Editing Interferon (section)

==Viral resistance to interferons==
Many viruses have evolved mechanisms to resist interferon activity.<ref name=vin>{{cite journal | vauthors = Navratil V, de Chassey B, Meyniel L, Pradezynski F, André P, Rabourdin-Combe C, Lotteau V | title = System-level comparison of protein-protein interactions between viruses and the human type I interferon system network | journal = Journal of Proteome Research | volume = 9 | issue = 7 | pages = 3527–3536 | date = July 2010 | pmid = 20459142 | doi = 10.1021/pr100326j }}</ref>  They circumvent the IFN response by blocking downstream signaling events that occur after the cytokine binds to its receptor, by preventing further IFN production, and by inhibiting the functions of proteins that are induced by IFN.<ref name="Lin">{{cite journal | vauthors = Lin RJ, Liao CL, Lin E, Lin YL | title = Blocking of the alpha interferon-induced Jak-Stat signaling pathway by Japanese encephalitis virus infection | journal = Journal of Virology | volume = 78 | issue = 17 | pages = 9285–9294 | date = September 2004 | pmid = 15308723 | pmc = 506928 | doi = 10.1128/JVI.78.17.9285-9294.2004 }}</ref>  Viruses that inhibit IFN signaling include [[Japanese Encephalitis]] Virus (JEV), [[Dengue virus|dengue type 2 virus]] (DEN-2), and viruses of the herpesvirus family, such as human [[cytomegalovirus]] (HCMV) and [[Kaposi's sarcoma-associated herpesvirus]]  (KSHV or HHV8).<ref name="Lin"/><ref name=sen>{{cite journal | vauthors = Sen GC | title = Viruses and interferons | journal = Annual Review of Microbiology | volume = 55 | pages = 255–281 | year = 2001 | pmid = 11544356 | doi = 10.1146/annurev.micro.55.1.255 }}</ref> Viral proteins proven to affect IFN signaling include [[EBV nuclear antigen 1|EBV nuclear antigen 1 (EBNA1)]] and [[EBV nuclear antigen 2|EBV nuclear antigen 2 (EBNA-2)]] from [[Epstein-Barr virus]], the [[large T antigen]] of [[Polyomavirus]], the E7 protein of [[Human papillomavirus]] (HPV), and the B18R protein of [[vaccinia virus]].<ref name=sen/><ref name=alcami>{{cite journal | vauthors = Alcamí A, Symons JA, Smith GL | title = The vaccinia virus soluble alpha/beta interferon (IFN) receptor binds to the cell surface and protects cells from the antiviral effects of IFN | journal = Journal of Virology | volume = 74 | issue = 23 | pages = 11230–11239 | date = December 2000 | pmid = 11070021 | pmc = 113220 | doi = 10.1128/JVI.74.23.11230-11239.2000 }}</ref>  Reducing IFN-α activity may prevent signaling via  [[STAT1]], [[STAT2]],  or [[ISGF3G|IRF9]]  (as with JEV infection) or through the [[JAK-STAT]] pathway (as with DEN-2 infection).<ref name="Lin" />  Several [[poxvirus]]es encode soluble IFN receptor homologs—like the B18R protein of the vaccinia virus—that bind to and prevent IFN interacting with its cellular receptor, impeding communication between this cytokine and its target cells.<ref name=alcami/>  Some viruses can encode proteins that bind to [[double-stranded RNA]] (dsRNA) to prevent the activity of RNA-dependent [[protein kinase]]s; this is the mechanism [[reovirus]] adopts using its sigma 3 (σ3) protein, and vaccinia virus employs using the gene product of its E3L gene, p25.<ref>{{cite journal | vauthors = Minks MA, West DK, Benvin S, Baglioni C | title = Structural requirements of double-stranded RNA for the activation of 2',5'-oligo(A) polymerase and protein kinase of interferon-treated HeLa cells | journal = The Journal of Biological Chemistry | volume = 254 | issue = 20 | pages = 10180–10183 | date = October 1979 | pmid = 489592 | doi = 10.1016/S0021-9258(19)86690-5 | doi-access = free }}</ref><ref>{{cite journal | vauthors = Miller JE, Samuel CE | title = Proteolytic cleavage of the reovirus sigma 3 protein results in enhanced double-stranded RNA-binding activity: identification of a repeated basic amino acid motif within the C-terminal binding region | journal = Journal of Virology | volume = 66 | issue = 9 | pages = 5347–5356 | date = September 1992 | pmid = 1501278 | pmc = 289090 | doi = 10.1128/JVI.66.9.5347-5356.1992 }}</ref><ref>{{cite journal | vauthors = Chang HW, Watson JC, Jacobs BL | title = The E3L gene of vaccinia virus encodes an inhibitor of the interferon-induced, double-stranded RNA-dependent protein kinase | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 89 | issue = 11 | pages = 4825–4829 | date = June 1992 | pmid = 1350676 | pmc = 49180 | doi = 10.1073/pnas.89.11.4825 | doi-access = free | bibcode = 1992PNAS...89.4825C }}</ref> The ability of interferon to induce protein production from interferon stimulated genes (ISGs) can also be affected.  Production of [[protein kinase R]], for example, can be disrupted in cells infected with JEV.<ref name="Lin" />  Some viruses escape the anti-viral activities of interferons by gene (and thus protein) mutation.  The [[H5N1]] [[influenza]] virus, also known as bird flu, has resistance to interferon and other anti-viral cytokines that is attributed to a single [[amino acid]] change in its Non-Structural Protein 1 (NS1), although the precise mechanism of how this confers immunity is unclear.<ref>{{cite journal | vauthors = Seo SH, Hoffmann E, Webster RG | title = Lethal H5N1 influenza viruses escape host anti-viral cytokine responses | journal = Nature Medicine | volume = 8 | issue = 9 | pages = 950–954 | date = September 2002 | pmid = 12195436 | doi = 10.1038/nm757 | s2cid = 8293109 }}</ref>  The relative resistance of [[hepatitis C virus]] genotype I to interferon-based therapy has been attributed in part to homology between viral envelope protein E2 and host protein kinase R, a mediator of interferon-induced suppression of viral protein translation,<ref>{{cite journal | vauthors = Taylor DR, Shi ST, Romano PR, Barber GN, Lai MM | title = Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein | journal = Science | volume = 285 | issue = 5424 | pages = 107–110 | date = July 1999 | pmid = 10390359 | doi = 10.1126/science.285.5424.107 }}</ref><ref>{{cite journal | vauthors = Taylor DR, Tian B, Romano PR, Hinnebusch AG, Lai MM, Mathews MB | title = Hepatitis C virus envelope protein E2 does not inhibit PKR by simple competition with autophosphorylation sites in the RNA-binding domain | journal = Journal of Virology | volume = 75 | issue = 3 | pages = 1265–1273 | date = February 2001 | pmid = 11152499 | pmc = 114032 | doi = 10.1128/JVI.75.3.1265-1273.2001 | doi-access = free }}</ref> although mechanisms of acquired and intrinsic resistance to interferon therapy in HCV are polyfactorial.<ref>{{cite journal | vauthors = Abid K, Quadri R, Negro F | title = Hepatitis C virus, the E2 envelope protein, and alpha-interferon resistance | journal = Science | volume = 287 | issue = 5458 | pages = 1555 | date = March 2000 | pmid = 10733410 | doi = 10.1126/science.287.5458.1555a | doi-access = free }}</ref><ref>{{cite journal | vauthors = Pawlotsky JM | title = The nature of interferon-alpha resistance in hepatitis C virus infection | journal = Current Opinion in Infectious Diseases | volume = 16 | issue = 6 | pages = 587–592 | date = December 2003 | pmid = 14624110 | doi = 10.1097/00001432-200312000-00012 | s2cid = 72191620 }}</ref>