Human Cytomegaloviruses pp 15-28 | Cite as
Overview of Human Cytomegalovirus Pathogenesis
- 36 Citations
- 2.4k Downloads
Abstract
Human cytomegalovirus (HCMV) is a human pathogen that infects greater than 50 % of the human population. HCMV infection is usually asymptomatic in most individuals. That is, primary infection or reactivation of latent virus is generally clinically silent. HCMV infection, however, is associated with significant morbidity and mortality in the immunocompromised and chronic inflammatory diseases in the immunocompetent. In immunocompromised individuals (acquired immune deficiency syndrome and transplant patients, developing children (in utero), and cancer patients undergoing chemotherapy), HCMV infection increases morbidity and mortality. In those individuals with a normal immune system, HCMV infection is also associated with a risk of serious disease, as viral infection is now considered to be a strong risk factor for the development of various vascular diseases and to be associated with some types of tumor development. Intense research is currently being undertaken to better understand the mechanisms of viral pathogenesis that are briefly discussed in this chapter.
Key words
Human cytomegalovirus Viral pathogenesis Immunocompetent Immunocompromised Vascular disease Oncogenesis Congenital infection AIDS patients Transplant patientsReferences
- 1.Mocarsk ES Jr, Shenk T, Pass RF (2007) Cytomegaloviruses. In: Knipe DM, Howley PM (eds) Fields virology. Lippincott Williams & Wilkins, Philadelphia, PA, pp 2701–2772Google Scholar
- 2.Britt W (2008) Manifestations of human cytomegalovirus infection: proposed mechanisms of acute and chronic disease. In: Stinksi MF, Shenk T (eds) Human cytomegaloviruses. Springer, Berlin, pp 417–470Google Scholar
- 3.Bravender T (2010) Epstein-Barr virus, cytomegalovirus, and infectious mononucleosis. Adolesc Med State Art Rev 21:251–264, ix–64, ixPubMedGoogle Scholar
- 4.Eddleston M, Peacock S, Juniper M, Warrell DA (1997) Severe cytomegalovirus infection in immunocompetent patients. Clin Infect Dis 24:52–56PubMedGoogle Scholar
- 5.Söderberg-Nauclér C (2008) HCMV microinfections in inflammatory diseases and cancer. J Clin Virol 41:218–223PubMedGoogle Scholar
- 6.Michaelis M, Doerr HW, Cinatl J (2009) The story of human cytomegalovirus and cancer: increasing evidence and open questions. Neoplasia 11:1–9PubMedCentralPubMedGoogle Scholar
- 7.Caposio P, Orloff SL, Streblow DN (2011) The role of cytomegalovirus in angiogenesis. Virus Res 157:204–211PubMedCentralPubMedGoogle Scholar
- 8.Streblow DN, Dumortier J, Moses AV, Orloff SL, Nelson JA (2008) Mechanisms of cytomegalovirus-accelerated vascular disease: induction of paracrine factors that promote angiogenesis and wound healing. Curr Top Microbiol Immunol 325:397–415PubMedCentralPubMedGoogle Scholar
- 9.Manicklal S, Emery VC, Lazzarotto T, Boppana SB, Gupta RK (2013) The “silent” global burden of congenital cytomegalovirus. Clin Microbiol Rev 26:86–102PubMedCentralPubMedGoogle Scholar
- 10.Klemola E, Von Essen R, Henle G, Henle W (1970) Infectious-mononucleosis-like disease with negative heterophile agglutination test. Clinical features in relation to Epstein-Barr virus and cytomegalovirus antibodies. J Infect Dis 121:608–614PubMedGoogle Scholar
- 11.Jordan MC, Rousseau W, Stewart JA, Noble GR, Chin TD (1973) Spontaneous cytomegalovirus mononucleosis. Clinical and laboratory observations in nine cases. Ann Intern Med 79:153–160PubMedGoogle Scholar
- 12.Wreghitt TG, Teare EL, Sule O, Devi R, Rice P (2003) Cytomegalovirus infection in immunocompetent patients. Clin Infect Dis 37: 1603–1606PubMedGoogle Scholar
- 13.Streblow DN, Dumortier J, Moses AV, Orloff SL, Nelson JA (2008) Mechanisms of cytomegalovirus-accelerated vascular disease: induction of paracrine factors that promote angiogenesis and wound healing. In: Stinksi MF, Shenk T (eds) Human cytomegaloviruses. Springer, Berlin, pp 397–416Google Scholar
- 14.Adam E, Melnick JL, Probtsfield JL, Petrie BL, Burek J, Bailey KR, McCollum CH, DeBakey ME (1987) High levels of cytomegalovirus antibody in patients requiring vascular surgery for atherosclerosis. Lancet 2: 291–293PubMedGoogle Scholar
- 15.Hendrix MG, Salimans MM, van-Boven CP, Bruggeman CA (1990) High prevalence of latently present cytomegalovirus in arterial walls of patients suffering from grade III atherosclerosis. Am J Pathol 136:23–28PubMedCentralPubMedGoogle Scholar
- 16.Melnick JL, Petrie BL, Dreesman GR, Burek J, McCollum CH, DeBakey ME (1983) Cytomegalovirus antigen within human arterial smooth muscle cells. Lancet 2:644–647PubMedGoogle Scholar
- 17.Nieto FJ, Adam E, Sorlie P, Farzadegan H, Melnick JL, Comstock GW, Szklo M (1996) Cohort study of cytomegalovirus infection as a risk factor for carotid intimal-medial thickening, a measure of subclinical atherosclerosis. Circulation 94:922–927PubMedGoogle Scholar
- 18.Gyorkey F, Melnick JL, Guinn GA, Gyorkey P, DeBakey ME (1984) Herpesviridae in the endothelial and smooth muscle cells of the proximal aorta in atherosclerotic patients. Exp Mol Pathol 40:328–339PubMedGoogle Scholar
- 19.Zhou YF, Leon MB, Waclawiw MA, Popma JJ, Yu ZX, Finkel T, Epstein SE (1996) Association between prior cytomegalovirus infection and the risk of restenosis after coronary atherectomy. N Engl J Med 335: 624–630PubMedGoogle Scholar
- 20.Speir E, Modali R, Huang ES, Leon MB, Shawl F, Finkel T, Epstein SE (1994) Potential role of human cytomegalovirus and p53 interaction in coronary restenosis. Science 265:391–394PubMedGoogle Scholar
- 21.Hussain T, Burch M, Fenton MJ, Whitmore PM, Rees P, Elliott M, Aurora P (2007) Positive pretransplantation cytomegalovirus serology is a risk factor for cardiac allograft vasculopathy in children. Circulation 115:1798–1805PubMedGoogle Scholar
- 22.Söderberg-Nauclér C, Emery VC (2001) Viral infections and their impact on chronic renal allograft dysfunction. Transplantation 71:SS24–SS30PubMedGoogle Scholar
- 23.Zhu J, Quyyumi AA, Norman JE, Csako G, Epstein SE (1999) Cytomegalovirus in the pathogenesis of atherosclerosis: the role of inflammation as reflected by elevated C-reactive protein levels. J Am Coll Cardiol 34:1738–1743PubMedGoogle Scholar
- 24.Chan G, Nogalski MT, Stevenson EV, Yurochko AD (2012) Human cytomegalovirus induction of a unique signalsome during viral entry into monocytes mediates distinct functional changes: a strategy for viral dissemination. J Leukoc Biol 92:743–752PubMedCentralPubMedGoogle Scholar
- 25.Hansson GK, Libby P (2006) The immune response in atherosclerosis: a double-edged sword. Nat Rev Immunol 6:508–519PubMedGoogle Scholar
- 26.Bentz GL, Yurochko AD (2008) HCMV infection of endothelial cells induces an angiogenic response through viral-binding to the epidermal growth factor receptor and the β1 and β3 integrins. Proc Natl Acad Sci USA 105:5531–5536PubMedCentralPubMedGoogle Scholar
- 27.Falk E (2006) Pathogenesis of atherosclerosis. J Am Coll Cardiol 47:C7–C12PubMedGoogle Scholar
- 28.Lusis AJ (2000) Atherosclerosis. Nature 407:233–241PubMedCentralPubMedGoogle Scholar
- 29.Streblow DN, Soderberg-Naucler C, Vieira J, Smith P, Wakabayashi E, Ruchti F, Mattison K, Altschuler Y, Nelson JA (1999) The human cytomegalovirus chemokine receptor US28 mediates vascular smooth muscle cell migration. Cell 99:511–520PubMedGoogle Scholar
- 30.Streblow DN, Orloff SL, Nelson JA (2001) Do pathogens accelerate atherosclerosis? J Nutr 131:2798–2804Google Scholar
- 31.Chan G, Nogalski MT, Yurochko AD (2012) Human cytomegalovirus stimulates monocyte-to-macrophage differentiation via the temporal regulation of caspase 3. J Virol 92:10714–10723Google Scholar
- 32.Streblow DN, Kreklywich CN, Smith P, Soule JL, Meyer C, Yin M, Beisser P, Vink C, Nelson JA, Orloff SL (2005) Rat cytomegalovirus-accelerated transplant vascular sclerosis is reduced with mutation of the chemokine-receptor R33. Am J Transplant 5:436–442PubMedGoogle Scholar
- 33.Orloff SL, Hwee YK, Kreklywich C, Andoh TF, Hart E, Smith PA, Messaoudi I, Streblow DN (2011) Cytomegalovirus latency promotes cardiac lymphoid neogenesis and accelerated allograft rejection in CMV naïve recipients. Am J Transplant 11:45–55PubMedCentralPubMedGoogle Scholar
- 34.Streblow DN, Kreklywich CN, Andoh T, Moses AV, Dumortier J, Smith PP, Defilippis V, Fruh K, Nelson JA, Orloff SL (2008) The role of angiogenic and wound repair factors during CMV-accelerated transplant vascular sclerosis in rat cardiac transplants. Am J Transplant 8:277–287PubMedGoogle Scholar
- 35.Gombos RB, Brown JC, Teefy J, Gibeault RL, Conn KL, Schang LM, Hemmings DG (2013) Vascular dysfunction in young, mid-aged and aged mice with latent cytomegalovirus infections. Am J Physiol Heart Circ Physiol 304:H183–H194PubMedCentralPubMedGoogle Scholar
- 36.Tang-Feldman YJ, Lochhead SR, Lochhead GR, Yu C, George M, Villablanca AC, Pomeroy C (2013) Murine cytomegalovirus (MCMV) infection upregulates P38 MAP kinase in aortas of Apo E KO mice: a molecular mechanism for MCMV-induced acceleration of atherosclerosis. J Cardiovasc Transl Res 6:54–64PubMedGoogle Scholar
- 37.Bhattacharjee B, Renzette N, Kowalik TF (2012) Genetic analysis of cytomegalovirus in malignant gliomas. J Virol 86:6815–6824PubMedCentralPubMedGoogle Scholar
- 38.Harkins L, Volk AL, Samanta M, Mikolaenko I, Britt WJ, Bland KI, Cobbs CS (2002) Specific localisation of human cytomegalovirus nucleic acids and proteins in human colorectal cancer. Lancet 360:1557–1563PubMedGoogle Scholar
- 39.Samanta M, Harkins L, Klemm K, Britt WJ, Cobbs CS (2003) High prevalence of human cytomegalovirus in prostatic intraepithelial neoplasia and prostatic carcinoma. J Urol 170:998–1002PubMedGoogle Scholar
- 40.Harkins LE, Matlaf LA, Soroceanu L, Klemm K, Britt WJ, Wang W, Bland KI, Cobbs CS (2010) Detection of human cytomegalovirus in normal and neoplastic breast epithelium. Herpesviridae 1:8PubMedCentralPubMedGoogle Scholar
- 41.Cobbs CS, Harkins L, Samanta M, Gillespie GY, Bharara S, King PH, Nabors LB, Cobbs CG, Britt WJ (2002) Human cytomegalovirus infection and expression in human malignant glioma. Cancer Res 62:3347–3350PubMedGoogle Scholar
- 42.Hwang ES, Zhang Z, Cai H, Huang DY, Huong SM, Cha CY, Huang ES (2009) Human cytomegalovirus IE1-72 protein interacts with p53 and inhibits p53-dependent transactivation by a mechanism different from that of IE2-86 protein. J Virol 83: 12388–12398PubMedCentralPubMedGoogle Scholar
- 43.Shen Y, Zhu H, Shenk T (1997) Human cytomegalovirus IE1 and IE2 proteins are mutagenic and mediate “hit-and-run” oncogenic transformation in cooperation with the adenovirus E1A proteins. Proc Natl Acad Sci USA 94:3341–3345PubMedCentralPubMedGoogle Scholar
- 44.E X, Pickering MT, Debatis M, Castillo J, Lagadinos A, Wang S, Lu S, Kowalik TF (2011) An E2F1-mediated DNA damage response contributes to the replication of human cytomegalovirus. PLoS Pathog 7:e1001342PubMedCentralPubMedGoogle Scholar
- 45.Castillo JP, Frame FM, Rogoff HA, Pickering MT, Yurochko AD, Kowalik TF (2005) Human cytomegalovirus IE1-72 activates ataxia telangiectasia mutated kinase and a p53/p21-mediated growth arrest response. J Virol 79:11467–11475PubMedCentralPubMedGoogle Scholar
- 46.Hume AJ, Kalejta RF (2009) Regulation of the retinoblastoma proteins by the human herpesviruses. Cell Div 4:1PubMedCentralPubMedGoogle Scholar
- 47.Soroceanu L, Cobbs CS (2011) Is HCMV a tumor promoter? Virus Res 157:193–203PubMedCentralPubMedGoogle Scholar
- 48.Cinatl J Jr, Cinatl J, Vogel JU, Rabenau H, Kornhuber B, Doerr HW (1996) Modulatory effects of human cytomegalovirus infection on malignant properties of cancer cells. Intervirology 39:259–269PubMedGoogle Scholar
- 49.Barami K (2010) Oncomodulatory mechanisms of human cytomegalovirus in gliomas. J Clin Neurosci 17:819–823PubMedGoogle Scholar
- 50.Söderberg-Nauclér C, Johnsen JI (2012) Cytomegalovirus infection in brain tumors: a potential new target for therapy? Oncoimmunology 1:739–740PubMedCentralPubMedGoogle Scholar
- 51.Maussang D, Verzijl D, van Walsum M, Leurs R, Holl J, Pleskoff O, Michel D, van Dongen GA, Smit MJ (2006) Human cytomegalovirus-encoded chemokine receptor US28 promotes tumorigenesis. Proc Natl Acad Sci USA 103:13068–13073PubMedCentralPubMedGoogle Scholar
- 52.Mitchell DA, Xie W, Schmittling R, Learn C, Friedman AD, McLendon RE, Sampson JH (2008) Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma. Neuro Oncol 10:10–18PubMedCentralPubMedGoogle Scholar
- 53.Scheurer ME, Bondy ML, Aldape KD, Albrecht T, El-Zein R (2008) Detection of human cytomegalovirus in different histological types of gliomas. Acta Neuropathol 116:79–86PubMedCentralPubMedGoogle Scholar
- 54.Shen CY, Ho MS, Chang SF, Yen MS, Ng HT, Huang E-S, Wu CW (1993) High rate of concurrent genital infections with human cytomegalovirus and human papillomaviruses in cervical cancer patients. J Infect Dis 168:449–452PubMedGoogle Scholar
- 55.Rahbar A, Stragliotto G, Orrego A, Peredo I, Taher C, Willems J, Söderberg-Naucler C (2012) Low levels of human cytomegalovirus infection in glioblastoma multiforme associates with patient survival—a case-control study. Herpesviridae 3:3PubMedCentralPubMedGoogle Scholar
- 56.Dumortier J, Streblow DN, Moses AV, Jacobs JM, Kreklywich CN, Camp D, Smith RD, Orloff SL, Nelson JA (2008) Human cytomegalovirus secretome contains factors that induce angiogenesis and wound healing. J Virol 82:6524–6535PubMedCentralPubMedGoogle Scholar
- 57.Fortunato EA, Spector DH (2003) Viral induction of site-specific chromosome damage. Rev Med Virol 13:21–37PubMedGoogle Scholar
- 58.Adler SP (2005) Congenital cytomegalovirus screening. Pediatr Infect Dis J 24:1105–1106PubMedGoogle Scholar
- 59.Adler SP (2011) Screening for cytomegalovirus during pregnancy. Infect Dis Obstet Gynecol 2011:1–9PubMedGoogle Scholar
- 60.Nigro G, Adler SP (2011) Cytomegalovirus infections during pregnancy. Curr Opin Obstet Gynecol 23:123–128PubMedGoogle Scholar
- 61.Marshall BC, Adler SP (2009) The frequency of pregnancy and exposure to cytomegalovirus infections among women with a young child in day care. Am J Obstet Gynecol 200:163.e1–163.e5Google Scholar
- 62.Fowler KB, Stagno S, Pass RF, Britt WJ, Boll TJ, Alford CA (1992) The outcome of congenital cytomegalovirus infection in relation to maternal antibody status. N Engl J Med 326:663–667PubMedGoogle Scholar
- 63.Ross SA, Boppana SB (2005) Congenital cytomegalovirus infection: outcome and diagnosis. Semin Pediatr Infect Dis 16:44–49PubMedGoogle Scholar
- 64.Vancikova Z, Dvorak P (2001) Cytomegalovirus infection in immunocompetent and immunocompromised individuals—a review. Curr Drug Targets Immune Endocr Metabol Disord 1:179–187PubMedGoogle Scholar
- 65.Mussi-Pinhata MM, Yamamoto AY, Moura Brito RM, de Lima Isaac M, de Carvalho Oliveira PF, Boppana S, Britt WJ (2009) Birth prevalence and natural history of congenital cytomegalovirus infection in a highly seroimmune population. Clin Infect Dis 49:522–528PubMedCentralPubMedGoogle Scholar
- 66.Boppana SB, Pass RF, Britt WJ, Stagno S, Alford CA (1992) Symptomatic congenital cytomegalovirus infection: neonatal morbidity and mortality. Pediatr Infect Dis J 11:93–99PubMedGoogle Scholar
- 67.Nassetta L, Kimberlin D, Whitley R (2009) Treatment of congenital cytomegalovirus infection: implications for future therapeutic strategies. J Antimicrob Chemother 63: 862–867PubMedCentralPubMedGoogle Scholar
- 68.Bale JF Jr, Blackman JA, Sato Y (1990) Outcome in children with symptomatic congenital cytomegalovirus infection. J Child Neurol 5:131–136PubMedGoogle Scholar
- 69.Williamson WD, Percy AK, Yow MD, Gerson P, Catlin FI, Koppelman ML, Thurber S (1990) Asymptomatic congenital cytomegalovirus infection. Audiologic, neuroradiologic, and neurodevelopmental abnormalities during the first year. Am J Dis Child 144:1365–1368PubMedGoogle Scholar
- 70.Saigal S, Lunyk O, Larke RP, Chernesky MA (1982) The outcome in children with congenital cytomegalovirus infection. A longitudinal follow-up study. Am J Dis Child 136:896–901PubMedGoogle Scholar
- 71.Stagno S, Pass RF, Cloud G, Britt WJ, Henderson RE, Walton PD, Veren DA, Page F, Alford CA (1986) Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome. JAMA 256:1904–1908PubMedGoogle Scholar
- 72.Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF (1999) Symptomatic congenital cytomegalovirus infection in infants born to mothers with preexisting immunity to cytomegalovirus. Pediatrics 104:55–60PubMedGoogle Scholar
- 73.Stagno S, Pass RF, Dworsky ME, Alford CA Jr (1982) Maternal cytomegalovirus infection and perinatal transmission. Clin Obstet Gynecol 25:563–576PubMedGoogle Scholar
- 74.Cannon MJ, Hyde TB, Schmid DS (2011) Review of cytomegalovirus shedding in bodily fluids and relevance to congenital cytomegalovirus infection. Rev Med Virol 21:240–255PubMedGoogle Scholar
- 75.Reynolds DW, Stagno S, Hosty TS, Tiller M, Alford CA Jr (1973) Maternal cytomegalovirus excretion and perinatal infection. N Engl J Med 289:1–5PubMedGoogle Scholar
- 76.Dworsky M, Yow M, Stagno S, Pass RF, Alford C (1983) Cytomegalovirus infection of breast milk and transmission in infancy. Pediatrics 72:295–299PubMedGoogle Scholar
- 77.Jim WT, Shu CH, Chiu NC, Kao HA, Hung HY, Chang JH, Peng CC, Hsieh WS, Liu KC, Huang FY (2004) Transmission of cytomegalovirus from mothers to preterm infants by breast milk. Pediatr Infect Dis J 23:848–851PubMedGoogle Scholar
- 78.Vochem M, Hamprecht K, Jahn G, Speer CP (1998) Transmission of cytomegalovirus to preterm infants through breast milk. Pediatr Infect Dis J 17:53–58PubMedGoogle Scholar
- 79.Chiba S, Hori S, Kawamura N, Nakao T (1975) Primary cytomegalovirus infection and liver involvement in early infancy. Tohoku J Exp Med 117:143–151PubMedGoogle Scholar
- 80.Stagno S, Brasfield DM, Brown MB, Cassell GH, Pifer LL, Whitley RJ, Tiller RE (1981) Infant pneumonitis associated with cytomegalovirus, Chlamydia, Pneumocystis, and Ureaplasma: a prospective study. Pediatrics 68:322–329PubMedGoogle Scholar
- 81.Kumar ML, Nankervis GA, Cooper AR, Gold E (1984) Postnatally acquired cytomegalovirus infections in infants of CMV-excreting mothers. J Pediatr 104:669–673PubMedGoogle Scholar
- 82.Ballard RA, Drew WL, Hufnagle KG, Riedel PA (1979) Acquired cytomegalovirus infection in preterm infants. Am J Dis Child 133:482–485PubMedGoogle Scholar
- 83.Yeager AS, Grumet FC, Hafleigh EB, Arvin AM, Bradley JS, Prober CG (1981) Prevention of transfusion-acquired cytomegalovirus infections in newborn infants. J Pediatr 98:281–287PubMedGoogle Scholar
- 84.Hamprecht K, Maschmann J, Vochem M, Dietz K, Speer CP, Jahn G (2001) Epidemiology of transmission of cytomegalovirus from mother to preterm infant by breastfeeding. Lancet 357:513–518PubMedGoogle Scholar
- 85.Eisenfeld L, Silver H, McLaughlin J, Klevjer-Anderson P, Mayo D, Anderson J, Herson V, Krause P, Savidakis J, Lazar A, Rosenkrantz T, Pisciotto P (1992) Prevention of transfusion-associated cytomegalovirus infection in neonatal patients by the removal of white cells from blood. Transfusion 32:205–209PubMedGoogle Scholar
- 86.Gilbert GL, Hayes K, Hudson IL, James J (1989) Prevention of transfusion-acquired cytomegalovirus infection in infants by blood filtration to remove leucocytes. Neonatal Cytomegalovirus Infection Study Group. Lancet 1:1228–1231PubMedGoogle Scholar
- 87.Chou SW (1986) Acquisition of donor strains of cytomegalovirus by renal-transplant recipients. N Engl J Med 314:1418–1423PubMedGoogle Scholar
- 88.Drew WL, Sweet ES, Miner RC, Mocarski ES (1984) Multiple infections by cytomegalovirus in patients with acquired immunodeficiency syndrome: documentation by southern blot hybridization. J Infect Dis 150:952–953PubMedGoogle Scholar
- 89.Grundy JE, Lui SF, Super M, Berry NJ, Sweny P, Fernando ON, Moorhead J, Griffiths PD (1988) Symptomatic cytomegalovirus infection in seropositive kidney recipients: reinfection with donor virus rather than reactivation of recipient virus. Lancet 2:132–135PubMedGoogle Scholar
- 90.Snydman DR, Werner BG, Heinze-Lacey B, Berardi VP, Tilney NL, Kirkman RL, Milford EL, Cho SI, Bush HL Jr, Levey AS, Strom TB, Carpenter CB, Levey RH, Harmon WE, Zimmerman CE II, Shapiro ME, Steinman T, LoGerfo F, Idelson B, Schröter GPJ, Levin MJ, McIver J, Leszczynski J, Grady GF (1987) Use of cytomegalovirus immune globulin to prevent cytomegalovirus disease in renal-transplant recipients. N Engl J Med 317:1049–1054PubMedGoogle Scholar
- 91.Walter EA, Greenberg PD, Gilbert MJ, Finch RJ, Watanabe KS, Thomas ED, Riddell SR (1995) Reconstitution of cellular immunity against cytomegalovirus in recipients of allogeneic bone marrow by transfer of T-cell clones from the donor. N Engl J Med 333:1038–1044PubMedGoogle Scholar
- 92.Plotkin SA, Smiley ML, Friedman HM, Starr SE, Fleisher GR, Wlodaver C, Dafoe DC, Friedman AD, Grossman RA, Barker CF (1984) Towne-vaccine-induced prevention of cytomegalovirus disease after renal transplants. Lancet 1:528–530PubMedGoogle Scholar
- 93.Erice A, Gil-Roda C, Perez JL, Balfour HH Jr, Sannerud KJ, Hanson MN, Boivin G, Chou S (1997) Antiviral susceptibilities and analysis of UL97 and DNA polymerase sequences of clinical cytomegalovirus isolates from immunocompromised patients. J Infect Dis 175:1087–1092PubMedGoogle Scholar
- 94.Legendre CM, Norman DJ, Keating MR, Maclaine GD, Grant DM (2000) Valaciclovir prophylaxis of cytomegalovirus infection and disease in renal transplantation: an economic evaluation. Transplantation 70:1463–1468PubMedGoogle Scholar
- 95.Mauskopf JA, Richter A, Annemans L, Maclaine G (2000) Cost-effectiveness model of cytomegalovirus management strategies in renal transplantation. Comparing valaciclovir prophylaxis with current practice. Pharmacoeconomics 18:239–251PubMedGoogle Scholar
- 96.Boeckh M, Geballe AP (2011) Cytomegalovirus: pathogen, paradigm, and puzzle. J Clin Invest 121:1673–1680PubMedCentralPubMedGoogle Scholar
- 97.Kowalsky S, Arnon R, Posada R (2013) Prevention of cytomegalovirus following solid organ transplantation: a literature review. Pediatr Transplant 17:499–509PubMedGoogle Scholar
- 98.Eid AJ, Razonable RR (2010) New developments in the management of cytomegalovirus infection after solid organ transplantation. Drugs 70:965–981PubMedGoogle Scholar
- 99.Ljungman P, Hakki M, Boeckh M (2011) Cytomegalovirus in hematopoietic stem cell transplant recipients. Hematol Oncol Clin North Am 25:151–169PubMedCentralPubMedGoogle Scholar
- 100.Boeckh M, Bowden R (1995) Cytomegalovirus infection in marrow transplantation. Cancer Treat Res 76:97–136PubMedGoogle Scholar
- 101.Boeckh M, Leisenring W, Riddell SR, Bowden RA, Huang ML, Myerson D, Stevens-Ayers T, Flowers ME, Cunningham T, Corey L (2003) Late cytomegalovirus disease and mortality in recipients of allogeneic hematopoietic stem cell transplants: importance of viral load and T-cell immunity. Blood 101:407–414PubMedGoogle Scholar
- 102.Boeckh M, Nichols WG, Papanicolaou G, Rubin R, Wingard JR, Zaia J (2003) Cytomegalovirus in hematopoietic stem cell transplant recipients: current status, known challenges, and future strategies. Biol Blood Marrow Transplant 9:543–558PubMedGoogle Scholar
- 103.Ljungman P (1996) Cytomegalovirus infections in transplant patients. Scand J Infect Dis Suppl 100:59–63PubMedGoogle Scholar
- 104.Hebart H, Kanz L, Jahn G, Einsele H (1998) Management of cytomegalovirus infection after solid-organ or stem-cell transplantation. Current guidelines and future prospects. Drugs 55:59–72PubMedGoogle Scholar
- 105.Prentice HG, Kho P (1997) Clinical strategies for the management of cytomegalovirus infection and disease in allogeneic bone marrow transplant. Bone Marrow Transplant 19:135–142PubMedGoogle Scholar
- 106.Akalin E, Sehgal V, Ames S, Hossain S, Daly L, Barbara M, Bromberg JS (2003) Cytomegalovirus disease in high-risk transplant recipients despite ganciclovir or valganciclovir prophylaxis. Am J Transplant 3:731–735PubMedGoogle Scholar
- 107.Limaye AP, Bakthavatsalam R, Kim HW, Kuhr CS, Halldorson JB, Healey PJ, Boeckh M (2004) Late-onset cytomegalovirus disease in liver transplant recipients despite antiviral prophylaxis. Transplantation 78:1390–1396PubMedGoogle Scholar
- 108.Razonable RR, Rivero A, Rodriguez A, Wilson J, Daniels J, Jenkins G, Larson T, Hellinger WC, Spivey JR, Paya CV (2001) Allograft rejection predicts the occurrence of late-onset cytomegalovirus (CMV) disease among CMV-mismatched solid organ transplant patients receiving prophylaxis with oral ganciclovir. J Infect Dis 184:1461–1464PubMedGoogle Scholar
- 109.Barry PA, Pratt-Lowe E, Peterlin BM, Luciw PA (1990) Cytomegalovirus activates transcription directed by the long terminal repeat of human immunodeficiency virus type 1. J Virol 64:2932–2940PubMedCentralPubMedGoogle Scholar
- 110.McKeating JA, Griffiths PD, Weiss RA (1990) HIV susceptibility conferred to human fibroblasts by cytomegalovirus-induced Fc receptor. Nature 343:659–661PubMedGoogle Scholar
- 111.Griffiths PD (2006) CMV as a cofactor enhancing progression of AIDS. J Clin Virol 35:489–492PubMedGoogle Scholar
- 112.Ostrowski MA, Krakauer DC, Li Y, Justement SJ, Learn G, Ehler LA, Stanley SK, Nowak M, Fauci AS (1998) Effect of immune activation on the dynamics of human immunodeficiency virus replication and on the distribution of viral quasispecies. J Virol 72:7772–7784PubMedCentralPubMedGoogle Scholar
- 113.Gallant JE, Moore RD, Richman DD, Keruly J, Chaisson RE (1992) Incidence and natural history of cytomegalovirus disease in patients with advanced human immunodeficiency virus disease treated with zidovudine. The Zidovudine Epidemiology Study Group. J Infect Dis 166:1223–1227PubMedGoogle Scholar
- 114.Cheung TW, Teich SA (1999) Cytomegalovirus infection in patients with HIV infection. Mt Sinai J Med 66:113–124PubMedGoogle Scholar
- 115.Deayton J, Mocroft A, Wilson P, Emery VC, Johnson MA, Griffiths PD (1999) Loss of cytomegalovirus (CMV) viraemia following highly active antiretroviral therapy in the absence of specific anti-CMV therapy. AIDS 13:1203–1206PubMedGoogle Scholar
- 116.O’Sullivan CE, Drew WL, McMullen DJ, Miner R, Lee JY, Kaslow RA, Lazar JG, Saag MS (1999) Decrease of cytomegalovirus replication in human immunodeficiency virus infected-patients after treatment with highly active antiretroviral therapy. J Infect Dis 180: 847–849PubMedGoogle Scholar
- 117.Jacobson MA, Schrier R, McCune JM, Torriani FJ, Holland GN, O’Donnell JJ, Freeman WR, Bredt BM (2001) Cytomegalovirus (CMV)-specific CD4+ T lymphocyte immune function in long-term survivors of AIDS-related CMV end-organ disease who are receiving potent antiretroviral therapy. J Infect Dis 183:1399–1404PubMedGoogle Scholar
- 118.Spector SA, Hsia K, Crager M, Pilcher M, Cabral S, Stempien MJ (1999) Cytomegalovirus (CMV) DNA load is an independent predictor of CMV disease and survival in advanced AIDS. J Virol 73:7027–7030PubMedCentralPubMedGoogle Scholar
- 119.Deayton JR, Sabin CA, Johnson MA, Emery VC, Wilson P, Griffiths PD (2004) Importance of cytomegalovirus viraemia in risk of disease progression and death in HIV-infected patients receiving highly active antiretroviral therapy. Lancet 363:2116–2121PubMedGoogle Scholar
- 120.Dock JN, Effros RB (2011) Role of CD8 T cell replicative senescence in human aging and in HIV-mediated immunosenescence. Aging Dis 2:382–397PubMedCentralPubMedGoogle Scholar