Catch me if you can: the arms race between human cytomegalovirus and the innate immune system

Papers of special note have been highlighted as: • of interest; •• of considerable interest

References

• 1 Mocarski ES, Shenk T, Pass R. Cytomegaloviruses. In: Fields Virology. Knipe DM, Howley PM (Eds). Lippincott Williams & Wilkins, Philadelphia, PA, USA, 2701–2772 (2007).
  Google Scholar
• 2 Stern-Ginossar N, Weisburd B, Michalski A et al. Decoding human cytomegalovirus. Science 338(6110), 1088–1093 (2012).
  Medline CASGoogle Scholar
• 3 Griffiths P, Baraniak I, Reeves M. The pathogenesis of human cytomegalovirus. J. Pathol. 235(2), 288–297 (2015).
  Medline CASGoogle Scholar
• 4 Navarro D. Expanding role of cytomegalovirus as a human pathogen. J. Med. Virol. 88(7), 1103–1112 (2016).
  MedlineGoogle Scholar
• 5 Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK. The “silent” global burden of congenital cytomegalovirus. Clin. Microbiol. Rev. 26(1), 86–102 (2013).
  Medline CASGoogle Scholar
• 6 Britt WJ. Congenital human cytomegalovirus infection and the enigma of maternal immunity. J. Virol. 91(15), e02392–16 (2017).
  Medline CASGoogle Scholar
• 7 Sackman AM, Pfeifer SP, Kowalik TF, Jensen JD. On the demographic and selective forces shaping patterns of human cytomegalovirus variation within hosts. Pathogens 7(1), 16 (2018).
  CASGoogle Scholar
• 8 Britt WJ. Maternal immunity and the natural history of congenital human cytomegalovirus infection. Viruses 10(8), 405 (2018).
  Google Scholar
• 9 Pawelec G. Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun. Ageing 9(1), 15 (2012).
  Medline CASGoogle Scholar
• 10 Tu W, Rao S. Mechanisms underlying T cell immunosenescence: aging and cytomegalovirus infection. Front. Microbiol. 7, 2111 (2016).
  MedlineGoogle Scholar
• 11 Lunardi C, Dolcino M, Peterlana D et al. Antibodies against human cytomegalovirus in the pathogenesis of systemic sclerosis: a gene array approach. PLoS Med. 3(1), e2 (2006).
  MedlineGoogle Scholar
• 12 Halenius A, Hengel H. Human cytomegalovirus and autoimmune disease. Biomed. Res. Int. 2014, 472978 (2014).
  MedlineGoogle Scholar
• 13 Marou E, Liaskos C, Efthymiou G et al. Increased immunoreactivity against human cytomegalovirus UL83 in systemic sclerosis. Clin. Exp. Rheumatol. 106(4), 31–34 (2017).
  Google Scholar
• 14 Arcangeletti M-C, Maccari C, Vescovini R et al. A paradigmatic interplay between human cytomegalovirus and host immune system: possible involvement of viral antigen-driven CD8+ T cell responses in systemic sclerosis. Viruses 10(9), 508 (2018).
  Google Scholar
• 15 Lin W-R, Wozniak MA, Wilcock GK, Itzhaki RF. Cytomegalovirus is present in a very high proportion of brains from vascular dementia patients. Neurobiol. Dis. 9(1), 82–87 (2002).
  Medline CASGoogle Scholar
• 16 Ji Y-N, An L, Zhan P, Chen X-H. Cytomegalovirus infection and coronary heart disease risk: a meta-analysis. Mol. Biol. Rep. 39(6), 6537–6546 (2012).
  Medline CASGoogle Scholar
• 17 Du Y, Zhang G, Liu Z. Human cytomegalovirus infection and coronary heart disease: a systematic review. Virol. J. 15(1), 31 (2018).
  MedlineGoogle Scholar
• 18 Schmaltz HN, Fried LP, Xue Q-L, Walston J, Leng SX, Semba RD. Chronic cytomegalovirus infection and inflammation are associated with prevalent frailty in community-dwelling older women. J. Am. Geriatr. Soc. 53(5), 747–754 (2005).
  MedlineGoogle Scholar
• 19 Strandberg TE, Pitkala KH, Tilvis RS. Cytomegalovirus antibody level and mortality among community-dwelling older adults with stable cardiovascular disease. JAMA 301(4), 380–382 (2009).
  Medline CASGoogle Scholar
• 20 Söderberg-Nauclér C, Johnsen JI. Cytomegalovirus infection in brain tumors. Oncoimmunology 1(5), 739–740 (2012).
  MedlineGoogle Scholar
• 21 Harkins L, Volk AL, Samanta M et al. Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet 360(9345), 1557–1563 (2002).
  Medline CASGoogle Scholar
• 22 Samanta M, Harkins L, Klemm K, Britt WJ, Cobbs CS. High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma. J. Urol. 170(3), 998–1002 (2003).
  MedlineGoogle Scholar
• 23 Cobbs CS. Cytomegalovirus and brain tumor: epidemiology, biology and therapeutic aspects. Curr. Opin. Oncol. 25(6), 682–688 (2013).
  MedlineGoogle Scholar
• 24 Herbein G. The human cytomegalovirus, from oncomodulation to oncogenesis. Viruses. 10(8), (2018).
  Google Scholar
• 25 Britt WJ, Prichard MN. New therapies for human cytomegalovirus infections. Antiviral Res. 159, 153–174 (2018).
  Medline CASGoogle Scholar
• 26 Schleiss MR, Permar SR, Plotkin SA. Progress toward development of a vaccine against congenital cytomegalovirus infection. Clin. Vaccine Immunol. 24(12), e00268–17 (2017).
  Medline CASGoogle Scholar
• 27 Plotkin SA, Boppana SB. Vaccination against the human cytomegalovirus. Vaccine pii:S0264-410X(18)30288-3 (2018) (Epub ahead of print).
  Google Scholar
• 28 Lurain NS, Chou S. Antiviral drug resistance of human cytomegalovirus. Clin. Microbiol. Rev. 23(4), 689–712 (2010).
  Medline CASGoogle Scholar
• 29 Piret J, Goyette N, Boivin G. Drug susceptibility and replicative capacity of multidrug-resistant recombinant human cytomegalovirus harboring mutations in UL56 and UL54 genes. Antimicrob. Agents Chemother. 61(11), e01044–17 (2017).
  Medline CASGoogle Scholar
• 30 Chou S. Rapid in vitro evolution of human cytomegalovirus UL56 mutations that confer letermovir resistance. Antimicrob. Agents Chemother. 59(10), 6588–6593 (2015).
  Medline CASGoogle Scholar
• 31 James SH, Prichard MN. The genetic basis of human cytomegalovirus resistance and current trends in antiviral resistance analysis. Infect. Disord. Drug Targets 11(5), 504–513 (2011).
  Medline CASGoogle Scholar
• 32 Christensen MH, Paludan SR. Viral evasion of DNA-stimulated innate immune responses. Cell. Mol. Immunol. 14(1), 4–13 (2017).
  Medline CASGoogle Scholar
• 33 Rossini G, Cerboni C, Santoni A et al. Interplay between human cytomegalovirus and intrinsic/innate host responses: a complex bidirectional relationship. Mediators Inflamm. 2012, 607276 (2012).
  MedlineGoogle Scholar
• 34 Goodier MR, Jonjić S, Riley EM, Juranić Lisnić V. CMV and natural killer cells: shaping the response to vaccination. Eur. J. Immunol. 48(1), 50–65 (2018).
  Medline CASGoogle Scholar
• 35 Zingoni A, Molfetta R, Fionda C et al. NKG2D and its ligands: “One for All, All for One.” Front. Immunol. 9, 476 (2018).
  MedlineGoogle Scholar
• 36 Chang WLW, Barry PA. Attenuation of innate immunity by cytomegalovirus IL-10 establishes a long-term deficit of adaptive antiviral immunity. Proc. Natl Acad. Sci. USA 107(52), 22647–22652 (2010).
  Medline CASGoogle Scholar
• 37 Arnon TI, Markel G, Mandelboim O. Tumor and viral recognition by natural killer cells receptors. Semin. Cancer Biol. 16(5), 348–358 (2006).
  Medline CASGoogle Scholar
• 38 Corrales-Aguilar E, Hoffmann K, Hengel H. CMV-encoded Fcγ receptors: modulators at the interface of innate and adaptive immunity. Semin. Immunopathol. 36(6), 627–640 (2014).
  Medline CASGoogle Scholar
• 39 Spear GT, Lurain NS, Parker CJ, Ghassemi M, Payne GH, Saifuddin M. Host cell-derived complement control proteins CD55 and CD59 are incorporated into the virions of two unrelated enveloped viruses. Human T cell leukemia/lymphoma virus type I (HTLV-I) and human cytomegalovirus (HCMV). J. Immunol. 155(9), 4376–4381 (1995).
  Medline CASGoogle Scholar
• 40 Spiller OB, Morgan BP, Tufaro F, Devine DV. Altered expression of host-encoded complement regulators on human cytomegalovirus-infected cells. Eur. J. Immunol. 26(7), 1532–1538 (1996).
  Medline CASGoogle Scholar
• 41 Gafa V, Manches O, Pastor A et al. Human cytomegalovirus downregulates complement receptors (CR3, CR4) and decreases phagocytosis by macrophages. J. Med. Virol. 76(3), 361–366 (2005).
  Medline CASGoogle Scholar
• 42 Bieniasz PD. Restriction factors: a defense against retroviral infection. Trends Microbiol. 11(6), 286–291 (2003). •• Provides the definition of RFs and their molecular mechanisms for retrovirus replication inhibition.
  Medline CASGoogle Scholar
• 43 Neil S, Bieniasz P. Human immunodeficiency virus, restriction factors, and interferon. J. Interferon Cytokine Res. 29(9), 569–580 (2009).
  Medline CASGoogle Scholar
• 44 Simon V, Bloch N, Landau NR. Intrinsic host restrictions to HIV-1 and mechanisms of viral escape. Nat. Immunol. 16(6), 546–553 (2015).
  Medline CASGoogle Scholar
• 45 Jakobsen MR, Olagnier D, Hiscott J. Innate immune sensing of HIV-1 infection. Curr. Opin. HIV AIDS 10(2), 96–102 (2015).
  Medline CASGoogle Scholar
• 46 Paludan SR, Bowie AG, Horan KA, Fitzgerald KA. Recognition of herpesviruses by the innate immune system. Nat. Rev. Immunol. 11(2), 143–154 (2011). •• Describes the main pathways involved in innate immune detection of herpesviruses.
  Medline CASGoogle Scholar
• 47 Adler M, Tavalai N, Müller R, Stamminger T. Human cytomegalovirus immediate-early gene expression is restricted by the nuclear domain 10 component Sp100. J. Gen. Virol. 92(Pt 7), 1532–1538 (2011).
  Medline CASGoogle Scholar
• 48 Tavalai N, Adler M, Scherer M, Riedl Y, Stamminger T. Evidence for a dual antiviral role of the major nuclear domain 10 component Sp100 during the immediate-early and late phases of the human cytomegalovirus replication cycle. J. Virol. 85(18), 9447–9458 (2011).
  Medline CASGoogle Scholar
• 49 Scherer M, Stamminger T. Emerging role of PML nuclear bodies in innate immune signaling. J. Virol. 90(13), 5850–5854 (2016).
  Medline CASGoogle Scholar
• 50 Zhang K, van Drunen Littel-van den Hurk S. Herpesvirus tegument and immediate early proteins are pioneers in the battle between viral infection and nuclear domain 10-related host defense. Virus Res. 238, 40–48 (2017).
  Medline CASGoogle Scholar
• 51 Glass M, Everett RD. Components of promyelocytic leukemia nuclear bodies (ND10) act cooperatively to repress herpesvirus infection. J. Virol. 87(4), 2174–2185 (2013).
  Medline CASGoogle Scholar
• 52 Wagenknecht N, Reuter N, Scherer M, Reichel A, Müller R, Stamminger T. Contribution of the major ND10 proteins PML, hDaxx and Sp100 to the regulation of human cytomegalovirus latency and lytic replication in the monocytic cell line THP-1. Viruses 7(6), 2884–2907 (2015).
  Medline CASGoogle Scholar
• 53 Ashley CL, Glass MS, Abendroth A, McSharry BP, Slobedman B. Nuclear domain 10 components upregulated via interferon during human cytomegalovirus infection potently regulate viral infection. J. Gen. Virol. 98(7), 1795–1805 (2017).
  Medline CASGoogle Scholar
• 54 Biolatti M, Gugliesi F, Dell'Oste V, Landolfo S. Modulation of the innate immune response by human cytomegalovirus. Infect. Genet. Evol. 64, 105–114 (2018).
  Medline CASGoogle Scholar
• 55 Gariano GR, Dell'Oste V, Bronzini M et al. The intracellular DNA sensor IFI16 gene acts as restriction factor for human cytomegalovirus replication. PLoS Pathog. 8(1), e1002498 (2012).
  Medline CASGoogle Scholar
• 56 Dell'Oste V, Gatti D, Giorgio AG, Gariglio M, Landolfo S, De Andrea M. The interferon-inducible DNA-sensor protein IFI16: a key player in the antiviral response. New Microbiol. 38(1), 5–20 (2015).
  MedlineGoogle Scholar
• 57 Landolfo S, De Andrea M, Dell'Oste V, Gugliesi F. Intrinsic host restriction factors of human cytomegalovirus replication and mechanisms of viral escape. World J. Virol. 5(3), 87–96 (2016).
  MedlineGoogle Scholar
• 58 Cristea IM, Moorman NJ, Terhune SS et al. Human cytomegalovirus pUL83 stimulates activity of the viral immediate-early promoter through its interaction with the cellular IFI16 protein. J. Virol. 84(15), 7803–7814 (2010).
  Medline CASGoogle Scholar
• 59 Dell'Oste V, Gatti D, Gugliesi F et al. Innate nuclear sensor IFI16 translocates into the cytoplasm during the early stage of in vitro human cytomegalovirus infection and is entrapped in the egressing virions during the late stage. J. Virol. 88(12), 6970–6982 (2014).
  MedlineGoogle Scholar
• 60 Biolatti M, Dell'Oste V, Pautasso S et al. Regulatory interaction between the cellular restriction factor IFI16 and viral pp65 (pUL83) modulates viral gene expression and IFI16 protein stability. J. Virol. 90(18), 8238–8250 (2016).
  Medline CASGoogle Scholar
• 61 Diner BA, Lum KK, Toettcher JE, Cristea IM. Viral DNA sensors IFI16 and cyclic GMP-AMP synthase possess distinct functions in regulating viral gene expression, immune defenses, and apoptotic responses during herpesvirus infection. MBio 7(6), e01553–16 (2016).
  Medline CASGoogle Scholar
• 62 Biolatti M, Dell'Oste V, Pautasso S et al. Human cytomegalovirus tegument protein pp65 (pUL83) dampens type I interferon production by inactivating the DNA sensor cGAS without affecting STING. J. Virol. 92(6), e01774–17 (2018).
  MedlineGoogle Scholar
• 63 Chin KC, Cresswell P. Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus. Proc. Natl Acad. Sci. USA 98(26), 15125–15130 (2001).
  Medline CASGoogle Scholar
• 64 Seo J-Y, Yaneva R, Cresswell P. Viperin: a multifunctional, interferon-inducible protein that regulates virus replication. Cell Host Microbe 10(6), 534–539 (2011).
  Medline CASGoogle Scholar
• 65 Seo J-Y, Yaneva R, Hinson ER, Cresswell P. Human cytomegalovirus directly induces the antiviral protein viperin to enhance infectivity. Science 332(6033), 1093–1097 (2011).
  Medline CASGoogle Scholar
• 66 Seo J-Y, Cresswell P. Viperin regulates cellular lipid metabolism during human cytomegalovirus infection. PLoS Pathog. 9(8), e1003497 (2013).
  Medline CASGoogle Scholar
• 67 Knisbacher BA, Gerber D, Levanon EY. DNA Editing by APOBECs: a genomic preserver and transformer. Trends Genet. 32(1), 16–28 (2016).
  Medline CASGoogle Scholar
• 68 Blanco-Melo D, Venkatesh S, Bieniasz PD. Intrinsic cellular defenses against human immunodeficiency viruses. Immunity 37(3), 399–411 (2012).
  Medline CASGoogle Scholar
• 69 Suspène R, Guétard D, Henry M, Sommer P, Wain-Hobson S, Vartanian J-P. Extensive editing of both hepatitis B virus DNA strands by APOBEC3 cytidine deaminases in vitro and in vivo. Proc. Natl Acad. Sci. USA 102(23), 8321–8326 (2005).
  Medline CASGoogle Scholar
• 70 Turelli P, Mangeat B, Jost S, Vianin S, Trono D. Inhibition of hepatitis B virus replication by APOBEC3G. Science 303(5665), 1829 (2004).
  MedlineGoogle Scholar
• 71 Nakaya Y, Stavrou S, Blouch K, Tattersall P, Ross SR. In vivo examination of mouse APOBEC3- and human APOBEC3A- and APOBEC3G-mediated restriction of parvovirus and herpesvirus infection in mouse models. J. Virol. 90(17), 8005–8012 (2016).
  Medline CASGoogle Scholar
• 72 Narvaiza I, Linfesty DC, Greener BN et al. Deaminase-independent inhibition of parvoviruses by the APOBEC3A cytidine deaminase. PLoS Pathog. 5(5), e1000439 (2009).
  MedlineGoogle Scholar
• 73 Vartanian J-P, Guétard D, Henry M, Wain-Hobson S. Evidence for editing of human papillomavirus DNA by APOBEC3 in benign and precancerous lesions. Science 320(5873), 230–233 (2008).
  Medline CASGoogle Scholar
• 74 Peretti A, Geoghegan EM, Pastrana DV et al. Characterization of BK polyomaviruses from kidney transplant recipients suggests a role for APOBEC3 in driving in-host virus evolution. Cell Host Microbe 23(5), 628.e7–635.e7 (2018).
  Google Scholar
• 75 Suspène R, Aynaud M-M, Koch S et al. Genetic editing of herpes simplex virus 1 and Epstein-Barr herpesvirus genomes by human APOBEC3 cytidine deaminases in culture and in vivo. J. Virol. 85(15), 7594–7602 (2011).
  Medline CASGoogle Scholar
• 76 Weisblum Y, Oiknine-Djian E, Zakay-Rones Z et al. APOBEC3A is upregulated by human cytomegalovirus (HCMV) in the maternal-fetal interface, acting as an innate Anti-HCMV effector. J. Virol. 91(23), e01296–17 (2017).
  Medline CASGoogle Scholar
• 77 Pautasso S, Galitska G, Dell'Oste V et al. Evasion strategy of human cytomegalovirus to escape interferon-β-induced APOBEC3G editing activity. J. Virol. 92(19), e01224–18 (2018).
  MedlineGoogle Scholar
• 78 Kremer M, Suezer Y, Martinez-Fernandez Y, Münk C, Sutter G, Schnierle BS. Vaccinia virus replication is not affected by APOBEC3 family members. Virol. J. 3, 86 (2006).
  MedlineGoogle Scholar
• 79 Harris RS, Dudley JP. APOBECs and virus restriction. Virology 479–480, 131–145 (2015). •• Discusses the viral pathogens whose replication is impaired by APOBEC enzymes.
  Medline CASGoogle Scholar
• 80 Bördlein A, Scherthan H, Nelkenbrecher C et al. SPOC1 (PHF13) is required for spermatogonial stem cell differentiation and sustained spermatogenesis. J. Cell. Sci. 124(Pt 18), 3137–3148 (2011).
  MedlineGoogle Scholar
• 81 Kinkley S, Staege H, Mohrmann G et al. SPOC1: a novel PHD-containing protein modulating chromatin structure and mitotic chromosome condensation. J. Cell. Sci. 122(Pt 16), 2946–2956 (2009).
  Medline CASGoogle Scholar
• 82 Frohns A, Frohns F, Naumann SC, Layer PG, Löbrich M. Inefficient double-strand break repair in murine rod photoreceptors with inverted heterochromatin organization. Curr. Biol. 24(10), 1080–1090 (2014).
  Medline CASGoogle Scholar
• 83 Mund A, Schubert T, Staege H et al. SPOC1 modulates DNA repair by regulating key determinants of chromatin compaction and DNA damage response. Nucleic Acids Res. 40(22), 11363–11379 (2012).
  Medline CASGoogle Scholar
• 84 Chung H-R, Xu C, Fuchs A et al. PHF13 is a molecular reader and transcriptional co-regulator of H3K4me2/3. Elife 5, e10607 (2016).
  MedlineGoogle Scholar
• 85 Schreiner S, Kinkley S, Bürck C et al. SPOC1-mediated antiviral host cell response is antagonized early in human adenovirus type 5 infection. PLoS Pathog. 9(11), e1003775 (2013).
  MedlineGoogle Scholar
• 86 Reichel A, Stilp A-C, Scherer M et al. Chromatin-remodeling factor SPOC1 acts as a cellular restriction factor against human cytomegalovirus by repressing the major immediate early promoter. J. Virol. 92(14), e00342–18 (2018).
  Medline CASGoogle Scholar
• 87 Haller O, Kochs G. Human MxA protein: an interferon-induced dynamin-like GTPase with broad antiviral activity. J. Interferon Cytokine Res. 31(1), 79–87 (2011).
  Medline CASGoogle Scholar
• 88 Haller O, Staeheli P, Schwemmle M, Kochs G. Mx GTPases: dynamin-like antiviral machines of innate immunity. Trends Microbiol. 23(3), 154–163 (2015).
  Medline CASGoogle Scholar
• 89 Goujon C, Moncorgé O, Bauby H et al. Human MX2 is an interferon-induced post-entry inhibitor of HIV-1 infection. Nature 502(7472), 559–562 (2013).
  Medline CASGoogle Scholar
• 90 Liu Z, Pan Q, Ding S et al. The interferon-inducible MxB protein inhibits HIV-1 infection. Cell Host Microbe 14(4), 398–410 (2013).
  Medline CASGoogle Scholar
• 91 Kane M, Yadav SS, Bitzegeio J et al. MX2 is an interferon-induced inhibitor of HIV-1 infection. Nature 502(7472), 563–566 (2013).
  Medline CASGoogle Scholar
• 92 Xu B, Pan Q, Liang C. Role of MxB in alpha interferon-mediated inhibition of HIV-1 infection. J. Virol. 92(17), e00422–18 (2018).
  Medline CASGoogle Scholar
• 93 Mitchell PS, Young JM, Emerman M, Malik HS. Evolutionary analyses suggest a function of MxB immunity proteins beyond lentivirus restriction. PLoS Pathog. 11(12), e1005304 (2015).
  MedlineGoogle Scholar
• 94 Schilling M, Bulli L, Weigang S et al. Human MxB protein is a pan-herpesvirus restriction factor. J. Virol. 92(17), e01056–18 (2018).
  MedlineGoogle Scholar
• 95 Crameri M, Bauer M, Caduff N et al. MxB is an interferon-induced restriction factor of human herpesviruses. Nat. Commun. 9(1), 1980 (2018).
  MedlineGoogle Scholar
• 96 Hoffmann H-H, Schneider WM, Rice CM. Interferons and viruses: an evolutionary arms race of molecular interactions. Trends Immunol. 36(3), 124–138 (2015). •• Outlines the knowledge about the interplay and the evolution between interferon pathways and viral infections.
  Medline CASGoogle Scholar
• 97 Mogensen TH. Pathogen recognition and inflammatory signaling in innate immune defenses. Clin. Microbiol. Rev. 22(2), 240–273; Table of Contents (2009).
  Medline CASGoogle Scholar
• 98 Pollard KM, Cauvi DM, Toomey CB, Morris KV, Kono DH. Interferon-γ and systemic autoimmunity. Discov. Med. 16(87), 123–131 (2013).
  MedlineGoogle Scholar
• 99 DeFilippis VR, Alvarado D, Sali T, Rothenburg S, Früh K. Human cytomegalovirus induces the interferon response via the DNA sensor ZBP1. J. Virol. 84(1), 585–598 (2010).
  Medline CASGoogle Scholar
• 100 Paijo J, Döring M, Spanier J et al. cGAS senses human cytomegalovirus and induces type I interferon responses in human monocyte-derived cells. PLoS Pathog. 12(4), e1005546 (2016).
  MedlineGoogle Scholar
• 101 Xie M, Xuan B, Shan J et al. Human cytomegalovirus exploits interferon-induced transmembrane proteins to facilitate morphogenesis of the virion assembly compartment. J. Virol. 89(6), 3049–3061 (2015).
  Medline CASGoogle Scholar
• 102 Perreira JM, Chin CR, Feeley EM, Brass AL. IFITMs restrict the replication of multiple pathogenic viruses. J. Mol. Biol. 425(24), 4937–4955 (2013).
  Medline CASGoogle Scholar
• 103 Warren CJ, Griffin LM, Little AS, Huang I-C, Farzan M, Pyeon D. The antiviral restriction factors IFITM1, 2 and 3 do not inhibit infection of human papillomavirus, cytomegalovirus and adenovirus. PLoS ONE 9(5), e96579 (2014).
  MedlineGoogle Scholar
• 104 Abate DA, Watanabe S, Mocarski ES. Major human cytomegalovirus structural protein pp65 (ppUL83) prevents interferon response factor 3 activation in the interferon response. J Virol. 78(20), 10995–11006 (2004).
  Medline CASGoogle Scholar
• 105 Browne EP, Shenk T. Human cytomegalovirus UL83-coded pp65 virion protein inhibits antiviral gene expression in infected cells. Proc. Natl Acad. Sci. USA 100(20), 11439–11444 (2003).
  Medline CASGoogle Scholar
• 106 Li T, Chen J, Cristea IM. Human cytomegalovirus tegument protein pUL83 inhibits IFI16-mediated DNA sensing for immune evasion. Cell Host Microbe 14(5), 591–599 (2013).
  Medline CASGoogle Scholar
• 107 Reich NC. Nuclear/cytoplasmic localization of IRFs in response to viral infection or interferon stimulation. J. Interferon Cytokine Res. 22(1), 103–109 (2002).
  Medline CASGoogle Scholar
• 108 Huang Z-F, Zou H-M, Liao B-W et al. Human cytomegalovirus protein UL31 inhibits DNA sensing of cGAS to mediate immune evasion. Cell Host Microbe 24(1), 69.e4–80.e4 (2018).
  Google Scholar
• 109 Fu Y-Z, Su S, Gao Y-Q et al. Human cytomegalovirus tegument protein UL82 inhibits STING-mediated signaling to evade antiviral immunity. Cell Host Microbe 21(2), 231–243 (2017).
  Medline CASGoogle Scholar
• 110 Choi HJ, Park A, Kang S et al. Human cytomegalovirus-encoded US9 targets MAVS and STING signaling to evade type I interferon immune responses. Nat. Commun. 9(1), 125 (2018).
  MedlineGoogle Scholar
• 111 DeFilippis VR, Robinson B, Keck TM, Hansen SG, Nelson JA, Früh KJ. Interferon regulatory factor 3 is necessary for induction of antiviral genes during human cytomegalovirus infection. J. Virol. 80(2), 1032–1037 (2006).
  Medline CASGoogle Scholar
• 112 Taylor RT, Bresnahan WA. Human cytomegalovirus immediate-early 2 gene expression blocks virus-induced beta interferon production. J. Virol. 79(6), 3873–3877 (2005).
  Medline CASGoogle Scholar
• 113 Taylor RT, Bresnahan WA. Human cytomegalovirus immediate-early 2 protein IE86 blocks virus-induced chemokine expression. J. Virol. 80(2), 920–928 (2006).
  Medline CASGoogle Scholar
• 114 Kim J-E, Kim Y-E, Stinski MF, Ahn J-H, Song Y-J. Human cytomegalovirus IE2 86 kDa protein induces STING degradation and inhibits cGAMP-mediated IFN-β induction. Front. Microbiol. 8, 1854 (2017).
  MedlineGoogle Scholar
• 115 Platanias LC. Mechanisms of type-I- and type-II-interferon-mediated signalling. Nat. Rev. Immunol. 5(5), 375–386 (2005).
  Medline CASGoogle Scholar
• 116 Feng L, Sheng J, Vu G-P et al. Human cytomegalovirus UL23 inhibits transcription of interferon-γ stimulated genes and blocks antiviral interferon-γ responses by interacting with human N-myc interactor protein. PLoS Pathog. 14(1), e1006867 (2018).
  MedlineGoogle Scholar
• 117 Kim YJ, Kim ET, Kim Y-E et al. Consecutive inhibition of ISG15 expression and ISGylation by cytomegalovirus regulators. PLoS Pathog. 12(8), e1005850 (2016).
  MedlineGoogle Scholar
• 118 Bianco C, Mohr I. Restriction of human cytomegalovirus replication by ISG15, a host effector regulated by cGAS-STING double-stranded-DNA sensing. J. Virol. 91(9), e02483–16 (2017).
  Medline CASGoogle Scholar
• 119 Munir M, Berg M. The multiple faces of proteinkinase R in antiviral defense. Virulence 4(1), 85–89 (2013).
  MedlineGoogle Scholar
• 120 Schulz O, Pichlmair A, Rehwinkel J et al. Protein kinase R contributes to immunity against specific viruses by regulating interferon mRNA integrity. Cell Host Microbe 7(5), 354–361 (2010).
  Medline CASGoogle Scholar
• 121 Zamanian-Daryoush M, Mogensen TH, DiDonato JA, Williams BR. NF-kappaB activation by double-stranded-RNA-activated protein kinase (PKR) is mediated through NF-kappaB-inducing kinase and IkappaB kinase. Mol. Cell. Biol. 20(4), 1278–1290 (2000).
  Medline CASGoogle Scholar
• 122 Marshall EE, Bierle CJ, Brune W, Geballe AP. Essential role for either TRS1 or IRS1 in human cytomegalovirus replication. J Virol. 83(9), 4112–4120 (2009).
  Medline CASGoogle Scholar
• 123 Ziehr B, Vincent HA, Moorman NJ. Human cytomegalovirus pTRS1 and pIRS1 antagonize protein kinase R to facilitate virus replication. J. Virol. 90(8), 3839–3848 (2016).
  Medline CASGoogle Scholar
• 124 Mathers C, Schafer X, Martínez-Sobrido L, Munger J. The human cytomegalovirus UL26 protein antagonizes NF-κB activation. J. Virol. 88(24), 14289–14300 (2014).
  MedlineGoogle Scholar
• 125 Lorz K, Hofmann H, Berndt A et al. Deletion of open reading frame UL26 from the human cytomegalovirus genome results in reduced viral growth, which involves impaired stability of viral particles. J. Virol. 80(11), 5423–5434 (2006).
  Medline CASGoogle Scholar
• 126 Munger J, Yu D, Shenk T. UL26-deficient human cytomegalovirus produces virions with hypophosphorylated pp28 tegument protein that is unstable within newly infected cells. J. Virol. 80(7), 3541–3548 (2006).
  Medline CASGoogle Scholar
• 127 Costa H, Nascimento R, Sinclair J, Parkhouse RME. Human cytomegalovirus gene UL76 induces IL-8 expression through activation of the DNA damage response. PLoS Pathog. 9(9), e1003609 (2013).
  Medline CASGoogle Scholar
• 128 Yu D, Silva MC, Shenk T. Functional map of human cytomegalovirus AD169 defined by global mutational analysis. Proc. Natl Acad. Sci. USA 100(21), 12396–12401 (2003).
  Medline CASGoogle Scholar
• 129 Terhune SS, Schröer J, Shenk T. RNAs are packaged into human cytomegalovirus virions in proportion to their intracellular concentration. J. Virol. 78(19), 10390–10398 (2004).
  Medline CASGoogle Scholar
• 130 Varnum SM, Streblow DN, Monroe ME et al. Identification of proteins in human cytomegalovirus (HCMV) particles: the HCMV proteome. J. Virol. 78(20), 10960–10966 (2004).
  Medline CASGoogle Scholar
• 131 Nogalski MT, Podduturi JP, DeMeritt IB, Milford LE, Yurochko AD. The human cytomegalovirus virion possesses an activated casein kinase II that allows for the rapid phosphorylation of the inhibitor of NF-κB, IκBα. J. Virol. 81(10), 5305–5314 (2007).
  Medline CASGoogle Scholar
• 132 Hancock MH, Nelson JA. Modulation of the NFκb signalling pathway by human cytomegalovirus. Virology 1(1), 104 (2017).
  MedlineGoogle Scholar
• 133 Benedict CA, Butrovich KD, Lurain NS et al. Cutting edge: a novel viral TNF receptor superfamily member in virulent strains of human cytomegalovirus. J. Immunol. 162(12), 6967–6970 (1999).
  Medline CASGoogle Scholar
• 134 Poole E, King CA, Sinclair JH, Alcami A. The UL144 gene product of human cytomegalovirus activates NFkappaB via a TRAF6-dependent mechanism. EMBO J. 25(18), 4390–4399 (2006).
  Medline CASGoogle Scholar
• 135 Gealy C, Humphreys C, Dickinson V, Stinski M, Caswell R. An activation-defective mutant of the human cytomegalovirus IE2p86 protein inhibits NF-kappaB-mediated stimulation of the human interleukin-6 promoter. J. Gen. Virol. 88(Pt 9), 2435–2440 (2007).
  Medline CASGoogle Scholar
• 136 Poole E, Atkins E, Nakayama T et al. NF-κB-mediated activation of the chemokine CCL22 by the product of the human cytomegalovirus gene UL144 escapes regulation by viral IE86. J. Virol. 82(9), 4250–4256 (2008).
  Medline CASGoogle Scholar
• 137 Goodwin CM, Ciesla JH, Munger J. Who's Driving? Human cytomegalovirus, interferon, and NFκB signaling. Viruses 10(9), 447 (2018).
  Google Scholar
• 138 Kotenko SV, Saccani S, Izotova LS, Mirochnitchenko OV, Pestka S. Human cytomegalovirus harbors its own unique IL-10 homolog (cmvIL-10). Proc. Natl Acad. Sci. USA 97(4), 1695–1700 (2000).
  Medline CASGoogle Scholar
• 139 Jones BC, Logsdon NJ, Josephson K, Cook J, Barry PA, Walter MR. Crystal structure of human cytomegalovirus IL-10 bound to soluble human IL-10R1. Proc. Natl Acad. Sci. USA 99(14), 9404–9409 (2002).
  Medline CASGoogle Scholar
• 140 Nachtwey J, Spencer JV. HCMV IL-10 suppresses cytokine expression in monocytes through inhibition of nuclear factor-kappaB. Viral Immunol. 21(4), 477–482 (2008).
  Medline CASGoogle Scholar
• 141 Sinclair J, Sissons P. Latency and reactivation of human cytomegalovirus. J. Gen. Virol. 87(Pt 7), 1763–1779 (2006).
  Medline CASGoogle Scholar
• 142 Boomker JM, The TH, de Leij LFMH, Harmsen MC. The human cytomegalovirus-encoded receptor US28 increases the activity of the major immediate-early promoter/enhancer. Virus Res. 118(1–2), 196–200 (2006).
  Medline CASGoogle Scholar
• 143 Beisser PS, Laurent L, Virelizier JL, Michelson S. Human cytomegalovirus chemokine receptor gene US28 is transcribed in latently infected THP-1 monocytes. J. Virol. 75(13), 5949–5957 (2001).
  Medline CASGoogle Scholar
• 144 Cheng S, Caviness K, Buehler J, Smithey M, Nikolich-Žugich J, Goodrum F. Transcriptome-wide characterization of human cytomegalovirus in natural infection and experimental latency. Proc. Natl Acad. Sci. USA 114(49), E10586–E10595 (2017).
  Medline CASGoogle Scholar
• 145 Shnayder M, Nachshon A, Krishna B et al. Defining the transcriptional landscape during cytomegalovirus latency with single-cell RNA sequencing. mBio 9(2), e00013–e00018 (2018).
  Medline CASGoogle Scholar
• 146 Casarosa P, Bakker RA, Verzijl D et al. Constitutive signaling of the human cytomegalovirus-encoded chemokine receptor US28. J. Biol. Chem. 276(2), 1133–1137 (2001).
  Medline CASGoogle Scholar
• 147 Krishna BA, Poole EL, Jackson SE, Smit MJ, Wills MR, Sinclair JH. Latency-associated expression of human cytomegalovirus US28 attenuates cell signaling pathways to maintain latent infection. mBio 8(6), e01754–17 (2017).
  Medline CASGoogle Scholar
• 148 Weekes MP, Tan SYL, Poole E et al. Latency-associated degradation of the MRP1 drug transporter during latent human cytomegalovirus infection. Science 340(6129), 199–202 (2013).
  Medline CASGoogle Scholar
• 149 Lee SH, Caviness K, Albright ER et al. Long and short isoforms of the human cytomegalovirus UL138 protein silence IE transcription and promote latency. J. Virol. 90(20), 9483–9494 (2016).
  Medline CASGoogle Scholar
• 150 Fruci D, Rota R, Gallo A. The Role of HCMV and HIV-1 microRNAs: processing, and mechanisms of action during viral infection. Front. Microbiol. 8, 689 (2017).
  MedlineGoogle Scholar
• 151 Ng KR, Li JYZ, Gleadle JM. Human cytomegalovirus encoded microRNAs: hitting targets. Expert Rev. Anti Infect. Ther. 13(12), 1469–1479 (2015).
  Medline CASGoogle Scholar
• 152 Hook L, Hancock M, Landais I, Grabski R, Britt W, Nelson JA. Cytomegalovirus microRNAs. Curr. Opin. Virol. 7, 40–46 (2014).
  MedlineGoogle Scholar
• 153 Lau B, Poole E, Krishna B et al. The expression of human cytomegalovirus microRNA MiR-UL148D during latent infection in primary myeloid cells inhibits activin A-triggered secretion of IL-6. Sci. Rep. 6, 31205 (2016).
  Medline CASGoogle Scholar