REVIEWS OF INFECTIOUS DISEASES • VOL. 12, SUPPLEMENT 7 • SEPTEMBER-OCTOBER 1990 © 1990 by The University of Chicago. All rights reserved. 0162-0886/90/1205-0041$02.00

Cytomegalovirus: Where Have We Been and Where Are We Going? Thomas C. Merigan and SDvia Resta

From the Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine, Stanford, California

In the 3 decades since Rowe, Weller, and colleagues discovered human cytomegalovirus (CMV) [1, 2], we have learned much about the virus and the disease it causes. As the replication cycleof CMV is lengthy and virus yields are low, its isolation and characterization have always been difficult. CMV is the major cause of mental retardation and congenital deafness due to infection and also is responsible for a great deal of focal disease in the immunosuppressed. We know that the virus spreads by close contact with infected secretions or by the introduction of infected blood or organs into the host. CMV originally was classified as a herpesvirus on the basis of morphologic and biochemical criteria, a classification verified by current molecular biologic and virologic analyses. It has been suggested that CMV might playa fundamental role in the pathology of atherosclerosis, tumors, or produce general systemic effects such as wasting in patients with AIDS. These are some of the issues that we must consider in the next decade of research on human CMV. My presentation will focus on each issue to be discussed in this symposium from the standpoint of the most important advances and the unsolved problems. Please address requests for reprints to Dr. Thomas C. Merigan, Division of Infectious Diseases, Department of Me.dicin~ Stanford University School of Medicine, Stanford, California 94305.

Epidemiology of CMV Studies of the epidemiology of CMV in schools and day care centers as well as in families have demonstrated that close contact is required for the spread of CMV [3, 4]. The persistent and recurrent shedding of the virus in both oral and genital secretions permits it to spread from either of these sites by sexual and nonsexual means to produce primary infection or reinfection. Serologic evidence of CMV infection in humans is more likely to be present as age increases. In the absence of immunosuppression, infections are usually asymptomatic [5]. Studies in the newborn nursery show that infected infants do not necessarily represent a danger to the seronegative care giver, who can take appropriate hygienic measures (e.g., hand washing)to avoid infection. Yet, these infants do serve as a source of infection for their seronegative cohorts, indicating that intimate contact is important for the spread of virus [6, 7]. During the last 2 decades, organ transplantation has provided the setting in which to study the spread of CMV as wellas the type of iatrogenic immunosuppression that potentiates CMV-related diseases [8]. We have learned that not only blood but also kidney, heart, liver, and bone marrow can be reservoirs of the infection. The critical epidemiologic questions that remain are how close the contact must be for CMV to spread


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Nearly 30 years have elapsed since Rowe and Weller and their colleague~ di~covered human cytomegalovirus (CMV). Because of its complex structure, long replicative cycle,low yield in vitro, and highly species-specific cell-substrate requiremen~, the cellular and molecular biologic analyses of human CMV have been slow,but recombinant DNA and mo?oclonal antibody technologies are bringing about rapid changes. Because of the long penod of latency and wide range of disease presentations, epidemiologic and medical insights have also come slowly. However,the clinical events that occur during iatrogenic immunosuppression (transplantation and cancer therapy) and as a result of im~unocompromise~ue to human immunodeficiency virus infection are currently promoting our understandl~g of the epidemiology of CMV disease and the definition of its clinical .spectr~m. Rapid diagnostic methods, antiviral drugs, and vaccines for CMV are becoming available. We may not yet understand completely the impact of this agent on the nonimmunosuppressed or aspects of its pathogenesis: e.g., the immune functions controlling rec.rudescence and the possibility of increased disease severity in those with no dete:t~ble Immune defect. With the availability of new approaches, other issues should be clarified, such as the functions of host and virus involved in the mechanism of persistence.


by nonsexual means and how epidemiologic insights can be used in specifically targeting future vaccine preparations. Virology and Pathogenesis

in immunosuppressed patients, observations that seem to indicate a lifelong latency of the virus after initial infection [23,24]. Because blood transfusions as well as transplanted organs have the potential for spreading the virus, we believe that latent virus is maintained within blood cells [25]. Until recently, the site of latency was thought to be lymphocytes and monocytes, It now appears that, during or after symptomatic infection, scavenger polymorphonuclear cells can ingest virus from infected sites and then recirculate to become another potentially important source of virus in transfused blood [26-31]. CMV messenger RNAs have also been detected in lymphocytesfrom both seropositive and symptomatic individuals. Although attempts are made to remove much of the blood from transplanted organs, it is possible that these cells are present within tissues and are important in transplant-related infection. Among the host defense mechanisms against CMV are specific humoral and cellular immune responses as well as nonspecific responses [32,33]. Evidence of the importance of natural killer cells, macrophages, and interferon-a in animal and human CMV infection has been found and a correlation established between an effective cellular immune response and the recovery phase of CMV disease [32-37]. In addition, in the murine CMV model, T lymphocytes specific for immediate early proteins can limit the replication of the virus and the tissue damage that occurs as a consequence of infection; moreover, evidence has been produced that murine CMV is under the control of genes of the H-2 complex of the mouse; Clinical studies also have suggested a role for HLA in modulation of the response to human CMV [33, 38, 39]. Humoral immunity has provided the best evidence .of prior infection and, hence, the ability to transmit infection. There is some evidence that passive administration of antibodies modifies or possibly prevents disease in both mice and humans. Neutralizing antibodies are directed against glycoproteins in the 86-kDa and 55-kDa classes [40-42]. IgM antibodies detected by ELISA occur not only with acute initial infection but also with recrudescent episodes, especially with symptomatic disease. However, patients with AIDS may lack the ability to produce an IgM response to CMV during the disease, inasmuch as they can fail to respond serologically to other infections such as toxoplasmosis. Among the cellular immune responses, the most important appear to be those of cytotoxic T cells,

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CMV is similar to the other herpesviruses, down to the level of a significant relatedness in the DNA sequences controlling some proteins, such as glycoprotein B and glycoprotein H [9]. The replication of CMV occurs in a temporally regulated fashion, with the immediate early (a) genes regulating the subsequent transcription and translation of the early (13) and late (y) gene products [10, 11]. CMV has a complex double-stranded DNA helical core that is coated with matrix protein and enclosed by a lipid bilayer envelope containing peplomers. The whole virion has a final diameter of 1'\J180 nm. The nucleic acid-deficient dense bodies (a transitional, noninfectious form of the virus) are enveloped and contain the glycoproteins as wellas the matrix protein [12]. The nucleus of the infected cell hosts the production of the CMV nucleocapsids, whereas the CMV envelope is eventually derived from the internal nuclear membrane [13] and/or the endoplasmic reticulum [14]. From the immunologic standpoint, the envelope components, which are mainly glycoproteins, are of importance since they stimulate critical antibody responses and the specific cellular immunity developed by infected individuals [15-19]. It is of interest that it has been convincinglydemonstrated that in the murine model of CMV the immediate early gene products are recognized by specific cytotoxic T cells [20, 21]. The double-stranded DNA is synthesized by a rolling-circle form of replication that uses a viruscoded DNA polymerase. As with other herpesviruses, in CMV the unique sequences are contained in two portions of the genome, termed long and short, each of which can be inverted relative to the other. Hence, four possible isomers are found in equimolar amounts in virus passaged in cell culture. Inverted repeat sequences are found at the ends of the unique regions. The locations of some of the proteins and glycoproteins have been mapped on the genome, which is one of the largest DNA structures (l55,OOO kDa) undergoing complete sequencing [22]. Titers of CMV antibody persist for life. Asymptomatic shedding of virus occurs in normal individuals, and symptomatic recurrent infections are common

Merigan and Resta

Cytomegalovirus: History and Future

Transplantation and CMV Infection With the enormous increase in the application of transplantation techniques that has occurred in the last 2 decades, we have learned much more about how CMV can be transmitted and what clinical syndromes it can cause during iatrogenic immunosuppression. In the first 3-4 months after transplantation, CMV infection syndromes such as mononucleosis, unexplained leukopenia, pneumonia, and/or (rarely) hepatitis can occur, or later CMV infection can manifest itself in the form of retinitis or (uncommonly) encephalitis [14]. All of these manifestations occur only with exogenous immunosuppression, particularly with the administration of antilymphocyte globulin [52, 53]. They are never observed in organ transplantation between identical twins, which does not require immunosuppression for graft maintenance. Fever and pneumonia can occur before spe-

cific antibodies or even virus shedding is detectable. Of course, virus can be recovered from organs such as the lungs while other agents, such as fungi or bacteria, are responsible for most of the pathology in pneumonia. Hence, invasive biopsy procedures may be necessary to establish a precise diagnosis and often are required as part of effective chemotherapy. To prevent infected organs from transmitting disease, it has become common practice in the case of kidney transplants to match donor and recipient for CMV status. In certain settings, reactivation and reinfection are indistinguishable from primary manifestations. Onehalf of transplant recipients will develop active CMV infection after transplantation. Fortunately, for renal transplant recipients the chance of developing symptomatic disease decreases 3-4 months after transplantation, when the dosage of exogenous immunosuppressive agents is decreased [54]. In bone marrow transplantation, the major problems are encountered during the first 40 days after transplantation, before the graft begins to develop normal immune function. Heart transplant recipients, who are more intensively immunosuppressed than kidney transplant recipients, have greater difficulty with CMV complications. However, in these patients the incidence of CMV disease decreases a few months after transplantation and the period of heaviest exogenous immunosuppression [55-59]. Among the problems remaining is the need for better diagnostic criteria for CMV pneumonia, encephalitis, and the early leukopenic syndrome, and several major questions remain. Does this virus playa central role in triggering rejection, or is it simply activated as a sequela of therapy for rejection? Also, what is the role of CMV in reducing the host's resistance to bacterial and fungal infections? Such superinfections are a major problem in transplantation, and, for heart transplant recipients, can lead to a significantly greater likelihood of death in the first year after surgery for seronegative recipients of hearts from seropositive donors. Perinatal CMV Now that congenital rubella and other diseases have been brought under control by vaccination, CMV is clearly the major cause of infectious mental retardation and deafness. Every year in the United States, 1'\.15,000 infants are born who are handicapped as a result of CMV infection [60]. Evidence indicates

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which seem to be of both the class I and class II human lymphocyte antigen (HLA)-restricted phenotypes [34, 35, 45, 46]. A relationship between cytotoxic cell activity against CMV in vitro and protection against infection in vivo has been observed in renal and bone marrow transplant recipients [47,48]. With the availability of vaccinia vectors that carry CMV proteins, we may now be able to measure these responses more easily in monocytes or cultured skin cells during disease to see if the prognostic implication of the presence of such HLA-restricted antiCMV T cells holds up. The postulated methods by which CMV evades host defenses include the induction of Fc receptors' and the binding of ~ rmicroglobulin by CMV-infected cells for protection against humoral immune responses [5, 49, 50]. Potentially very important to the pathologic effects of this virus is its ability to suppress immunity and potentiate injury by other infectious agents. In addition, there is some evidence that autoimmune responses can be important in the pathology of human C~V, especially in recipients of bone marrow and renal transplants. Many important questions remain regarding the virology and pathogenesis of CMV. For example, does the lymphoreticular tropism of human CMV lead to its persistence in vivo? What cells are critical to the latency of CMV in vivo? What mechanismsvirus- and host-related - are involved in disruption of latency in vivo? How does the HLA system relate to persistence of the virus?


Merigan and Resta


AIDS and CMV Infection Virtually all homosexual men, especially those with multiple sexual partners, are exposed to CMV [65]. Because of the immunosuppression caused by human immunodeficiency virus (HIV), all the disease manifestations caused by CMV can occur in this setting [66-69]. In addition, viremia is noted in many of the patients, and at autopsy many have evidence of CMV disease [70]. The most common clinical manifestations of CMV in the HIV-infected patients are episodes of severe colitis and progressive retinitis. Both occur as near-terminal events, and colitis often occurs in response to other gastrointestinal pathogens. The high frequency of these two complications in homosexual men results in better and more rapid diagnosis. Early diagnosis of colitis in homosexual men enables evaluation for drug prophylaxis [71].

Pneumocystis is the usual pulmonary pathogen in patients with AIDS; CMV appears to be only a passenger but could be important in further compromising local host defenses in lung tissue, as well as systemic defenses. The catabolic state in the patient with AIDS can be reversed by therapy for CMV, a response that suggests infection with CMV contributes more to the pathology of AIDS than just the specific focal pathologies discussed above. Two major questions remain in regard to AIDS and CMV. What are the specific immune dysfunctions caused by HIV that lead to severe systemic and local CMV pathology? Does CMV infection accelerate the pathologic outcome of HIV infection? Diagnostic Issues ELISA tests for CMV IgM and IgG are now readily available and are accurate for diagnosis of prior infection or seroconversion. On the other hand, they usually are not done in a way that enables precise assessment of changes in titer. IgG antibodies appear to persist for life, whereas IgM antibodies tend to be associated with acute infection, either primary or recrudescent [33]. Culture of the virus from infected sites, whether biopsy specimens or body fluids such as oral or genital secretions, remains the standard for determining infection. In certain cases, appropriately specific monoclonal or polyclonal antisera directed to late antigens have been shown to detect virus in tissues during infection, or DNA probes have been used to demonstrate infection in cells or virus shedding. However, neither of these techniques has added significantly to our diagnostic acumen [72, 73]. On the other hand, infection can be demonstrated overnight by using monoclonal antibody to early antigens to stain infected cells in tissue culture after virus is centrifuged into cells. This shell vial technique appears to represent a real contribution to our ability to diagnose infection with this virus [74]. A remaining question, however, is how to develop easy and reliable methods for quantitating virus (useful for assessing the response to antiviral agents) and simple methods for measuring drug sensitivity of individual isolates. Control of Infection Two approaches that could ultimately control infection are therapy with antiviral drugs and immunoprophylaxis (or both). The use of antiviral drugs in

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that primary CMV infection during pregnancy is responsible for the more severe intrauterine infections [14, 61-63]. As with other herpesviruses, IgG antibody that crosses the placenta during recrudescent infection may decrease the severity of CMV infection for the fetus. On the other hand, perinatal infection includes any infection acquired during travel down the birth canal, through close postnatal contact with the mother, or from infected breast milk. Because of the immunologic immaturity of the host, the virus can cause virtually all the organ pathologies seen during CMV infection in transplant recipients and patients with AIDS, including encephalitis and retinitis; bone marrow, liver, lung, and heart involvement; and adrenalitis. The sequelae of infection of the CNS that are of the greatest importance later in life are among the most difficult to assess in the early postnatal period. Information from animal models, as well as from observations of humans, has suggested that macrophage and lymphoid functions in the infected newborns are affected [64]. Understanding the nature of such impairment could be very useful in determining strategies for the control of the sequelae of CMV infections. One preventive strategy now being employed in the newborn nursery is the use of CMV-seronegative blood. 'Questions about prenatal CMV infections remain concerning (1) how the virus reaches the fetus, (2) the sequelae of infection, and (3) the nature of the impairment in host defenses critical to explaining how the virus causes the pathology observed in infants and children.

Cytomegalovirus: History and Future

decreasing virus shedding. However, the data that indicate it can prevent progression of clinical disease are not as extensive as those for ganciclovir [82]. The primary limiting adverse effect of foscarnet is nephrotoxicity, and because the drug is incorporated into the bone, it is not clear what the long-term consequences of continuing therapy will be. Still, it is the best agent available for treatment of ganciclovirresistant CMV infections. Although the activity of these two drugs clearly indicates that intervention against human CMV infection is possible, one question remains: can we find safer, better targeted, and therefore more effective agents? Prophylaxis Both immune globulin and human leukocyte interferon have been used to delay the onset of CMV excretion and decrease the frequency of CMV disease and superinfection with other, nonviral pathogens. Acyclovir also appears to be sufficiently active against CMV to have some effect on virus isolation in recipients of bone marrow transplants who are treated during the first few weeks after transplantation. Administration of immune globulin appears to limit serious CMV disease without having an impact on acute infection in both bone marrow and renal transplant recipients [83-85]. The Food and Drug Administration has recently licensed immune globulins for use in the prevention of CMV disease in renal transplant recipients. Possibly, pooled monoclonal antibodies to the major epitopes of the surface glycoproteins of CMV will prove clinically useful and reproducibly prevent disease.

Vaccines Attenuated vaccines have been developed and given to small numbers of healthy volunteers as well as to renal transplant recipients [86]. Though protection is not complete, such vaccines may have some impact on the severity of symptomatic illness. However, larger-scale trials are required for confirmation of this point. A major question for the long term is whether the vaccine strains will recrudesce and cause disease under the conditions associated with unforeseen immunosuppressive sequelae. Thus far, such vaccines have not been evaluated for the major target population - seronegative women. New technologic advances, specifically the development of monoclonal antibodies and molecular DNA cloning techniques, have made the glycopro-

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CMV infection has been under investigation for some years. In the past, agents such as adenine arabinoside, interferon-a, acyclovir, CMV immune globulin, and transfer factor have been investigated [75]. No consistent evidence of an effect on virus shedding or improvement in disease has been noted with these agents. Only recently have two active agents for therapeutic use against human CMV been developed. Ganciclovir, a close relative of acyclovir, appears to act against CMV in humans, with a consistent impact on virus shedding. The effectiveness of the drug against CMV disease appears to be related to the time of initiation of therapy and particularly to the extent of tissue involvement [76-78]. If the extent of involvement is only modest - for example, in minimal or peripheral retinitis - spread to other sites is prevented by drug therapy, although this has not yet been shown in placebo-controlled, randomized, double-blind trials [79, 80]. Such trials of ganciclovir are under way to evaluate its efficacy for CMV colitis in AIDS patients and as prophylaxis against the development of CMV pneumonia in heart and bone marrow transplant recipients [81]. The demonstration of such effects with either prophylaxis or early therapy will be useful in obtaining licensing for the drug in such applications. At present, however, clinicians are relying on the use of the drug for serious CMV infections because of the apparent demonstration of some efficacy in open trials. Granulocytopenia is a major limiting toxic effect of therapy, but bone marrow suppression generally seems to clear after cessation of therapy. The course of therapy is 2 weeks, with repeat treatment necessary for maintenance of effects, especially in patients whose underlying immunosuppression does not reverse, such as AIDS patients. Recent data suggest that this drug cannot be given with zidovudine because the toxic effects of the two drugs overlap. In addition, clinically significant drug-resistant thymidine kinase mutant strains are being reported with prolonged therapy; hence, alternative therapy must be developed. Interestingly, administration of high-titer anti-CMV immune globulin in combination with ganciclovir is emerging as the first therapy that may improve mortality in bone marrow transplant recipients with CMV pneumonia. However, with this agent carcinogenicity and toxic effects on the gonads and the embryo must be considered as long-term consequences. Foscarnet (phosphonoformic acid) also is active against CMV infection in humans, consistently



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RJ. Cytopathogenic agent resembling human salivary gland virus recovered from tissue cultures of human adenoids. Proc Soc Exp Bioi Med 1956;92:418-24 Weller TH. Serial propagation of agents producing inclusion bodies derived from varicella and herpes zoster. Proc Soc Exp Bioi Med 1953;83:340-6 Pass RF, Hutto C, Ricks R, Cloud GA. Increased rate of cytomegalovirus infection amongst parents of children attending day-care centers. N Engl J Med 1986;314:1414-8 YowMO, White NH, Taber LH, Frank AL, Gruber WC, May RA, Norton HJ. Acquisition of cytomegalovirus infection from birth to 10 years: a longitudinal serologic study. J Pediatr 1987;110:37-42 Griffiths PO, Grundy JE. The status of CMV as a human pathogen. Epidemiol Infect 1988;100:1-15 Onorato 1M, Morens OM, Martone WJ, Stansfield SK. Epidemiology of cytomegaloviral infections: recommendations for prevention and control. Rev Infect Dis 1985; 7:479-97 Walmus BF, Yow MO, Lester JW, Leeds L, Thompson PK, Woodward RM. Factors predictive of cytomegalovirus im-

mune status in pregnant women. J Infect Dis 1988;157: 172-7 8. Chou S. Acquisition of donor strains of cytomegalovirus by renal transplant recipients. N Engl J Med 1986;314:1418-23 9. Griffiths PD, Grundy JE. Molecular biology and immunology of cytomegalovirus. Biochem J 1987;241:313-24 10. Stinski MF. The proteins of human cytomegalovirus. Birth Defects 1984;20:49-62 11. Landini M-P, Michelson S. Human cytomegalovirus proteins. Prog Med Virol 1988;35:152-85 12. Smith JD, DeHarven E. Herpes simplex virus and human cytomegalovirus replication in WI-38 cells. I. Sequence of viral replication. J Virol 1973;12:919-30 13. Severi B, Landini M, Musiani M, Zerbini M. A study of the passage of cytomegalovirus from the nucleus to the cytoplasm. Microbiologia 1979;2:265-73 14. Ho M. Cytomegalovirus: biology and infection. In: Greenough WB, Merigan TC, eds. Current topics in infectious diseases. New York: Plenum, 1982 15. Farrar GH, Oram JD. Characterization of the human cytomegalovirus envelope glycoproteins, J Gen ViroI1984;65: 1991-2001 16. Mach M, Utz U, Fleckenstein B. Mapping of the major glycoprotein gene of human cytomegalovirus. J Gen Virol 1986;67:1461-7 17. Pereira L, Hoffman M, Tatsuno M, Dondero D. Polymorphism of human cytomegalovirus glycoproteins characterized by monoclonal antibodies. Virology 1984;139:73-86 18. Stinski MF. Human cytomegalovirus: glycoproteins associated with virions and dense bodies. J Virol 1976;19:594-609 19. Gibson W. Protein counterparts of human and simian cytomegaloviruses. Virology 1983;128:391-406 20. Koszinowski UH, Keil GM, Schwarz H, Schickedanz J, Reddehase MJ. A nonstructural polypeptide encoded by immediate-early transcription unit 1 of murine cytomegalovirus is recognized by cytolytic T lymphocytes. J Exp Med 1987; 166:289-99 21. Koszinowski UH, Reddehase MJ, Keil GM, Schickedanz J. Host immune response to cytomegalovirus: products of transfected viral immediate-early genes are recognized by cloned cytolytic T lymphocytes. J Virol 1987;61:2054-8 22. Somogyi T, Colimon R, Michelson S. An illustrated guide to the structure of the human cytomegalovirus genome and a review of transcription data. Prog Med ViroI1986;33: 99-133 23. Sissons JG. The immunology of cytomegalovirus infection. J R Coli Physicians Lond 1986;20:40-4 24. Pass RF, Griffiths PD, August AM. Antibody response to cytomegalovirus after renal transplantation: comparison of patients with primary and recurrent infections. J Infect Dis 1983;147:40-6 25. Spector SA, Rua JA, Spector DH, McMillan R. Detection of human cytomegalovirus in clinical specimens by DNADNA hybridization. J Infect Dis 1984;150:121-6 26. Chou S, Kim DY, Norman OJ. Transmission of cytomegalovirus by pretransplant leukocyte transfusions in renal transplant candidates. J Infect Dis 1987;155:565-7 27. Preiksaitis JK, Brown L, McKenzie M. The risk of cytomegalovirus infection in seronegative transfusion recipients not receiving exogenous immunosuppression. J Infect Dis 1988;157:523-9

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teins of the virus available and immunization with subunits a possibility [33, 87-90]. It seems likely that as we learn more about the immune mechanisms involved in control of the virus and the structure of the virus, it will become possible to induce protection with inactivated, recombinant DNA-produced vaccines. Such immunity, if produced during phases of nonimmunosuppression, should be able to prevent disease as well as the antibody preparations that are currently available. However, studies with this virus may be limited by the inability of normal or vaccineinduced immunity to protect against repeated infections, albeit ones that may be less severe. Only time will tell whether we can learn enough about immunity to be able to consistently manipulate the host and provide adequate resistance to infection with immunoprophylaxis. Other major questions about the prevention of CMV disease remain unanswered: Can a method of eradicating virus at the molecular levelbe developed? How much better will prophylactic therapy with antiviral agents be than early treatment? Will vaccines ever be highly protective against infection and disease? What biologic properties of antisera mediate their protective action? Overall, much work on CMV remains to be done. However, progress has clearly been made, and with the new tools now available, we can predict that we will make progress at a faster pace than ever before.

Merigan and Resta

Cytomegalovirus: History and Future

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Cytomegalovirus: where have we been and where are we going?

Nearly 30 years have elapsed since Rowe and Weller and their colleagues discovered human cytomegalovirus (CMV). Because of its complex structure, long...
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