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Abstract

Gammaherpesviruses are an important class of oncogenic pathogens that are exquisitely evolved to their respective hosts. As such, the human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi sarcoma herpesvirus (KSHV) do not naturally infect nonhuman primates or rodents. There is a clear need to fully explore mechanisms of gammaherpesvirus pathogenesis, host control, and immune evasion in the host. A gammaherpesvirus pathogen isolated from murid rodents was first reported in 1980; 40 years later, murine gammaherpesvirus 68 (MHV68, MuHV-4, γHV68) infection of laboratory mice is a well-established pathogenesis system recognized for its utility in applying state-of-the-art approaches to investigate virus-host interactions ranging from the whole host to the individual cell. Here, we highlight recent advancements in our understanding of the processes by which MHV68 colonizes the host and drives disease. Lessons that inform KSHV and EBV pathogenesis and provide future avenues for novel interventions against infection and virus-associated cancers are emphasized.

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2021-09-29
2024-04-24
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Literature Cited

  1. 1. 
    Mistríková J, Briestenská K. 2020. Murid herpesvirus 4 (MuHV-4, prototype strain MHV-68) as an important model in global research of human oncogenic gammaherpesviruses. Acta Virol 64:2167–76
    [Google Scholar]
  2. 2. 
    François S, Vidick S, Sarlet M, Michaux J, Koteja P et al. 2010. Comparative study of murid gammaherpesvirus 4 infection in mice and in a natural host, bank voles. J. Gen. Virol. 91:102553–63
    [Google Scholar]
  3. 3. 
    Virgin HW 4th, Latreille P, Wamsley P, Hallsworth K, Weck KE et al. 1997. Complete sequence and genomic analysis of murine gammaherpesvirus 68. J. Virol. 71:85894–904
    [Google Scholar]
  4. 4. 
    O'Grady T, Feswick A, Hoffman BA, Wang Y, Medina EM et al. 2019. Genome-wide transcript structure resolution reveals abundant alternate isoform usage from murine gammaherpesvirus 68. Cell Rep 27:133988–4002.e5Multiplatform genomics reveals numerous novel transcripts with underappreciated regulatory and coding potential.
    [Google Scholar]
  5. 5. 
    Schaller AM, Tucker J, Willis I, Glaunsinger BA 2020. Conserved herpesvirus kinase ORF36 activates B2 retrotransposons during murine gammaherpesvirus infection. J. Virol. 94:14e00262-20
    [Google Scholar]
  6. 6. 
    Wong-Ho E, Wu T-T, Davis ZH, Zhang B, Huang J et al. 2014. Unconventional sequence requirement for viral late gene core promoters of murine gammaherpesvirus 68. J. Virol. 88:63411–22
    [Google Scholar]
  7. 7. 
    Hartenian E, Gilbertson S, Federspiel JD, Cristea IM, Glaunsinger BA 2020. RNA decay during gammaherpesvirus infection reduces RNA polymerase II occupancy of host promoters but spares viral promoters. PLOS Pathog 16:2e1008269Reports a previously unidentified and novel viral manipulation of host gene transcription through mRNA decay.
    [Google Scholar]
  8. 8. 
    Karijolich J, Abernathy E, Glaunsinger BA. 2015. Infection-induced retrotransposon-derived noncoding RNAs enhance herpesviral gene expression via the NF-κB pathway. PLOS Pathog 11:11e1005260
    [Google Scholar]
  9. 9. 
    Sifford JM, Stahl JA, Salinas E, Forrest JC. 2016. Murine gammaherpesvirus 68 LANA and SOX homologs counteract ATM-driven p53 activity during lytic viral replication. J. Virol. 90:52571–85
    [Google Scholar]
  10. 10. 
    Salinas E, Byrum SD, Moreland LE, Mackintosh SG, Tackett AJ, Forrest JC. 2016. Identification of viral and host proteins that interact with murine gammaherpesvirus 68 latency-associated nuclear antigen during lytic replication: a role for Hsc70 in viral replication. J. Virol. 90:31397–413
    [Google Scholar]
  11. 11. 
    Milho R, Smith CM, Marques S, Alenquer M, May JS et al. 2009. In vivo imaging of murid herpesvirus-4 infection. J. Gen. Virol. 90:121–32
    [Google Scholar]
  12. 12. 
    Lawler C, Milho R, May JS, Stevenson PG. 2015. Rhadinovirus host entry by co-operative infection. PLOS Pathog 11:3e1004761
    [Google Scholar]
  13. 13. 
    Barton E, Mandal P, Speck SH. 2011. Pathogenesis and host control of gammaherpesviruses: lessons from the mouse. Annu. Rev. Immunol. 29:351–97
    [Google Scholar]
  14. 14. 
    Li G, Ward C, Yeasmin R, Skiena S, Krug LT, Forrest JC. 2017. A codon-shuffling method to prevent reversion during production of replication-defective herpesvirus stocks: implications for herpesvirus vaccines. Sci. Rep. 7:44404
    [Google Scholar]
  15. 15. 
    Noh C-W, Cho H-J, Kang H-R, Jin HY, Lee S et al. 2012. The virion-associated open reading frame 49 of murine gammaherpesvirus 68 promotes viral replication both in vitro and in vivo as a derepressor of RTA. J. Virol. 86:21109–18
    [Google Scholar]
  16. 16. 
    Hikita S-I, Yanagi Y, Ohno S. 2015. Murine gammaherpesvirus 68 ORF35 is required for efficient lytic replication and latency. J. Gen. Virol. 96:123624–34
    [Google Scholar]
  17. 17. 
    Qi J, Han C, Gong D, Liu P, Zhou S, Deng H. 2015. Murine gammaherpesvirus 68 ORF48 is an RTA-responsive gene product and functions in both viral lytic replication and latency during in vivo infection. J. Virol. 89:115788–800
    [Google Scholar]
  18. 18. 
    Latif MB, Machiels B, Xiao X, Mast J, Vanderplasschen A, Gillet L. 2015. Deletion of murid herpesvirus 4 ORF63 affects the trafficking of incoming capsids toward the nucleus. J. Virol. 90:52455–72
    [Google Scholar]
  19. 19. 
    Sattler C, Steer B, Adler H. 2016. Multiple lytic origins of replication are required for optimal gammaherpesvirus fitness in vitro and in vivo. PLOS Pathog 12:3e1005510
    [Google Scholar]
  20. 20. 
    Glauser DL, Milho R, Frederico B, May JS, Kratz A-S et al. 2013. Glycoprotein B cleavage is important for murid herpesvirus 4 to infect myeloid cells. J. Virol. 87:1910828–42
    [Google Scholar]
  21. 21. 
    Minkah N, Macaluso M, Oldenburg DG, Paden CR, White DW et al. 2015. Absence of the uracil DNA glycosylase of murine gammaherpesvirus 68 impairs replication and delays the establishment of latency in vivo. J. Virol. 89:63366–79
    [Google Scholar]
  22. 22. 
    Dong Q, Smith KR, Oldenburg DG, Shapiro M, Schutt WR et al. 2018. Combinatorial loss of the enzymatic activities of viral uracil-DNA glycosylase and viral dUTPase impairs murine gammaherpesvirus pathogenesis and leads to increased recombination-based deletion in the viral genome. mBio 9:5e01831-18Two proteins nonessential for replication in culture have a critical role in promoting viral fitness in vivo.
    [Google Scholar]
  23. 23. 
    Van Skike ND, Minkah NK, Hogan CH, Wu G, Benziger PT et al. 2018. Viral FGARAT ORF75A promotes early events in lytic infection and gammaherpesvirus pathogenesis in mice. PLOS Pathog 14:2e1006843
    [Google Scholar]
  24. 24. 
    Ling PD, Tan J, Sewatanon J, Peng R. 2008. Murine gammaherpesvirus 68 open reading frame 75c tegument protein induces the degradation of PML and is essential for production of infectious virus. J. Virol. 82:168000–12
    [Google Scholar]
  25. 25. 
    He S, Zhao J, Song S, He X, Minassian A et al. 2015. Viral pseudo-enzymes activate RIG-I via deamidation to evade cytokine production. Mol. Cell 58:1134–46Reveals a novel RIG-I activation mechanism by a herpesvirus pseudoenzyme that dampens host innate immunity.
    [Google Scholar]
  26. 26. 
    Gaspar M, May JS, Sukla S, Frederico B, Gill MB et al. 2011. Murid herpesvirus-4 exploits dendritic cells to infect B cells. PLOS Pathog 7:11e1002346
    [Google Scholar]
  27. 27. 
    Feldman ER, Kara M, Oko LM, Grau KR, Krueger BJ et al. 2016. A gammaherpesvirus noncoding RNA is essential for hematogenous dissemination and establishment of peripheral latency. mSphere 1:2e00105-15
    [Google Scholar]
  28. 28. 
    Frederico B, Chao B, May JS, Belz GT, Stevenson PG 2014. A murid gamma-herpesviruses exploits normal splenic immune communication routes for systemic spread. Cell Host Microbe 15:4457–70In vivo tracking system maps key steps in dissemination to the spleen.
    [Google Scholar]
  29. 29. 
    Lawler C, de Miranda MP, May J, Wyer O, Simas JP, Stevenson PG. 2018. Gammaherpesvirus colonization of the spleen requires lytic replication in B cells. J. Virol. 92:7e02199-17
    [Google Scholar]
  30. 30. 
    Stevenson PG. 2020. Immune control of γ-herpesviruses. Viral Immunol 33:3225–32
    [Google Scholar]
  31. 31. 
    Sunil-Chandra NP, Efstathiou S, Arno J, Nash AA. 1992. Virological and pathological features of mice infected with murine gammaherpesvirus 68. J. Gen. Virol. 73:2347–56
    [Google Scholar]
  32. 32. 
    Weck KE, Kim SS, Virgin HW 4th, Speck SH 1999. Macrophages are the major reservoir of latent murine gammaherpesvirus 68 in peritoneal cells. J. Virol. 73:43273–83
    [Google Scholar]
  33. 33. 
    Yamano T, Steinert M, Steer B, Klein L, Hammerschmidt W, Adler H. 2019. B cells latently infected with murine gammaherpesvirus 68 (MHV-68) are present in the mouse thymus—a step toward immune evasion?. Eur. J. Immunol. 49:2351–52
    [Google Scholar]
  34. 34. 
    Coleman CB, McGraw JE, Feldman ER, Roth AN, Keyes LR et al. 2014. A gammaherpesvirus Bcl-2 ortholog blocks B cell receptor-mediated apoptosis and promotes the survival of developing B cells in vivo. PLOS Pathog 10:2e1003916
    [Google Scholar]
  35. 35. 
    Hoffman BA, Wang Y, Feldman ER, Tibbetts SA 2019. Epstein-Barr virus EBER1 and murine gammaherpesvirus TMER4 share conserved in vivo function to promote B cell egress and dissemination. PNAS 116:5125392–94
    [Google Scholar]
  36. 36. 
    Salinas E, Gupta A, Sifford JM, Oldenburg DG, White DW, Forrest JC. 2018. Conditional mutagenesis in vivo reveals cell type- and infection stage-specific requirements for LANA in chronic MHV68 infection. PLOS Pathog 14:1e1006865Cre/loxP-mediated gene targeting in vivo uncovers cell type– and stage-specific mLANA functions.
    [Google Scholar]
  37. 37. 
    Owens SM, Oldenburg DG, White DW, Forrest JC. 2020. Deletion of murine gammaherpesvirus gene M2 in activation-induced cytidine deaminase-expressing B cells impairs host colonization and viral reactivation. J. Virol. 95:1e01933-20
    [Google Scholar]
  38. 38. 
    Zelazowska MA, McBride K, Krug LT. 2020. Dangerous liaisons: gammaherpesvirus subversion of the immunoglobulin repertoire. Viruses 12:8788
    [Google Scholar]
  39. 39. 
    Johnson KE, Tarakanova VL. 2020. Gammaherpesviruses and B cells: a relationship that lasts a lifetime. Viral Immunol 33:4316–26
    [Google Scholar]
  40. 40. 
    Flaño E, Kim I-J, Moore J, Woodland DL, Blackman MA. 2003. Differential γ-herpesvirus distribution in distinct anatomical locations and cell subsets during persistent infection in mice. J. Immunol. 170:73828–34
    [Google Scholar]
  41. 41. 
    Willer DO, Speck SH. 2003. Long-term latent murine gammaherpesvirus 68 infection is preferentially found within the surface immunoglobulin D-negative subset of splenic B cells in vivo. J. Virol. 77:158310–21
    [Google Scholar]
  42. 42. 
    Speck SH, Ganem D. 2010. Viral latency and its regulation: lessons from the γ-herpesviruses. Cell Host Microbe 8:1100–15
    [Google Scholar]
  43. 43. 
    Rekow MM, Darrah EJ, Mboko WP, Lange PT, Tarakanova VL. 2016. Gammaherpesvirus targets peritoneal B-1 B cells for long-term latency. Virology 492:140–44
    [Google Scholar]
  44. 44. 
    Weck KE, Kim SS, Virgin HW 4th, Speck SH ; 1999. B cells regulate murine gammaherpesvirus 68 latency. J. Virol. 73:64651–61
    [Google Scholar]
  45. 45. 
    François S, Vidick S, Sarlet M, Desmecht D, Drion P et al. 2013. Illumination of murine gammaherpesvirus-68 cycle reveals a sexual transmission route from females to males in laboratory mice. PLOS Pathog 9:4e1003292
    [Google Scholar]
  46. 46. 
    Zeippen C, Javaux J, Snoeck R, Neyts J, Gillet L. 2018. Antiviral effect of the nucleoside analogue cidofovir in the context of sexual transmission of a gammaherpesvirus in mice. J. Antimicrob. Chemother. 73:82095–103
    [Google Scholar]
  47. 47. 
    Briestenská K, Šamšulová V, Poláková M, Mistríková J. 2019. Recombinant luciferase-expressing murine gammaherpesvirus 68 as a tool for rapid antiviral screening. Acta Virol 63:4439–49
    [Google Scholar]
  48. 48. 
    Trompet E, Topalis D, Gillemot S, Snoeck R, Andrei G 2020. Viral fitness of MHV-68 viruses harboring drug resistance mutations in the protein kinase or thymidine kinase. Antivir. Res. 182:104901
    [Google Scholar]
  49. 49. 
    Leang RS, Wu T-T, Hwang S, Liang LT, Tong L et al. 2011. The anti-interferon activity of conserved viral dUTPase ORF54 is essential for an effective MHV-68 infection. PLOS Pathog 7:10e1002292
    [Google Scholar]
  50. 50. 
    Sun C, Schattgen SA, Pisitkun P, Jorgensen JP, Hilterbrand AT et al. 2015. Evasion of innate cytosolic DNA sensing by a gammaherpesvirus facilitates establishment of latent infection. J. Immunol. 194:41819–31
    [Google Scholar]
  51. 51. 
    Correia B, Cerqueira SA, Beauchemin C, de Miranda MP, Li S et al. 2013. Crystal structure of the gamma-2 herpesvirus LANA DNA binding domain identifies charged surface residues which impact viral latency. PLOS Pathog 9:10e1003673
    [Google Scholar]
  52. 52. 
    Habison AC, Beauchemin C, Simas JP, Usherwood EJ, Kaye KM. 2012. Murine gammaherpesvirus 68 LANA acts on terminal repeat DNA to mediate episome persistence. J. Virol. 86:2111863–76
    [Google Scholar]
  53. 53. 
    Paden CR, Forrest JC, Tibbetts SA, Speck SH. 2012. Unbiased mutagenesis of MHV68 LANA reveals a DNA-binding domain required for LANA function in vitro and in vivo. PLOS Pathog 8:9e1002906
    [Google Scholar]
  54. 54. 
    Cerqueira SA, Tan M, Li S, Juillard F, McVey CE et al. 2016. Latency-associated nuclear antigen E3 ubiquitin ligase activity impacts gammaherpesvirus-driven germinal center B cell proliferation. J. Virol. 90:177667–83
    [Google Scholar]
  55. 55. 
    de Miranda MP, Quendera AP, McVey CE, Kaye KM, Simas JP. 2018. In vivo persistence of chimeric virus after substitution of the Kaposi's sarcoma-associated herpesvirus LANA DNA binding domain with that of murid herpesvirus 4. J. Virol. 92:21e01251-18
    [Google Scholar]
  56. 56. 
    Juillard F, de Miranda MP, Li S, Franco A, Seixas AF et al. 2020. KSHV LANA acetylation-selective acidic domain reader sequence mediates virus persistence. PNAS 117:3622443–51
    [Google Scholar]
  57. 57. 
    Hellert J, Weidner-Glunde M, Krausze J, Richter U, Adler H et al. 2013. A structural basis for BRD2/4-mediated host chromatin interaction and oligomer assembly of Kaposi sarcoma-associated herpesvirus and murine gammaherpesvirus LANA proteins. PLOS Pathog 9:10e1003640
    [Google Scholar]
  58. 58. 
    Gupta A, Oldenburg DG, Salinas E, White DW, Forrest JC. 2017. Murine gammaherpesvirus 68 expressing Kaposi sarcoma-associated herpesvirus latency-associated nuclear antigen (LANA) reveals both functional conservation and divergence in LANA homologs. J. Virol. 91:19e00992-17
    [Google Scholar]
  59. 59. 
    Habison AC, de Miranda MP, Beauchemin C, Tan M, Cerqueira SA et al. 2017. Cross-species conservation of episome maintenance provides a basis for in vivo investigation of Kaposi's sarcoma herpesvirus LANA. PLOS Pathog 13:9e1006555KSHV LANA functionally substitutes for MHV68 mLANA to promote episome maintenance and latency in vivo.
    [Google Scholar]
  60. 60. 
    Rangaswamy US, Speck SH. 2014. Murine gammaherpesvirus M2 protein induction of IRF4 via the NFAT pathway leads to IL-10 expression in B cells. PLOS Pathog 10:1e1003858
    [Google Scholar]
  61. 61. 
    Terrell S, Speck SH 2017. Murine gammaherpesvirus M2 antigen modulates splenic B cell activation and terminal differentiation in vivo. PLOS Pathog 13:8e1006543Single expression of M2 latency gene drives B cell activation and plasmablast differentiation, promoting reactivation.
    [Google Scholar]
  62. 62. 
    de Oliveira VL, Almeida SCP, Soares HR, Parkhouse RME. 2013. Selective B-cell expression of the MHV-68 latency-associated M2 protein regulates T-dependent antibody response and inhibits apoptosis upon viral infection. J. Gen. Virol. 94:71613–23
    [Google Scholar]
  63. 63. 
    Liang X, Collins CM, Mendel JB, Iwakoshi NN, Speck SH. 2009. Gammaherpesvirus-driven plasma cell differentiation regulates virus reactivation from latently infected B lymphocytes. PLOS Pathog 5:11e1000677
    [Google Scholar]
  64. 64. 
    Lee KS, Suarez AL, Claypool DJ, Armstrong TK, Buckingham EM, van Dyk LF. 2012. Viral cyclins mediate separate phases of infection by integrating functions of distinct mammalian cyclins. PLOS Pathog 8:2e1002496
    [Google Scholar]
  65. 65. 
    Williams LM, Niemeyer BF, Franklin DS, Clambey ET, van Dyk LF 2015. A conserved gammaherpesvirus cyclin specifically bypasses host p18INK4c to promote reactivation from latency. J. Virol. 89:2110821–31Genetic complementation of v-cyclin mutant virus identifies a host CDK inhibitor antagonist.
    [Google Scholar]
  66. 66. 
    Niemeyer BF, Oko LM, Medina EM, Oldenburg DG, White DW et al. 2018. Host tumor suppressor p18INK4c functions as a potent cell-intrinsic inhibitor of murine gammaherpesvirus 68 reactivation and pathogenesis. J. Virol. 92:6e01604-17
    [Google Scholar]
  67. 67. 
    Johnson KE, Lange PT, Jondle CN, Volberding PJ, Lorenz UM et al. 2020. B cell-intrinsic SHP1 expression promotes the gammaherpesvirus-driven germinal center response and the establishment of chronic infection. J. Virol. 94:1e01232-19
    [Google Scholar]
  68. 68. 
    Lange PT, Schorl C, Sahoo D, Tarakanova VL. 2018. Liver X receptors suppress activity of cholesterol and fatty acid synthesis pathways to oppose gammaherpesvirus replication. mBio 9:4e01115-18
    [Google Scholar]
  69. 69. 
    Lange PT, Jondle CN, Darrah EJ, Johnson KE, Tarakanova VL. 2019. LXR alpha restricts gammaherpesvirus reactivation from latently infected peritoneal cells. J. Virol. 93:6e02071-18
    [Google Scholar]
  70. 70. 
    Cieniewicz B, Santana AL, Minkah N, Krug LT. 2016. Interplay of murine gammaherpesvirus 68 with NF-kappaB signaling of the host. Front. Microbiol. 7:1202
    [Google Scholar]
  71. 71. 
    Santana AL, Oldenburg DG, Kirillov V, Malik L, Dong Q et al. 2017. RTA occupancy of the origin of lytic replication during murine gammaherpesvirus 68 reactivation from B cell latency. Pathogens 6:19
    [Google Scholar]
  72. 72. 
    Reddy SS, Foreman H-CC, Sioux TO, Park GH, Poli V et al. 2016. Ablation of STAT3 in the B cell compartment restricts gammaherpesvirus latency in vivo. mBio 7:4e00723-16
    [Google Scholar]
  73. 73. 
    Kim I-J, Flaño E, Woodland DL, Lund FE, Randall TD, Blackman MA. 2003. Maintenance of long term γ-herpesvirus B cell latency is dependent on CD40-mediated development of memory B cells. J. Immunol. 171:2886–92
    [Google Scholar]
  74. 74. 
    Rangaswamy US, O'Flaherty BM, Speck SH 2014. Tyrosine 129 of the murine gammaherpesvirus M2 protein is critical for M2 function in vivo. PLOS ONE 9:8e105197
    [Google Scholar]
  75. 75. 
    Collins CM, Speck SH. 2015. Interleukin 21 signaling in B cells is required for efficient establishment of murine gammaherpesvirus latency. PLOS Pathog 11:4e1004831
    [Google Scholar]
  76. 76. 
    Liu S, Lei Z, Li J, Wang L, Jia R et al. 2020. Interleukin 16 contributes to gammaherpesvirus pathogenesis by inhibiting viral reactivation. PLOS Pathog 16:7e1008701
    [Google Scholar]
  77. 77. 
    Foreman H-CC, Armstrong J, Santana AL, Krug LT, Reich NC. 2017. The replication and transcription activator of murine gammaherpesvirus 68 cooperatively enhances cytokine-activated, STAT3-mediated gene expression. J. Biol. Chem. 292:3916257–66
    [Google Scholar]
  78. 78. 
    Siegel AM, Rangaswamy US, Napier RJ, Speck SH. 2010. Blimp-1-dependent plasma cell differentiation is required for efficient maintenance of murine gammaherpesvirus latency and antiviral antibody responses. J. Virol. 84:2674–85
    [Google Scholar]
  79. 79. 
    Matar CG, Rangaswamy US, Wakeman BS, Iwakoshi N, Speck SH. 2014. Murine gammaherpesvirus 68 reactivation from B cells requires IRF4 but not XBP-1. J. Virol. 88:1911600–10
    [Google Scholar]
  80. 80. 
    Crepeau RL, Zhang P, Usherwood EJ. 2016. MicroRNA miR-155 is necessary for efficient gammaherpesvirus reactivation from latency, but not for establishment of latency. J. Virol. 90:177811–21
    [Google Scholar]
  81. 81. 
    López-Rodríguez DM, Kirillov V, Krug LT, Mesri EA, Andreansky S. 2019. A role of hypoxia-inducible factor 1 alpha in murine gammaherpesvirus 68 (MHV68) lytic replication and reactivation from latency. PLOS Pathog 15:12e1008192
    [Google Scholar]
  82. 82. 
    Darrah EJ, Kulinski JM, Mboko WP, Xin G, Malherbe LP et al. 2017. B cell-specific expression of ataxia-telangiectasia mutated protein kinase promotes chronic gammaherpesvirus infection. J. Virol. 91:19e01103-17
    [Google Scholar]
  83. 83. 
    Kulinski JM, Darrah EJ, Broniowska KA, Mboko WP, Mounce BC et al. 2015. ATM facilitates mouse gammaherpesvirus reactivation from myeloid cells during chronic infection. Virology 483:264–74
    [Google Scholar]
  84. 84. 
    Sarawar SR, Shen J, Dias P. 2020. Insights into CD8 T cell activation and exhaustion from a mouse gammaherpesvirus model. Viral Immunol 33:3215–24
    [Google Scholar]
  85. 85. 
    Barton ES, Lutzke ML, Rochford R, Virgin HW 4th 2005. Alpha/beta interferons regulate murine gammaherpesvirus latent gene expression and reactivation from latency. J. Virol. 79:2214149–60
    [Google Scholar]
  86. 86. 
    Jacobs S, Zeippen C, Wavreil F, Gillet L, Michiels T. 2019. IFN-λ decreases murid herpesvirus-4 infection of the olfactory epithelium but fails to prevent virus reactivation in the vaginal mucosa. Viruses 11:8757
    [Google Scholar]
  87. 87. 
    Mboko WP, Rekow MM, Ledwith MP, Lange PT, Schmitz KE et al. 2017. Interferon regulatory factor 1 and type I interferon cooperate to control acute gammaherpesvirus infection. J. Virol. 91:1e01444-16
    [Google Scholar]
  88. 88. 
    Stempel M, Chan B, Brinkmann MM 2019. Coevolution pays off: Herpesviruses have the license to escape the DNA sensing pathway. Med. Microbiol. Immunol. 208:3–4495–512
    [Google Scholar]
  89. 89. 
    Johnson KE, Aurubin CA, Jondle CN, Lange PT, Tarakanova VL. 2020. Interferon regulatory factor 7 attenuates chronic gammaherpesvirus infection. J. Virol. 94:24e01554-20
    [Google Scholar]
  90. 90. 
    Bussey KA, Murthy S, Reimer E, Chan B, Hatesuer B et al. 2019. Endosomal toll-like receptors 7 and 9 cooperate in detection of murine gammaherpesvirus 68 infection. J. Virol. 93:3e01173-18
    [Google Scholar]
  91. 91. 
    Jondle CN, Johnson KE, Uitenbroek AA, Sylvester PA, Nguyen C et al. 2020. B cell-intrinsic expression of interferon regulatory factor 1 supports chronic murine gammaherpesvirus 68 infection. J. Virol. 94:13e00399-20B cell–specific deletion of an antiviral host factor reveals an unexpected role in promoting latency.
    [Google Scholar]
  92. 92. 
    Hussein HAM, Briestenska K, Mistrikova J, Akula SM. 2018. IFITM1 expression is crucial to gammaherpesvirus infection, in vivo. Sci. Rep 8:114105
    [Google Scholar]
  93. 93. 
    Darrah EJ, Jondle CN, Johnson KE, Xin G, Lange PT et al. 2019. Conserved gammaherpesvirus protein kinase selectively promotes irrelevant B cell responses. J. Virol. 93:8e01760-18
    [Google Scholar]
  94. 94. 
    Wilke CA, Chadwick MM, Chan PR, Moore BB, Zhou X. 2019. Stem cell transplantation impairs dendritic cell trafficking and herpesvirus immunity. JCI Insight 4:18e130210
    [Google Scholar]
  95. 95. 
    Tao L, Lemoff A, Wang G, Zarek C, Lowe A et al. 2020. Reactive oxygen species oxidize STING and suppress interferon production. eLife 9:e57837
    [Google Scholar]
  96. 96. 
    Cieniewicz B, Dong Q, Li G, Forrest JC, Mounce BC et al. 2015. Murine gammaherpesvirus 68 pathogenesis is independent of caspase-1 and caspase-11 in mice and impairs interleukin-1β production upon extrinsic stimulation in culture. J. Virol. 89:136562–74
    [Google Scholar]
  97. 97. 
    Minkah N, Chavez K, Shah P, MacCarthy T, Chen H et al. 2014. Host restriction of murine gammaherpesvirus 68 replication by human APOBEC3 cytidine deaminases but not murine APOBEC3. Virology 454–455:215–26
    [Google Scholar]
  98. 98. 
    Nakaya Y, Stavrou S, Blouch K, Tattersall P, Ross SR. 2016. In vivo examination of mouse APOBEC3- and human APOBEC3A- and APOBEC3G-mediated restriction of parvovirus and herpesvirus infection in mouse models. J. Virol. 90:178005–12
    [Google Scholar]
  99. 99. 
    Freeman ML, Burkum CE, Cookenham T, Roberts AD, Lanzer KG et al. 2014. CD4 T cells specific for a latency-associated γ-herpesvirus epitope are polyfunctional and cytotoxic. J. Immunol. 193:125827–34
    [Google Scholar]
  100. 100. 
    Tan CSE, Lawler C, Stevenson PG. 2017. CD8+ T cell evasion mandates CD4+ T cell control of chronic gamma-herpesvirus infection. PLOS Pathog 13:4e1006311
    [Google Scholar]
  101. 101. 
    Lawler C, Stevenson PG. 2020. A CD4+ T cell-NK cell axis of gammaherpesvirus control. J. Virol. 94:3e01545-19
    [Google Scholar]
  102. 102. 
    Kimball AK, Oko LM, Kaspar RE, van Dyk LF, Clambey ET. 2019. High-dimensional characterization of IL-10 production and IL-10-dependent regulation during primary gammaherpesvirus infection. ImmunoHorizons 3:394–109
    [Google Scholar]
  103. 103. 
    Park S, Buck MD, Desai C, Zhang X, Loginicheva E et al. 2016. Autophagy genes enhance murine gammaherpesvirus 68 reactivation from latency by preventing virus-induced systemic inflammation. Cell Host Microbe 19:191–101
    [Google Scholar]
  104. 104. 
    Freeman ML, Lanzer KG, Cookenham T, Peters B, Sidney J et al. 2010. Two kinetic patterns of epitope-specific CD8 T-cell responses following murine gammaherpesvirus 68 infection. J. Virol. 84:62881–92
    [Google Scholar]
  105. 105. 
    Dong S, Tan L, Chen G, Liang X 2017. CD95-CD95L interaction mediates the growth control of MHV68 immortalized B cells by cytotoxic T cells. Virol. Sin. 32:3257–59
    [Google Scholar]
  106. 106. 
    Preiss NK, Kang T, Usherwood Y-K, Huang YH, Branchini BR, Usherwood EJ. 2020. Control of B cell lymphoma by gammaherpesvirus-induced memory CD8 T cells. J. Immunol. 205:123372–82
    [Google Scholar]
  107. 107. 
    Freeman ML, Roberts AD, Burkum CE, Woodland DL, Blackman MA. 2014. Promotion of a subdominant CD8 T cell response during murine gammaherpesvirus 68 infection in the absence of CD4 T cell help. J. Virol. 88:147862–69
    [Google Scholar]
  108. 108. 
    Glauser DL, Milho R, Lawler C, Stevenson PG. 2019. Antibody arrests γ-herpesvirus olfactory super-infection independently of neutralization. J. Gen. Virol. 100:2246–58
    [Google Scholar]
  109. 109. 
    Sakakibara S, Yasui T, Jinzai H, O'Donnell K, Tsai C-Y et al. 2020. Self-reactive and polyreactive B cells are generated and selected in the germinal center during γ-herpesvirus infection. Int. Immunol. 32:127–38
    [Google Scholar]
  110. 110. 
    Getahun A, Wemlinger SM, Rudra P, Santiago ML, van Dyk LF, Cambier JC. 2017. Impaired B cell function during viral infections due to PTEN-mediated inhibition of the PI3K pathway. J. Exp. Med. 214:4931–41
    [Google Scholar]
  111. 111. 
    Dong S, Forrest JC, Liang X 2017. Murine gammaherpesvirus 68: a small animal model for gammaherpesvirus-associated diseases. Advances in Experimental Medicine and Biology Q Cai, Z Yuan, K Lan 225–36 Singapore: Springer Nature
    [Google Scholar]
  112. 112. 
    MacDuff DA, Reese TA, Kimmey JM, Weiss LA, Song C et al. 2015. Phenotypic complementation of genetic immunodeficiency by chronic herpesvirus infection. eLife 4:e04494
    [Google Scholar]
  113. 113. 
    Qian W, Miner CA, Ingle H, Platt DJ, Baldridge MT, Miner JJ. 2019. A human STAT1 gain-of-function mutation impairs CD8+ T cell responses against gammaherpesvirus 68. J. Virol. 93:19e00307-19
    [Google Scholar]
  114. 114. 
    Tibbetts SA, Suarez F, Steed AL, Simmons JA, Virgin HW 4th 2006. A γ-herpesvirus deficient in replication establishes chronic infection in vivo and is impervious to restriction by adaptive immune cells. Virology 353:1210–19
    [Google Scholar]
  115. 115. 
    Lawler C, Simas JP, Stevenson PG. 2020. Vaccine protection against murid herpesvirus-4 is maintained when the priming virus lacks known latency genes. Immunol. Cell Biol. 98:167–78
    [Google Scholar]
  116. 116. 
    Brar G, Farhat NA, Sukhina A, Lam AK, Kim YH et al. 2020. Deletion of immune evasion genes provides an effective vaccine design for tumor-associated herpesviruses. NPJ Vaccines 5:102
    [Google Scholar]
  117. 117. 
    Sunil-Chandra NP, Arno J, Fazakerley J, Nash AA. 1994. Lymphoproliferative disease in mice infected with murine gammaherpesvirus 68. Am. J. Pathol. 145:4818–26
    [Google Scholar]
  118. 118. 
    Tarakanova VL, Suarez F, Tibbetts SA, Jacoby MA, Weck KE et al. 2005. Murine gammaherpesvirus 68 infection is associated with lymphoproliferative disease and lymphoma in BALB β2 microglobulin-deficient mice. J. Virol. 79:2314668–79
    [Google Scholar]
  119. 119. 
    Lee KS, Groshong SD, Cool CD, Kleinschmidt-DeMasters BK, van Dyk LF. 2009. Murine gammaherpesvirus 68 infection of IFNγ unresponsive mice: a small animal model for gammaherpesvirus-associated B-cell lymphoproliferative disease. Cancer Res 69:135481–89
    [Google Scholar]
  120. 120. 
    Tarakanova VL, Kreisel F, White DW, Virgin HW 4th 2008. Murine gammaherpesvirus 68 genes both induce and suppress lymphoproliferative disease. J. Virol. 82:21034–39
    [Google Scholar]
  121. 121. 
    Zhang J, Zhu L, Lu X, Feldman ER, Keyes LR et al. 2015. Recombinant murine gamma herpesvirus 68 carrying KSHV G protein-coupled receptor induces angiogenic lesions in mice. PLOS Pathog 11:6e1005001
    [Google Scholar]
  122. 122. 
    Liang X, Paden CR, Morales FM, Powers RP, Jacob J, Speck SH 2011. Murine gamma-herpesvirus immortalization of fetal liver-derived B cells requires both the viral cyclin D homolog and latency-associated nuclear antigen. PLOS Pathog 7:9e1002220
    [Google Scholar]
  123. 123. 
    Cardin RD, Brooks JW, Sarawar SR, Doherty PC. 1996. Progressive loss of CD8+ T cell-mediated control of a gamma-herpesvirus in the absence of CD4+ T cells. J. Exp. Med. 184:3863–71
    [Google Scholar]
  124. 124. 
    Lee KS, Cool CD, van Dyk LF. 2009. Murine gammaherpesvirus 68 infection of gamma interferon-deficient mice on a BALB/c background results in acute lethal pneumonia that is dependent on specific viral genes. J. Virol. 83:2111397–401
    [Google Scholar]
  125. 125. 
    Feldman ER, Kara M, Coleman CB, Grau KR, Oko LM et al. 2014. Virus-encoded microRNAs facilitate gammaherpesvirus latency and pathogenesis in vivo. mBio 5:3e00981-14
    [Google Scholar]
  126. 126. 
    Mora AL, Torres-González E, Rojas M, Xu J, Ritzenthaler J et al. 2007. Control of virus reactivation arrests pulmonary herpesvirus-induced fibrosis in IFN-γ receptor-deficient mice. Am. J. Respir. Crit. Care Med. 175:111139–50
    [Google Scholar]
  127. 127. 
    Chen H, Bartee MY, Yaron JR, Liu L, Zhang L et al. 2018. Mouse gamma herpesvirus MHV-68 induces severe gastrointestinal (GI) dilatation in interferon gamma receptor-deficient mice (IFNγR−/−) that is blocked by interleukin-10. Viruses 10:10518
    [Google Scholar]
  128. 128. 
    Weck KE, Dal Canto AJ, Gould JD, O'Guin AK, Roth KA et al. 1997. Murine γ-herpesvirus 68 causes severe large-vessel arteritis in mice lacking interferon-γ responsiveness: a new model for virus-induced vascular disease. Nat. Med. 3:121346–53
    [Google Scholar]
  129. 129. 
    O'Dwyer DN, Moore BB 2018. Animal models of pulmonary fibrosis. Methods Mol. Biol. 1809:363–78
    [Google Scholar]
  130. 130. 
    Krug LT, Torres-González E, Qin Q, Sorescu D, Rojas M et al. 2010. Inhibition of NF-κB signaling reduces virus load and gammaherpesvirus-induced pulmonary fibrosis. Am. J. Pathol. 177:2608–21
    [Google Scholar]
  131. 131. 
    LeBel M, Egarnes B, Brunet A, Lacerte P, Paré A et al. 2018. Ly6Chigh monocytes facilitate transport of murid herpesvirus 68 into inflamed joints of arthritic mice. Eur. J. Immunol. 48:2250–57
    [Google Scholar]
  132. 132. 
    Yaron JR, Ambadapadi S, Zhang L, Chavan RN, Tibbetts SA et al. 2020. Immune protection is dependent on the gut microbiome in a lethal mouse gammaherpesviral infection. Sci. Rep. 10:12371
    [Google Scholar]
  133. 133. 
    Kanai K, Park A-M, Watanabe A, Arikawa T, Yasui T et al. 2018. Murine γ-herpesvirus 68 induces severe lung inflammation in IL-27-deficient mice with liver dysfunction preventable by oral neomycin. J. Immunol. 200:82703–13
    [Google Scholar]
  134. 134. 
    Reese TA. 2016. Coinfections: another variable in the herpesvirus latency-reactivation dynamic. J. Virol. 90:125534–37
    [Google Scholar]
  135. 135. 
    Barton ES, White DW, Cathelyn JS, Brett-McClellan KA, Engle M et al. 2007. Herpesvirus latency confers symbiotic protection from bacterial infection. Nature 447:7142326–29
    [Google Scholar]
  136. 136. 
    Miller HE, Johnson KE, Tarakanova VL, Robinson RT. 2019. γ-herpesvirus latency attenuates Mycobacterium tuberculosis infection in mice. Tuberculosis 116:56–60
    [Google Scholar]
  137. 137. 
    Saito F, Ito T, Connett JM, Schaller MA, Carson WF 4th et al. 2013. MHV68 latency modulates the host immune response to influenza A virus. Inflammation 36:61295–303
    [Google Scholar]
  138. 138. 
    Reese TA, Bi K, Kambal A, Filali-Mouhim A, Beura LK et al. 2016. Sequential infection with common pathogens promotes human-like immune gene expression and altered vaccine response. Cell Host Microbe 19:5713–19
    [Google Scholar]
  139. 139. 
    Matar CG, Anthony NR, O'Flaherty BM, Jacobs NT, Priyamvada L et al. 2015. Gammaherpesvirus co-infection with malaria suppresses anti-parasitic humoral immunity. PLOS Pathog 11:5e1004858
    [Google Scholar]
  140. 140. 
    Reese TA, Wakeman BS, Choi HS, Hufford MM, Huang SC et al. 2014. Helminth infection reactivates latent γ-herpesvirus via cytokine competition at a viral promoter. Science 345:6196573–77
    [Google Scholar]
  141. 141. 
    Rolot M, Dougall AM, Chetty A, Javaux J, Chen T et al. 2018. Helminth-induced IL-4 expands bystander memory CD8+ T cells for early control of viral infection. Nat. Commun. 9:14516
    [Google Scholar]
  142. 142. 
    Bullard WL, Kara M, Gay LA, Sethuraman S, Wang Y et al. 2019. Identification of murine gammaherpesvirus 68 miRNA-mRNA hybrids reveals miRNA target conservation among gammaherpesviruses including host translation and protein modification machinery. PLOS Pathog 15:8e1007843
    [Google Scholar]
  143. 143. 
    Ungerleider NA, Jain V, Wang Y, Maness NJ, Blair RV et al. 2019. Comparative analysis of gammaherpesvirus circular RNA repertoires: conserved and unique viral circular RNAs. J. Virol. 93:6e01952-18
    [Google Scholar]
  144. 144. 
    Steer B, Strehle M, Sattler C, Bund D, Flach B et al. 2016. The small noncoding RNAs (sncRNAs) of murine gammaherpesvirus 68 (MHV-68) are involved in regulating the latent-to-lytic switch in vivo. Sci. Rep. 6:32128
    [Google Scholar]
  145. 145. 
    Wang Y, Feldman ER, Bullard WL, Tibbetts SA. 2019. A gammaherpesvirus microRNA targets EWSR1 (Ewing sarcoma breakpoint region 1) in vivo to promote latent infection of germinal center B cells. mBio 10:4e00996-19
    [Google Scholar]
  146. 146. 
    Diebel KW, Oko LM, Medina EM, Niemeyer BF, Warren CJ et al. 2015. Gammaherpesvirus small noncoding RNAs are bifunctional elements that regulate infection and contribute to virulence in vivo. mBio 6:1e01670-14
    [Google Scholar]
  147. 147. 
    Kara M, O'Grady T, Feldman ER, Feswick A, Wang Y et al. 2019. Gammaherpesvirus readthrough transcription generates a long non-coding RNA that is regulated by antisense miRNAs and correlates with enhanced lytic replication in vivo. Non-Coding RNA 5:16
    [Google Scholar]
  148. 148. 
    Zelazowska MA, Dong Q, Plummer JB, Zhong Y, Liu B et al. 2020. Gammaherpesvirus-infected germinal center cells express a distinct immunoglobulin repertoire. Life Sci. Alliance 3:3e201900526
    [Google Scholar]
  149. 149. 
    Collins CM, Scharer CD, Murphy TJ, Boss JM, Speck SH. 2020. Murine gammaherpesvirus infection is skewed toward Igλ+ B cells expressing a specific heavy chain V-segment. PLOS Pathog 16:4e1008438
    [Google Scholar]
  150. 150. 
    Totonchy J, Osborn JM, Chadburn A, Nabiee R, Argueta L et al. 2018. KSHV induces immunoglobulin rearrangements in mature B lymphocytes. PLOS Pathog 14:4e1006967
    [Google Scholar]
  151. 151. 
    Pellett PE, Roizman B 2013. Herpesviridae. Fields Virology DM Knipe, P Howley Philadelphia: Wolters Kluwer Health/Lippincott Williams & Wilkins, 6th ed..
    [Google Scholar]
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