ANNUAL REVIEWS
Annu. Rev. Med. 1990. 41:331-38 Copyright © 1990 by Annual Reviews Inc. All rights reserved
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Annu. Rev. Med. 1990.41:331-338. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
IMMUNE SUPPRESSION BY HERPESVIRUSES Charles R. Rinaldo, Jr., Ph.D. Department of Pathology, School of Medicine, and Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 1526 1 KEY WORDS:
cytomegalovirus,
Epstein-Barr
virus,
organ
transplantation,
human immunodeficiency virus, AIDS.
ABSTRACT A unifying theme among the herpesviruses is the intimate interrelationship of virus infection with host cellular immune competence. Herpesviruses suppress cellular immunity. Recent advances suggest mechanisms of herpesvirus-induced immunosuppression that include inhibition of cyto kine production and direct interaction of virus with major histocompati bility complex (MHC) components. This suppression appears to be of clini cal significance primarily in patients with underlying immune deficiencies.
INTRODUCTION
Herpesviruses are highly efficient opportunistic agents that normally are controlled by the host immune system. Most primary, acute infections with herpesviruses are self-limiting, with the virus remaining in a latent form in the host. If cellular immune responses are depressed by natural or iatrogenic factors, the virus can be reactivated. Both primary and reactivated infections can be life-threatening if the host is severely immunosuppressed, as in organ transplant recipients and persons with the acquired immune deficiency syndrome (AIDS). Understanding the nature of herpesvirus-host interactions will allow development of rational approaches to management of infected patients. This is made difficult, however, by the fact that herpesviruses themselves 331 0066--42 1 9/90/0401-0331$02.00
332
RINALDO
are immunosuppressive, thereby compounding the insult to the immune system. This review focuses on the latter property of the herpesviruses.
Annu. Rev. Med. 1990.41:331-338. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
CYTOMEGALOVIRUS
Of the six human herpesviruses, cytomegalovirus (CMV; human herpes virus 5) is by far the one most commonly associated with significant immunosuppression (l). CMV is frequently acquired early in age. Primary infection with CMV is predominantly asymptomatic, although individuals can undergo symptomatic illness, e.g. mononucleosis. After primary infec tion, virus can be excreted for extensive periods in the throat, urine, and semen before entering a latent, quiescent state. Actively infected, clinically ill individuals can undergo a prolonged depression in peripheral blood lymphocyte blastogenesis and gamma interferon production in response to in vitro treatment with certain mitogens, CMV antigen, and other viral antigens. In contrast, natural killer (NK) cell and humoral antibody responses appear relatively normal (2-4). Cellular immunity increases in association with resolution of symptoms and cessation of viral excretion. The mechanisms of CMV immunosuppression are as yet unclear. Only a small percentage of peripheral blood mononuclear cells appear to be infected with the virus, and such infection is abortive (5). Indeed, virus is most readily isolated from polymorphonuclear leukocytes (3) even though these cells do not fully replicate CMV or exhibit functional abnormalities. Hence it is unlikely that inhibition of cellular immunity in vivo is primarily a result of direct infection of immune effector cells with CMV. CD8+ T lymphocytes have been linked to CMV immunosuppression by the striking, protracted increase in their numbers noted in the peripheral blood of CMV mononucleosis patients (4). Furthermore, loss of cells expressing CD8 during in vitro culture is associated with recovery of T cell blastogenic responses to certain mitogens. It should be noted that these CD8+ cells may also be functioning as cytotoxic effectors in the host response against CMV. Monocytes appear to be more closely rclated to suppression of T lymphocyte responses during clinical CMV infection, in that they depress mitogen-induced blastogenesis in mononucleosis patients (6). Moreover, in vitro infection of blood monocytes with CMV, particularly low-passage isolates, can inhibit lymphocyte blastogenesis to mitogens (7). These inhibi tory effects may be due to decreased production of interleukin 1 by monocytes and interleukin 2 by T lymphocytes (8). In spite of the well-documented, relatively profound immunosuppressive effects noted during primary CMV infection, there is little evidence of enhanced susceptibility to secondary, opportunistic agents in these
Annu. Rev. Med. 1990.41:331-338. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
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333
patients. Thus, in the normal adult host, selective inhibition of T-lym phocyte responses during active CMV infection may be compensated by humoral and cellular responses that remain relatively intact (e.g. neu tralizing antibodies, NK and polymorphonuclear cell functions). These may be sufficient to prevent superinfections. The immunosuppressive effects of CMV infection have more significant impact on host antimicrobial resistance in persons who already have under lying immunodeficiencies. In particular, CMV-infected organ transplant recipients have immune deficits similar to CMV mononucleosis patients, with lower lymphocyte blastogenesis and interferon production (9) and elevated numbers of CD8+ T lymphocytes (10). However, CMV infection in transplant recipients can be followed by serious, secondary bacterial and fungal diseases. The immunosuppressive effects of CMV and their secondary clinical complications appear to be greater after primary as compared with reactivated infection (9), and in transplant recipients receiv ing antithymocyte globulin (11) and anti-T-cell monoclonal antibody (12). Cytotoxic T lymphocytes and NK cells have been implicated in resolution of CMV infection in transplant recipients ( l3 ). Clinical obser vations and data from animal experiments suggest that CMV pneumonitis in transplant recipients may actually be caused by cytotoxic immune reac tivity in the lung, rather than by CMV itself (14). Indeed, recent evidence has shown a homology between CMV and MHC Class I DNA (15). This may be the basis for the observed binding of CMV to beta-2-microglobulin (16) and could be of importance in disruption of immunity during CMV infection. The complexity of CMV-host immune interactions is further exemplified in persons with human immunodeficiency virus (HIV) infection (17). The majority of adults at risk for HIV infection are already latently infected with CMV. After infection with HIV, the herpesvirus is excreted at high frequency in semen of asymptomatic homosexual men. Levels of serum IgG antibodies specific for CMV are also elevated during HIV infection, particularly in homosexual men with increased risk for development of AIDS. Active CMV infection is more frequent in relation to advanced clinical disease, as CMV is the most common opportunistic viral pathogen in AIDS patients. Lymphocyte blastogenesis and gamma-interferon production in response to CMV antigen are depressed within the first few years of HIV infection in homosexual men (17, 18). Anti-CMV cytotoxic reactivity is also decreased during HIV infection (19). Such immunosuppression in HIV-infected individuals may be further complicated by the suppressive effects of CMV that occur after activation of the herpesvirus. It is not yet clear, however, whether active CMV infection is merely a marker of HIV-
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induced immunosuppression, or if it is actually a cofactor in the pro gression to AIDS. Based on the significant immunopathogenic effects of CMV, treatment of CMV infection with new generation antiviral drugs such as ganciclovir is likely to become a routine practice in transplant recipients as well as in AIDS patients. This will coincide with an emerging, new era in clinical virology that includes more timely diagnosis of CMV infection and testing for resistance of CMV isolates to antiviral drugs. EPSTEIN-BARR VIRUS
Primary Epstein-Barr virus (EBV; human herpesvirus 4) infection is predominantly asymptomatic and acquired at an early age (20). The herpesvirus establishes latent infection in a small percentage of B lympho cytes and can be reactivated during immunosuppressive conditions. The immunosuppressive effects of EBV are evident in adults with acute mononucleosis and are similar in nature to those of CMV: depression in lymphocyte responses to mitogens and nominal antigens, with a relatively intact humoral antibody response. EBV-induced immunosup pression is usually less severe and less prolonged than that caused by CMV, which correlates with the relatively milder clinical syndrome of EBV mononucleosis. Numbers of CD8+ cells are increased severalfold in peripheral blood of patients with EBV mononucleosis. In vitro infection of normal lym phocytes with EBV can enhance CD8+ suppressor cell inhibition of mitogen and antigen-specific T-cell responses (21). An IgG factor has been identified in sera of EBV mononucleosis patients that binds to T lymphocytes and inhibits their function (22). As in CMV mononucleosis, EBV-induced immunosuppression in mononucleosis patients has not been directly related to increased incidence of secondary, opportunistic infec tions. Fatal EBV mononucleosis can occur in males with X-linked lympho proliferative syndrome, a rare genetic disorder. This has been associ ated with underlying defects in MHC-restricted, cytotoxic T-cell immunity to EBV (23), although some of these patients have normal anti-EBV cytotoxic responses. It is possible that non-MHC-restricted cytotoxic cells are also important in control of EBV, as has been shown in conventional EBV mononucleosis patients. Organ transplant recipients commonly have primary or reactivated EBV infection. Primary EBV infection has more severe and longer lasting immunosuppressive effects. However, the most striking clinical outcome of loss of cellular immune control of EBV in such immunosuppressed
,
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patients is posttransplantation lymphoproliferative disease, in the form of neoplastic proliferation of EBV-positive lymphocytes (24). During HIV infection, EBV is frequently reactivated, as evidenced by enhanced oropharyngeal excretion and elevated IgG antibody titers to EBV early antigen and viral capsid antigen (25; in preparation). This activation can occur very soon after HIV infection and before serum antibodies to HIV can be detected by conventional assays. Furthermore, EBV-associated lymphomas and oral hairy leukoplakia have been noted in AIDS patients. Whether EBV is a cofactor in HIV infection and pro gression to AIDS is not known. However, in a nested case-control study, we have not found an association of active EBV infection with an accel erated decline in numbers of CD4 + lymphocytes during HIV infection of homosexual men (in preparation). HERPES SIMPLEX VIRUS TYPES 1 AND 2
The severity of infection with herpes simplex viruses 1 and 2 (HSV; human herpesvirus I and 2) is inversely correlated with the competency of the host cellular immune response (26). Serious, sometimes life-threatening primary or recurrent HSV infections can develop in immunocompromised individuals, particularly in transplant recipients and AIDS patients. Stud ies have shown that lymphocyte blastogenesis and cytokine production are diminished during acute HSV infection and after in vitro infection with HSV (27, 28). This suppression has been related to a moderate, variable increase in CD8+ lymphocyte numbers and to a solublc inhibitory factor. However, HSV infection does not in itself appear to commonly result in major impairment of immunity, as CMV and EBV do. VARICELLA-ZOSTER VIRUS
As with the other herpesviruses, the severity of varicella-zoster virus (VZV; human herpesvirus 3) infection is closely associated with the underlying immunocompetence of the host (29). The probability that a person will experience clinical reactivation of VZV increases dramatically with age, possibly linked to age-related decreases in immune function. There is evidence that CD8+ T-Iymphocyte numbers are increased during acute VZV infection (30). However, the immunosuppressive properties of VZV have not been elucidated. HUMAN HERPESVIRUS 6
In 1986 a new human herpesvirus, HHV-6, was identified (31). The virus has significant DNA homology with CMV, but not with EBV, HSV, or
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VZV (32). Serologic studies indicate that initial infection with HHV-6 usually occurs early in life (33). Primary infection with HHV-6 is likely the cause of exanthem subitum (34), a febrile illness of infants. The relation of HHV-6 to immunosuppression has not yet been estab lished. The virus can replicate in and lyse mitogen-activated T lymphocytes (35), similar to HSV. HHV-6 has been identified on occasion in cells bearing B-lymphocyte markers (31). Although the virus has been isolated from HIV-infected patients, the seroprevalence of HHV-6 is similar in HIV-seropositive and -seronegative subjects (36). Therefore, its role in the natural history of HIV infection remains to be determined.
ACKNOWLEDGMENTS
I thank Mr. John Ferbas and Ms. Judy Fossati for assistance in prep aration of the manuscript. Work cited from the author's laboratory was supported in part by Public Health Service grant ROl -AI-162l2 and con tracts NOI-AI-325l 3 and NOl-AT-72632 from the National Institutes of Health and by the Pathology Education and Research Foundation of the University of Pittsburgh.
Literature Cited
I. Griffiths, P. D., Grundy, J. E. 1987.
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Molecular biology and immunology of cytomegalovirus. Biochem. J. 241: 31324 Pass, R. F., Stagno, S. , Britt, W. J., Alford, C. A. 1983. Specific cell mediated immunity and the natural his tory of congenital infection with cyto megalovirus. J. Infect. Dis. 148: 953-61 Rinaldo, C. R. Jr., Carney, W. P. , Richter, B. S., Black, P. H., Hirsch, M. S. 1980. Mechanisms of immuno suppression in c yt omegalov irus mono nucleosis. J. Infect. Dis. 141: 488 95 Rinaldo, C. R. J r. , Ho, M., Hamoudi, W. H., GlIi, X-E., DeBiasio, R. L. 1983. Lymphocyte subsets and natural killer cell responses during cytomegalovirus mononucleosis. Infect. Immun. 40: 47277 Schrier, R. D., Nelson, J. A. , Oldstone, M. B. A. 1985. Detection of human cyto megalovirus in peripheral blood lym phocytes in a natural infection. Science 230: 1048-51 Carney, W. P., Hirsch, M. S. 1981. Mechanisms of immunosuppression in cytomegalovirus
mononucleosis.
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Virus-monocyte interactions. J. Infect. Dis. 144:47-54 7. Kapasi, K., Rice, G. P. A. 1986. Role of the monocyte in cytomegalovirus mcdiatcd immunosuppression in vitro. J. Infect. Dis. 154: 881-84 8. Kapasi, K., Rice, G. P. A. 1988. Cyto
megalovirus infection of peripheral blood mononuclear cells: effects on interleukin-l and -2 production and responsiveness. J. Virol. 62: 3603-7 9. Rinaldo, C. R. Jr., DeBiasio, R. L., Hamoudi, W. II., Rabin, B., Liebert, M., et al. 1986. Effect of herpesvirus infections on T lymphocyte slIbpopula tions and blastogenic responses in renal transplant recipients receiving cyclo sporine. Clin. Immunol. Immunopathol. 38: 357-66 10. Persson, U., Myrenfors, P. , Ringden, 0., Sundberg, B., Larsson, P., et al. 1987. T lymphocyte subpopul ati ons in bone marrow-transplanted patients in rela tion to graft-versus-host disease and cyto megalovirus-induced infection. Trans plantation 43: 663-68 I I. Pass, R. F., Reynolds, D. W., Whelchel,
J. D., Diethelm, A. G., Alford, C. A.
Annu. Rev. Med. 1990.41:331-338. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
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1981. impaired lymphocyte trans formation response to cytomegalovirus and phytohemagglutinin in recipients of renal transplants: association with anti thymocyte globulin. J. Infect. Dis. 143: 259-65 12. Singh, N., Dummer, J. S., Kusne, S., Breinig, M. K., Armstrong, J. A., et aL 1988. Infections with cytomegalovirus and other herpes viruses in 121 liver transplant recipients: transmission by dunated organ and the effect of OKT3 antibodies. J. Infect. Dis. 158: 124 31 13. Rook, A. H., Quinnan, G. V. Jr., Fre derick, W. J. R., Manischewitz, J. F., Kirmani, N., et al. 1984. Importance of cytotoxic lymphocytes during cyto megalovirus infection in renal transplant recipients. Am. J. Med. 76: 385-92 14. Grundy, J. E., Shanley, J. D., Griffiths, P. D. 1987. Is cytomegalovirus inter stitial pneumonitis in transplant recipi ents an immunopathological condition?
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15. Beck, S., Barrell, B. G. 1988. Human cytomegalovirus encodes a glycoprotein homologous to MHC class-I-antigens. Nature 331: 269-72 16. Grundy, J. E., McKeating, J. A., Griffiths, P. D. 1987. Cytomegalovirus strain ADI69 binds fJ2 microglobulin in vitro after release from cells. J. Gen. Virol. 68: 777-84 17. Rinaldo, C. R. Jr. 1989. Cyto megalovirus as a cofactor in HIV infec tion of AIDS: In Cofactors in HIV-J Infection and AIDS, ed. R. R. Watson, pp. 151· 85. Boca Raton, Fla: CRC Press 18. Rinaldo, C. R. Jr., Piazza, P., Wang, Y., Armstrong, J., Gupta, P., et al. 1988. HIV-I specific production of IFN-y and modulation by recombinant IL-2 during early HIV-I infection. J. Immunol. 140: 3389-93 19. Rook, A. H., Manischewitz, J. F., Fre derick, W. R., Epstein, 1. S., Jackson, L., et al. 1985. Deficient HLA-restricted, cytomegalovirus-specific cytotoxic T cells and natural killer cells in patients with the acquired immunodeficiency syndrome. J. Infect. Dis. 152: 627-30 20. Thorley-Lawson, D. A. 1988. Basic viro logical aspects of Epstein-Barr virus infection. Semin. Hematol. 25: 24760 21. Sundar, S. K., Menezes, J. 1987. Epstein-Barr virus immunosuppres sion: II. Generation of nonspecific sup pressor T lymphocytes in vitro. Microb. Pathog. 2: 259-67 22. Sundar, S. K., Stefanescu, I., Menezes, J. 1987. IgG from Epstein-Barr virus infectious mononucleosis patients
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inhibits interleukin-2 production. Int. J. Immunopharmacul. 9: 869-73 Grierson, H., Purtilo, D. T. 1987. Epstein-Barr virus infections in males with the X-linked Iymphoproliferative syndrome. Ann. Intern. Med. 106: 53845 Ho, M., Miller, G., Atchison, R. W., Breinig, M. K., Dummer, J. S., et al. 1985. Epstein-Barr virus infections and DNA hybridization studies in post transplantation lymphoma and Iym phoproliferative lesions: the role of pri mary infection. J. Infect. Dis. 152: 87686 Rahman, A., Kingsley, L. A., Breinig, M. K., Ho, M., Armstrong, J. A., et al. 1989. Enhanced antibody responses to Epstein-Barr virus in HIV-infected homosexual men. J. Infect. Dis. 159: 472-79 Corey, L., Spear, P. G. 1986. Infections with herpes simplex virus. N. Engl. J. Aled. 314: 686-91, 749-57 Sheridan, J. F., Beck, M., Smith, C. c., Aurelian, L. 1987. Reactivation of herpes simplex virus is associated with production of a low molecular weight factor that inhibits Iymphokine activity in vitro. J. Immunol. 138: 1234-39 Wainberg, M. A., Portney, J. D., Clecner, 8., Hubschman, S., Lagace Simard, J., et al. 1985. Viral inhibition of lymphocyte proliferative responsiveness in patients suffering from recurrent lesions caused by herpes simplex virus. J. Infect. Dis. 152: 441-48 Weller, T. H. 1983. Varicella and herpes zoster. Changing concepts of the natural history, control, and importance of a not-so-benign virus. N. Engl. J. Med. 309: 1362-68, 1434-40. Bertotto, A., Gentili, F., Vaccaro, K. 1982. Immunoregulatory T cells in var icella. N. Engl. J. Med. 307: 127 1-72 Salahuddin, S. Z., Ablashi, D. V., Markham, P. D., Josephs, S. F., Stur zenegger, S., et al. 1986. Isolation of a new virus, HBLV, in patients with Iym phoproliferative disorders. Science 234: 596-601 Efstathiou, S., Gompels, U. A., Craxton, M. A., Honess, R. W., Ward, K. 1988. DNA homology between a novel human herpesvirus (HHV-6) and human cytomegalovirus. Lancet I: 6364 Okuno, T., Takahashi, K., Balachandra, K., Shiraki, K., Yamanishi, K., et al. 1989. Seroepidemiology of human herpesvirus 6 infection in normal chil dren and adults. J. Clin. Microbiol. 27: 651-53
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34. Yamanishi, K., Okuno, T., Shiraki, K., Takahashi, M., Kondo, T., et al. 1988. Identification of human herpesvirus-6 as a causal agent for exanthem subitum. Lancet 1: 1065-67 35. Lusso, P . , Markham, P. D., Tschachler, E., diMarzo Veronese, F., Salahuddin, S. Z., eta!. 1988. In vitro cellular tropism
of human B-Iymphotropic virus (human herpesvirus-6). J. Exp. Med. 167: 165970 36. Fox, 1., B riggs, M., Tedder, R. S. 1988. Antibody to human herp esvirus 6 in HIV-l positive and negative homo sexual men. Lancet 2: 396--97
Annu. Rev. Med. 1990. 41:331-38 Copyright © 1990 by Annual Reviews Inc. All rights reserved
Further
Quick links to online content
Annu. Rev. Med. 1990.41:331-338. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
IMMUNE SUPPRESSION BY HERPESVIRUSES Charles R. Rinaldo, Jr., Ph.D. Department of Pathology, School of Medicine, and Department of Infectious Diseases and Microbiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania 1526 1 KEY WORDS:
cytomegalovirus,
Epstein-Barr
virus,
organ
transplantation,
human immunodeficiency virus, AIDS.
ABSTRACT A unifying theme among the herpesviruses is the intimate interrelationship of virus infection with host cellular immune competence. Herpesviruses suppress cellular immunity. Recent advances suggest mechanisms of herpesvirus-induced immunosuppression that include inhibition of cyto kine production and direct interaction of virus with major histocompati bility complex (MHC) components. This suppression appears to be of clini cal significance primarily in patients with underlying immune deficiencies.
INTRODUCTION
Herpesviruses are highly efficient opportunistic agents that normally are controlled by the host immune system. Most primary, acute infections with herpesviruses are self-limiting, with the virus remaining in a latent form in the host. If cellular immune responses are depressed by natural or iatrogenic factors, the virus can be reactivated. Both primary and reactivated infections can be life-threatening if the host is severely immunosuppressed, as in organ transplant recipients and persons with the acquired immune deficiency syndrome (AIDS). Understanding the nature of herpesvirus-host interactions will allow development of rational approaches to management of infected patients. This is made difficult, however, by the fact that herpesviruses themselves 331 0066--42 1 9/90/0401-0331$02.00
332
RINALDO
are immunosuppressive, thereby compounding the insult to the immune system. This review focuses on the latter property of the herpesviruses.
Annu. Rev. Med. 1990.41:331-338. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
CYTOMEGALOVIRUS
Of the six human herpesviruses, cytomegalovirus (CMV; human herpes virus 5) is by far the one most commonly associated with significant immunosuppression (l). CMV is frequently acquired early in age. Primary infection with CMV is predominantly asymptomatic, although individuals can undergo symptomatic illness, e.g. mononucleosis. After primary infec tion, virus can be excreted for extensive periods in the throat, urine, and semen before entering a latent, quiescent state. Actively infected, clinically ill individuals can undergo a prolonged depression in peripheral blood lymphocyte blastogenesis and gamma interferon production in response to in vitro treatment with certain mitogens, CMV antigen, and other viral antigens. In contrast, natural killer (NK) cell and humoral antibody responses appear relatively normal (2-4). Cellular immunity increases in association with resolution of symptoms and cessation of viral excretion. The mechanisms of CMV immunosuppression are as yet unclear. Only a small percentage of peripheral blood mononuclear cells appear to be infected with the virus, and such infection is abortive (5). Indeed, virus is most readily isolated from polymorphonuclear leukocytes (3) even though these cells do not fully replicate CMV or exhibit functional abnormalities. Hence it is unlikely that inhibition of cellular immunity in vivo is primarily a result of direct infection of immune effector cells with CMV. CD8+ T lymphocytes have been linked to CMV immunosuppression by the striking, protracted increase in their numbers noted in the peripheral blood of CMV mononucleosis patients (4). Furthermore, loss of cells expressing CD8 during in vitro culture is associated with recovery of T cell blastogenic responses to certain mitogens. It should be noted that these CD8+ cells may also be functioning as cytotoxic effectors in the host response against CMV. Monocytes appear to be more closely rclated to suppression of T lymphocyte responses during clinical CMV infection, in that they depress mitogen-induced blastogenesis in mononucleosis patients (6). Moreover, in vitro infection of blood monocytes with CMV, particularly low-passage isolates, can inhibit lymphocyte blastogenesis to mitogens (7). These inhibi tory effects may be due to decreased production of interleukin 1 by monocytes and interleukin 2 by T lymphocytes (8). In spite of the well-documented, relatively profound immunosuppressive effects noted during primary CMV infection, there is little evidence of enhanced susceptibility to secondary, opportunistic agents in these
Annu. Rev. Med. 1990.41:331-338. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
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patients. Thus, in the normal adult host, selective inhibition of T-lym phocyte responses during active CMV infection may be compensated by humoral and cellular responses that remain relatively intact (e.g. neu tralizing antibodies, NK and polymorphonuclear cell functions). These may be sufficient to prevent superinfections. The immunosuppressive effects of CMV infection have more significant impact on host antimicrobial resistance in persons who already have under lying immunodeficiencies. In particular, CMV-infected organ transplant recipients have immune deficits similar to CMV mononucleosis patients, with lower lymphocyte blastogenesis and interferon production (9) and elevated numbers of CD8+ T lymphocytes (10). However, CMV infection in transplant recipients can be followed by serious, secondary bacterial and fungal diseases. The immunosuppressive effects of CMV and their secondary clinical complications appear to be greater after primary as compared with reactivated infection (9), and in transplant recipients receiv ing antithymocyte globulin (11) and anti-T-cell monoclonal antibody (12). Cytotoxic T lymphocytes and NK cells have been implicated in resolution of CMV infection in transplant recipients ( l3 ). Clinical obser vations and data from animal experiments suggest that CMV pneumonitis in transplant recipients may actually be caused by cytotoxic immune reac tivity in the lung, rather than by CMV itself (14). Indeed, recent evidence has shown a homology between CMV and MHC Class I DNA (15). This may be the basis for the observed binding of CMV to beta-2-microglobulin (16) and could be of importance in disruption of immunity during CMV infection. The complexity of CMV-host immune interactions is further exemplified in persons with human immunodeficiency virus (HIV) infection (17). The majority of adults at risk for HIV infection are already latently infected with CMV. After infection with HIV, the herpesvirus is excreted at high frequency in semen of asymptomatic homosexual men. Levels of serum IgG antibodies specific for CMV are also elevated during HIV infection, particularly in homosexual men with increased risk for development of AIDS. Active CMV infection is more frequent in relation to advanced clinical disease, as CMV is the most common opportunistic viral pathogen in AIDS patients. Lymphocyte blastogenesis and gamma-interferon production in response to CMV antigen are depressed within the first few years of HIV infection in homosexual men (17, 18). Anti-CMV cytotoxic reactivity is also decreased during HIV infection (19). Such immunosuppression in HIV-infected individuals may be further complicated by the suppressive effects of CMV that occur after activation of the herpesvirus. It is not yet clear, however, whether active CMV infection is merely a marker of HIV-
Annu. Rev. Med. 1990.41:331-338. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
334
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induced immunosuppression, or if it is actually a cofactor in the pro gression to AIDS. Based on the significant immunopathogenic effects of CMV, treatment of CMV infection with new generation antiviral drugs such as ganciclovir is likely to become a routine practice in transplant recipients as well as in AIDS patients. This will coincide with an emerging, new era in clinical virology that includes more timely diagnosis of CMV infection and testing for resistance of CMV isolates to antiviral drugs. EPSTEIN-BARR VIRUS
Primary Epstein-Barr virus (EBV; human herpesvirus 4) infection is predominantly asymptomatic and acquired at an early age (20). The herpesvirus establishes latent infection in a small percentage of B lympho cytes and can be reactivated during immunosuppressive conditions. The immunosuppressive effects of EBV are evident in adults with acute mononucleosis and are similar in nature to those of CMV: depression in lymphocyte responses to mitogens and nominal antigens, with a relatively intact humoral antibody response. EBV-induced immunosup pression is usually less severe and less prolonged than that caused by CMV, which correlates with the relatively milder clinical syndrome of EBV mononucleosis. Numbers of CD8+ cells are increased severalfold in peripheral blood of patients with EBV mononucleosis. In vitro infection of normal lym phocytes with EBV can enhance CD8+ suppressor cell inhibition of mitogen and antigen-specific T-cell responses (21). An IgG factor has been identified in sera of EBV mononucleosis patients that binds to T lymphocytes and inhibits their function (22). As in CMV mononucleosis, EBV-induced immunosuppression in mononucleosis patients has not been directly related to increased incidence of secondary, opportunistic infec tions. Fatal EBV mononucleosis can occur in males with X-linked lympho proliferative syndrome, a rare genetic disorder. This has been associ ated with underlying defects in MHC-restricted, cytotoxic T-cell immunity to EBV (23), although some of these patients have normal anti-EBV cytotoxic responses. It is possible that non-MHC-restricted cytotoxic cells are also important in control of EBV, as has been shown in conventional EBV mononucleosis patients. Organ transplant recipients commonly have primary or reactivated EBV infection. Primary EBV infection has more severe and longer lasting immunosuppressive effects. However, the most striking clinical outcome of loss of cellular immune control of EBV in such immunosuppressed
,
Annu. Rev. Med. 1990.41:331-338. Downloaded from www.annualreviews.org Access provided by University of Manchester - John Rylands Library on 01/23/15. For personal use only.
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patients is posttransplantation lymphoproliferative disease, in the form of neoplastic proliferation of EBV-positive lymphocytes (24). During HIV infection, EBV is frequently reactivated, as evidenced by enhanced oropharyngeal excretion and elevated IgG antibody titers to EBV early antigen and viral capsid antigen (25; in preparation). This activation can occur very soon after HIV infection and before serum antibodies to HIV can be detected by conventional assays. Furthermore, EBV-associated lymphomas and oral hairy leukoplakia have been noted in AIDS patients. Whether EBV is a cofactor in HIV infection and pro gression to AIDS is not known. However, in a nested case-control study, we have not found an association of active EBV infection with an accel erated decline in numbers of CD4 + lymphocytes during HIV infection of homosexual men (in preparation). HERPES SIMPLEX VIRUS TYPES 1 AND 2
The severity of infection with herpes simplex viruses 1 and 2 (HSV; human herpesvirus I and 2) is inversely correlated with the competency of the host cellular immune response (26). Serious, sometimes life-threatening primary or recurrent HSV infections can develop in immunocompromised individuals, particularly in transplant recipients and AIDS patients. Stud ies have shown that lymphocyte blastogenesis and cytokine production are diminished during acute HSV infection and after in vitro infection with HSV (27, 28). This suppression has been related to a moderate, variable increase in CD8+ lymphocyte numbers and to a solublc inhibitory factor. However, HSV infection does not in itself appear to commonly result in major impairment of immunity, as CMV and EBV do. VARICELLA-ZOSTER VIRUS
As with the other herpesviruses, the severity of varicella-zoster virus (VZV; human herpesvirus 3) infection is closely associated with the underlying immunocompetence of the host (29). The probability that a person will experience clinical reactivation of VZV increases dramatically with age, possibly linked to age-related decreases in immune function. There is evidence that CD8+ T-Iymphocyte numbers are increased during acute VZV infection (30). However, the immunosuppressive properties of VZV have not been elucidated. HUMAN HERPESVIRUS 6
In 1986 a new human herpesvirus, HHV-6, was identified (31). The virus has significant DNA homology with CMV, but not with EBV, HSV, or
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VZV (32). Serologic studies indicate that initial infection with HHV-6 usually occurs early in life (33). Primary infection with HHV-6 is likely the cause of exanthem subitum (34), a febrile illness of infants. The relation of HHV-6 to immunosuppression has not yet been estab lished. The virus can replicate in and lyse mitogen-activated T lymphocytes (35), similar to HSV. HHV-6 has been identified on occasion in cells bearing B-lymphocyte markers (31). Although the virus has been isolated from HIV-infected patients, the seroprevalence of HHV-6 is similar in HIV-seropositive and -seronegative subjects (36). Therefore, its role in the natural history of HIV infection remains to be determined.
ACKNOWLEDGMENTS
I thank Mr. John Ferbas and Ms. Judy Fossati for assistance in prep aration of the manuscript. Work cited from the author's laboratory was supported in part by Public Health Service grant ROl -AI-162l2 and con tracts NOI-AI-325l 3 and NOl-AT-72632 from the National Institutes of Health and by the Pathology Education and Research Foundation of the University of Pittsburgh.
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