved a sustained virological response (SVR) to combination therapy. Pretreatment variables and amino acid substitutions were compared between responders and non-responders. The responders were younger than non-responders (37.2 +/- 10.4 vs. 45.4 +/- 9.5 years, P = 0.017), whereas no significant statistical differences were found in the number of amino acid substitutions in NS5A and E2-PePHD regions between the two groups. CONCLUSIONS Genetic heterogeneity in NS5A and E2-PePHD regions of the HCV genome may not serve as a predictor for treatment outcome with combination therapy in Taiwanese patients with chronic HCV genotype 1b infection.
Collapse
Affiliation(s)
- Sheng-Shun Yang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung, Taiwan
| | | | | | | | | |
Collapse
|
|
11
|
Vyas J, Elia A, Clemens MJ. Inhibition of the protein kinase PKR by the internal ribosome entry site of hepatitis C virus genomic RNA. RNA (NEW YORK, N.Y.) 2003; 9:858-870. [PMID: 12810919 PMCID: PMC1370452 DOI: 10.1261/rna.5330503] [Citation(s) in RCA: 45] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/17/2003] [Accepted: 04/10/2003] [Indexed: 05/24/2023]
Abstract
Translation of the hepatitis C genome is mediated by internal ribosome entry on the structurally complex 5' untranslated region of the large viral RNA. Initiation of protein synthesis by this mechanism is independent of the cap-binding factor eIF4E, but activity of the initiator Met-tRNA(f)-binding factor eIF2 is still required. HCV protein synthesis is thus potentially sensitive to the inhibition of eIF2 activity that can result from the phosphorylation of the latter by the interferon-inducible, double-stranded RNA-activated protein kinase PKR. Two virally encoded proteins, NS5A and E2, have been shown to reduce this inhibitory effect of PKR by impairing the activation of the kinase. Here we present evidence for a third viral strategy for PKR inhibition. A region of the viral RNA comprising part of the internal ribosome entry site (IRES) is able to bind to PKR in competition with double-stranded RNA and can prevent autophosphorylation and activation of the kinase in vitro. The HCV IRES itself has no PKR-activating ability. Consistent with these findings, cotransfection experiments employing a bicistronic reporter construct and wild-type PKR indicate that expression of the protein kinase is less inhibitory towards HCV IRES-driven protein synthesis than towards cap-dependent protein synthesis. These data suggest a dual function for the viral IRES, with both a structural role in promoting initiation complex formation and a regulatory role in preventing inhibition of initiation by PKR.
Collapse
Affiliation(s)
- Jashmin Vyas
- Translational Control Group, Department of Basic Medical Sciences, St. George's Hospital Medical School, London SW17 0RE, UK
| | | | | |
Collapse
|
|
12
|
Abstract
Hepatitis C virus (HCV) is an emerging virus of medical importance. A majority of HCV infections become chronic and lead to chronic hepatitis, liver cirrhosis and hepatocellular carcinoma. HCV usually induces robust immune responses, but it frequently escapes the immune defense to establish persistent infection. The fact that HCV exists as an evolving quasispecies plays an important role in the selection of escape mutants. Furthermore, several viral proteins interfere with cellular functions, in particular, those involved in the immune response of the host. Several HCV proteins also modulate cell signalling through interaction with different effectors involved in cell proliferation and apoptosis, or in the interferon-signalling pathway. In addition, HCV infects immune cells such as B and T cells, and thus affects their normal functions. These various strategies used by HCV to counter the immune response of the host are reviewed here. A better understanding of these mechanisms would help design new therapeutic targets.
Collapse
Affiliation(s)
- Nicole Pavio
- Department of Molecular Microbiology, University of Southern California, Keck School of Medicine, Los Angeles, CA 90033, USA
| | | |
Collapse
|
|
13
|
Basler CF, García-Sastre A. Viruses and the type I interferon antiviral system: induction and evasion. Int Rev Immunol 2002; 21:305-37. [PMID: 12486817 DOI: 10.1080/08830180213277] [Citation(s) in RCA: 101] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
The type I interferon (IFN) system responds to viral infection and induces an "antiviral state" in cells, providing an important first line of defense against virus infection. Interaction of type I IFNs (IFN alpha and IFN beta) with their receptor induces hundreds of cellular genes. Of the proteins induced by IFN, the antiviral function of only a few is known, and their mechanisms of action are only partly understood. Additionally, although viral-encoded mechanisms that counteract specific components of the type I IFN response have been known for some time, it has recently become clear that many (if not most) viruses encode some form of IFN-antagonist. Understanding the interplay between viral-encoded IFN antagonists and the interferon response will be essential if the therapeutic potential of IFNs is to be fully exploited.
Collapse
|