* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Viruses, cancer and aids
Survey
Document related concepts
Globalization and disease wikipedia , lookup
Sociality and disease transmission wikipedia , lookup
Neonatal infection wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Innate immune system wikipedia , lookup
Hospital-acquired infection wikipedia , lookup
Common cold wikipedia , lookup
Infection control wikipedia , lookup
Henipavirus wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Human cytomegalovirus wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Transcript
FEMS Immunology and Medical Microbiology 26 (1999) 227^232 Viruses, cancer and aids Robin A. Weiss Windeyer Institute of Medical Sciences, Royal Free and University College Medical School, 46 Cleveland Street, London W1P 6DB, UK Received 26 May 1999; accepted 26 July 1999 Abstract Patients with AIDS are at risk of lymphoma and Kaposi's sarcoma. These tumours are associated with the gamma herpesviruses, Epstein-Barr virus (EBV) and human herpesvirus 8 (HHV-8), although a proportion of AIDS lymphomas lacks both viruses. EBV and HHV-8 are latent in the tumour cells, with genes that play a direct role in driving cell proliferation. Human immunodeficiency virus, in contrast, while being the greatest risk factor for lymphoma and Kaposi's sarcoma, acts indirectly, mainly by causing immune suppression, as immunosuppressed transplant patients are at risk for the same types of tumour. ß 1999 Published by Elsevier Science B.V. All rights reserved. Keywords : Oncogenic virus ; Immune de¢ciency; AIDS ; Human herpesvirus 8 1. Introduction A little over 100 years ago Christiaan Eijkman showed that beri-beri, formerly believed to be an infectious disease, was, in fact, caused by a dietary de¢ciency for the vitamin B1 , thiamine. His work in Jakarta and later in Utrecht demonstrated innovative lateral thinking by a bacteriologist who was not hidebound by his own discipline. At the time he made his seminal discovery microbiologists like Louis Pasteur and Robert Koch had only fairly recently won the argument for the germ theory of disease against those who held that environmental miasmas were the culprit. Indeed, the incrimination of 'bad air' has its relic today in the term malaria, shown to be a mosquito-borne infection by Ronald Ross in 1898 too. E-mail: [email protected] It is also the centennial of the discovery of viruses, that is, of the demonstration that certain infectious agents were so small that they could be passed through small-pore ¢lters that held back all bacteria. Beijerinck's discovery in The Netherlands in 1898 of the ¢lterable nature of the agent for tobacco mosaic disease coincided with that of Lo«¥er and Frosch in Germany for foot and mouth disease in cattle. Thus was born the discipline of virology. One disease, cancer, remained ¢rmly in the noninfectious category regarding its aetiology. And yet some forms of cancer would soon be found to be transmissible, a change of path in the opposite direction to that which Eijkman made. The ¢rst clue came from chickens, when Ellerman and Bang in Denmark showed in 1908 that erythroleukaemia was transmissible by a ¢ltrate, but leukaemia was not yet recognised as a malignancy. In 1911, Peyton Rous in New York showed that sarcoma could be similarly passed by a ¢ltrate, but this shocked his 0928-8244 / 99 / $20.00 ß 1999 Published by Elsevier Science B.V. All rights reserved. PII: S 0 9 2 8 - 8 2 4 4 ( 9 9 ) 0 0 1 4 0 - 6 FEMSIM 1123 17-11-99 228 R.A. Weiss / FEMS Immunology and Medical Microbiology 26 (1999) 227^232 contemporaries and eventually Rous abandoned studies of his eponymous virus. It took 30 years for Eijkman to be recognised by the award of the Nobel Prize in 1928. Rous, who was happily blessed with longevity, waited 55 years for his Nobel recognition in 1966. virus types 16 and 18 and cervical cancer, and to HTLV-1 infection and adult T-cell leukaemia (5% of those with life-long infection), and up to 30% of those with chronic active hepatitis B or C virus infection later develop liver cancer. 3. Cancer and immune de¢ciency 2. Viruses and cancer In the meantime, several oncogenic viruses in mammals were discovered ^ pox and papilloma viruses in rabbits, mammary tumour virus in mice, leukaemic retroviruses in mice, cats and monkeys, lymphomagenic herpesviruses in chickens, monkeys and humans, and papovaviruses in rodents. The study of these viruses has provided much insight into the molecular biology of cancer, including the majority of malignancies without an infectious aetiology. The de¢nition of the src transforming gene of Rous sarcoma virus opened up the world of oncogenes, and the discovery of p53 as a protein which associated with SV40 T-antigen elucidated the molecular mechanism of tumour suppressor genes. Today, we estimate that approximately 15% of the worldwide burden of human cancer has a transmissible agent as a component of its aetiology [1]. The major killers are the viruses causing cancer of the liver, the uterine cervix and the nasopharynx, and the bacterium, Helicobacter pylori, associated with peptic ulcers, cancer of the stomach, and also mucosa-associated lymphoid tumours. Papilloma viruses cause skin cancer as well as genital cancers, and human T-cell lymphotropic virus (HTLV-1), a retrovirus, causes a form of adult T-cell leukaemia as well as tropical spastic paraparesis. Certain helminths are associated with bladder cancer and cholangiocarcinoma where chronic infestation occurs. Viral cancers are not contagious in the sense that an individual is likely to contract the disease from contact with an existing cancer patient. Rather, viral infection is a rare outcome of a much more frequent prevalence of infection. Thus greater than 90% of the human population is persistently infected by EpsteinBarr virus (EBV), whereas less than 1% of those infected develop EBV-related tumours such as lymphoma or nasopharyngeal carcinoma (NPC). Somewhat higher cancer rates apply to human papilloma In 1909, Paul Ehrlich ¢rst enunciated the immune surveillance hypothesis of cancer, namely that the immune system, in particular cell-mediated immunity, is continually monitoring and recognising 'errant' cells progressing towards malignancy. These cells might be su¤ciently di¡erent from normal cells to be identi¢ed as 'foreign' and thus eliminated. If it were not for immune surveillance, the argument goes, we should be at much higher risk of cancer occurring at younger ages. The immune surveillance hypothesis was supported and developed in the middle 20th century by immunologists such as McFarlane Burnet and Lewis Thomas, and it remains popular today, especially for those who espouse 'alternative' medicine and lifestyle modes of treating or preventing cancer. How ¢rm is the evidence for immune surveillance? One test is to compare the incidence and types of cancer in individuals who do not have intact immune systems, such as severe combined immune de¢ciency in mice or men, and other inherited de¢ciencies of immunity such as the nude mouse. The answer is that the major carcinomas do not occur at higher frequencies in these individuals, but that an increase in tumours of the immune system itself, lymphomas, and some tumours of viral aetiology are seen. Today, we have two larger groups of immunocompromised individuals to examine for malignancy: iatrogenically immunosuppressed recipients of tissue or organ transplantation; and the acquired immune de¢ciency syndrome (AIDS) that follows human immunode¢ciency virus (HIV) infection. Again, it is notable that most of the common carcinomas are not increased in acquired immune de¢ciency, and most of those that do occur more commonly are caused by viruses. So the immune surveillance hypothesis of cancer may need modi¢cation. It would appear that most non-viral cancers are not recognised as foreign and are not simply kept at bay by FEMSIM 1123 17-11-99 R.A. Weiss / FEMS Immunology and Medical Microbiology 26 (1999) 227^232 immune surveillance. This appears paradoxical as neo-antigens have been detected on certain tumours, e.g. melanoma (which is only slightly increased in transplant or AIDS patients). Indeed, these tumour antigens are targets for immunotherapy. Probably the immune system does play some role in surveillance of such tumours. Our modern knowledge of oncogenesis, however, tells us that somatic mutations ^ switching on oncogenes, inactivating tumour suppressor genes, and suppressing default, apoptotic pathways ^ are also required for tumour development, and without such genetic lesions, cells will not exert uncontrolled growth, even in the absence of immune surveillance. In human transplant recipients and AIDS patients, two tumour types stand out above all others as having greatly increased incidence compared to immunocompetent but otherwise matched controls. They are B-cell lymphoma and Kaposi's sarcoma. Both these tumours appear to be caused by gamma herpesviruses: EBV for most B-cell lymphomas, and human herpesvirus 8 (HHV-8 or KSHV) for Kaposi's sarcoma. 4. B-cell lymphoma EBV was originally linked with Burkitt's lymphoma (BL) in children, a tumour of small B-lymphocytes which also bear c-myc-Ig fusions on account of chromosome translocation. EBV is also linked to NPC in older adults, particularly men in southern China. BL is clearly increased in immunode¢ciency, but there are few data so far for NPC. Given that EBV is a worldwide infection it remains a puzzle why NPC is largely con¢ned to the Chinese (and also to North Africa), while children's BL occurs mainly in areas of holoendemic malaria. The most frequent lymphoma in AIDS and transplant recipients is immunoblastic lymphoma, of large B-lymphoblasts [2]. This may start as a polyclonal lymphoproliferative disease and progress to a monoclonal malignancy. Thus in early stages it resembles infectious mononucleosis, which represents primary EBV infection of adults, and also Duncan's syndrome in infants, an X-linked inherited disorder of a failure to mount an immune response to EBV infection. In transplant patients, over 90% of lympho- 229 mas are EBV-positive, whereas in AIDS only approximately 55% carry EBV. This poses the question of the aetiology of the other 45% of lymphomas in AIDS. Is there another oncogenic virus in EBV-negative AIDS lymphoma? A small percentage of lymphomas may be caused by HHV-8. In particular it is associated with a lymphoma known as primary e¡usion lymphoma (PEL), or body cavity-based lymphoma, rare among AIDS patients, a tumour lacking c-myc rearrangement [3]. PEL is often positive for EBV as well as HHV-8. Multicentric Castleman's disease, another lymphoproliferative syndrome seen in AIDS, is also associated with HHV-8 infection [4], and the herpesvirus can be detected in immunoblasts [5]. Primary B-cell lymphomas of the central nervous system in AIDS are almost always EBV-positive, yet a signi¢cant number of AIDS B-cell immunoblastic lymphomas in other sites remain negative for both EBV and HHV-8. Although these might perhaps contain a novel, currently unknown oncogenic virus, an alternative pathway to oncogenesis could be that in HIV infection, in contrast to transplant patients, there is chronic activation of B cells. Thus much research remains to be done to elucidate the aetiology and pathogenesis of lymphomas in AIDS. 5. Kaposi's sarcoma (KS) KS is the tumour that heralded the onset of the AIDS epidemic when young homosexual men in US cities presented with KS or Pneumocystis carinii pneumonia in 1981. Previously KS was known as a rare condition of elderly persons, mainly men, in Eastern Europe, Mediterranean countries (classic KS), in transplant recipients, and in Africa (endemic KS). Long before AIDS, KS was suspected of having an infectious aetiology, but the incriminating virus, KSHV or HHV-8, was not discovered until 1994 [6], when novel herpesvirus sequences were detected by using representational di¡erence analysis, a subtractive DNA hybridisation technique involving PCR ampli¢cation of non-hybridised fragments. HHV-8 is a gamma herpesvirus distantly related to EBV; it is more closely related to herpesvirus saimiri of new world squirrel monkeys, and to recently discovered viruses in macaques. FEMSIM 1123 17-11-99 230 R.A. Weiss / FEMS Immunology and Medical Microbiology 26 (1999) 227^232 Following its discovery [6], HHV-8 was soon shown to be present in all epidemiological forms of KS: classic, transplant, African endemic and AIDS [7]. The viral DNA sequences can be detected as latent infection in the spindle and endothelial tumour cells in KS [8], as well as the primary e¡usion lymphoma cells already discussed. Using a monoclonal antibody to the major latent nuclear antigen, we recently demonstrated the expression of latent viral antigen in the nuclei of tumour cells [5]. KS is an unusual tumour of endothelioblasts. The cells express the vascular endothelial growth factor receptor type 3 (VEGF-R3), which is a marker of lymphatic endothelium rather than of mature vascular endothelium [5]. However, VEGF-R3 may be more generally expressed on neo-angiogenic cells. It remains controversial whether KS tumours are monoclonal. Early lesions may not be, but nodules within advanced KS lesions may represent clonal proliferation. Classic KS typically presents in the extremities of the limbs, whereas AIDS KS appears in skin all over the body and also in internal organs. In AIDS, KS occurs most commonly among gay men in Western countries, and among both men and women in Africa. It is rarely seen in people who have acquired their HIV parenterally, such as injecting drug users and men with haemophilia [9]. Recent serological surveys for antibodies to HHV-8 indicate that by and large the presence of HHV-8 antibodies in risk groups or populations re£ects the incidence of KS, although the prevalence of HHV-8 infection is much higher than the risk of disease. Thus in Northern Europe and USA, HHV-8 seroprevalence is less than 10%, while it is 25% in Sicily and southern Italy, and over 30% in parts of Africa [7]. An exception is West Africa where KS is rare but HHV-8 infection is as frequent as the KS endemic region of East and Central Africa [10]. HHV-8 can be transmitted sexually, and this appears to be the major route among gay men. In endemic areas such as the Mediterranean and Africa, however, a steadily rising seroprevalence is seen throughout childhood and adulthood. The mode of transmission is unknown, although infants generally have HHV-8-positive mothers infected with the same strain. Saliva is a possible source of infection. The HHV-8 genome carries several homologues of cellular genes that may well contribute to its oncogenic potential [7]. For example, a cyclin D homologue interacts with cellular CDK6 to phosphorylate and inactivate Rb protein, and the HHV-8-encoded cyclin escapes the network of CDK inhibitors that regulate cellular cyclins [11]. Other HHV-8 genes such as a G-protein coupled receptor [12] and an interferon response factor [13] will transform NIH3T3 cells into tumorigenic counterparts. Our studies indicate that viral homologues of macrophage in£ammatory proteins (vMIP-I, vMIP-II) are angiogenic, perhaps helping to explain why HHV-8 stimulates endothelial cells to form KS [14]. Moreover, vMIP-II binds to the CCR3 chemokine receptor as an agonist, and can block HIV infection via this coreceptor [14], which may explain the protection HHV-8 appears to o¡er from HIV dementia as CCR3 is expressed on microglial cells [15]. 6. Conclusions and prospects An overall picture of the major AIDS-linked tumours has emerged in which two viruses play di¡erent roles in the disease process. The major role of HIV is to cause immune de¢ciency. The herpesvirus, either EBV or HHV-8, may then act as the directly oncogenic agent, one that is normally kept in check by cell-mediated immunity. This is well known for EBV infection [2] and we have recently identi¢ed cytotoxic T-lymphocyte responses for some HHV-8 antigens [16]. Thus the lymphomas are 'opportunistic neoplasms' like the opportunistic infections seen in AIDS and transplant patients. It is also possible that HIV plays a more direct role through a secreted form of the viral Tat protein. In vitro, Tat acts synergistically with basic ¢broblast growth factor to stimulate proliferation of endothelial cells [17]. This is a property of HIV-1 Tat rather than of HIV-2 [18], and it is notable that the few cases of AIDS KS in West Africa occur in association with HIV-1 infection, and much more rarely with HIV-2 [10]. The introduction of highly active anti-retroviral therapy to reduce HIV load can result in rapid involution of KS. To what extent this is a result of immune reconstitution or of the drop in Tat expression remains to be determined. Anti-herpesviral drugs that are active against HHV-8 might also FEMSIM 1123 17-11-99 R.A. Weiss / FEMS Immunology and Medical Microbiology 26 (1999) 227^232 help to control the tumour, but only if active viral replication is part of its pathogenesis. We have come a long way since Rous ¢rst demonstrated the induction of sarcoma in chickens by a ¢ltrate. We now have the opportunity to control human viral cancers through immunisation: vaccination to prevent primary infection should protect against malignancy. A safe, e¤cacious and relatively inexpensive hepatitis B vaccine exists [19], and trials are beginning for EBV and HPV vaccines. Eijkman explored vitamin de¢ciency and I can imagine that if he were alive today, he would be fascinated by immune de¢ciency and its associated cancers. As to the viral challenges for the future on infections in the 21st century, the control of HIV infection remains the greatest immediate challenge, as the current, experimental vaccines are not e¤cacious or cannot be applied to humans. Another `¢n de siecle' challenge concerns xenotransplantation, which may allow animal viruses to infect the transplant recipients and to spread to the community at large [20]. Novel human viruses will also come to light. Virus infections may emerge from mankind's changing habitat; they may also emerge to human knowledge from the study of chronic diseases. And the immunode¢cient person may be the sentinel for common but usually latent infections, like the discovery of HHV-6, HHV-7 and HHV-8 in AIDS patients. [4] [5] [6] [7] [8] [9] [10] [11] Acknowledgements The author's research is supported by the Cancer Research Campaign and Medical Research Council. [12] References [1] Parkin, D.M., Pisani, P., Mun¬oz, N. and Ferlay, J. (1999) The global health burden of infection associated cancers. In: Infections and Human Cancer (Newton, R., Beral, V. and Weiss, R.A., Eds.), pp. 5^33. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. [2] Brooks, L.A., Crook, T. and Crawford, D.H. (1999) EpsteinBarr virus and lymphomas. In: Infections and Human Cancer (Newton, R., Beral, V. and Weiss, R.A., Eds.), pp. 99^123. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. [3] Nador, R.G., Cesarman, E., Chadburn, A., Dawson, D.B., Ansari, M.Q., Said, J.W. and Knowles, D.M. (1996) Primary [13] [14] [15] [16] 231 e¡usion lymphoma: A distinct clinico-pathologic entity associated with the Kaposi's sarcoma-associated herpesvirus. Blood 88, 645^656. Soulier, J., Grollet, L., Oksenhendler, E., Cacoub, P., CazalsHatem, D., Babinet, P., d'Agay, M.F., Clauvel, J.P., Raphael, M. and Degos, L. (1995) Kaposi's sarcoma-associated herpesvirus-like DNA sequences in multicentric Castleman's disease. Blood 86, 1276^1280. Dupin, N., Fisher, C., Kellam, P., Ariad, S., Tulliez, M., Franck, N., van Marck, E., Salmon, D., Gorin, I., Escande, J.P., Weiss, R.A., Alitalo, K. and Bosho¡, C. (1999) Distribution of human herpesvirus-8 latently infected cells in Kaposi's sarcoma, multicentric Castleman's disease, and primary e¡usion lymphoma. Proc. Natl. Acad. Sci. USA 96, 4546^ 4551. Chang, Y., Cesarman, E., Pessin, M.S., Lee, F., Culpepper, J., Knowles, D.M. and Moore, P.S. (1994) Identi¢cation of herpesvirus-like DNA sequence in AIDS-associated Kaposi's sarcoma. Science 266, 1865^1869. Bosho¡, C. and Weiss, R.A. (1998) Kaposi's sarcoma-associated herpesvirus. Adv. Cancer Res. 75, 57^86. Bosho¡, C., Schulz, T.F., Kennedy, M.M., Graham, A.K., Fisher, C., Thomas, A., McGee, J.O'D., Weiss, R.A. and O'Leary, J. (1995) Kaposi's sarcoma-associated herpes virus (KSHV) infects endothelial and spindle cells. Nature Med. 1, 1274^1278. Beral, V., Peterman, T.A., Berkelman, R.L. and Ja¡e, H.W. (1990) Kaposi's sarcoma among persons with AIDS: a sexually transmitted infection? Lancet 335, 123^128. Ariyoshi, K., Schim van der Loe¡, M., Cook, P., Whitby, D., Corrah, T., Ja¡ar, S., Cham, F., Sabally, S., O'Donovan, D., Weiss, R.A., Schulz, T.F. and Whittle, H. (1998) Kaposi's sarcoma in the Gambia, West Africa is less frequent in HIV-2 than in HIV-1 infection despite a high prevalence of human herpesvirus 8. J. Hum. Virol. 1, 192^199. Ellis, M., Chew, Y.P., Fallis, L., Freddersdorf, S., Bosho¡, C., Weiss, R.A., Lu, X. and Mittnacht, S. (1999) Degradation of p27kip cdk inhibitor triggered by Kaposi's sarcoma virus cyclin-cdk6 complex. EMBO J. 18, 644^653. Bais, C., Santomasso, B., Coso, O., Arvanitakis, L., Raaka, E.G., Gutkind, J.S., Asche, A.S., Cesarman, E., Gershengorn, M.C., Mesri, E.A. and Gerhengorn, M.C. (1998) G proteincoupled receptor of Kaposi's sarcoma-associated herpesvirus is a viral oncogene and angiogenesis activator. Nature 391, 86^89. Moore, P.S., Bosho¡, C., Weiss, R.A. and Chang, Y. (1996) Molecular mimicry of human cytokine and cytokine response pathway genes by KSHV. Science 274, 1739^1744. Bosho¡, C., Endo, Y., Collins, P.D., Takeuchi, Y., Reeves, J.D., Schweickart, V.L., Siani, M.A., Sasaki, T., Williams, T.J., Gray, P.W., Moore, P.S., Chang, Y. and Weiss, R.A. (1997) Angiogenic and HIV-inhibitory functions of KSHVencoded chemokines. Science 278, 290^294. Baldeweg, T., Catalan, J., Gazzard, B.G., Weiss, R.A. and Bosho¡, C. (1998) Kaposi's sarcoma and protection from HIV dementia. Science 280, 361^362. Osman, M., Kubo, T., Gill, J., Neipel, F., Becker, M., Smith, FEMSIM 1123 17-11-99 232 R.A. Weiss / FEMS Immunology and Medical Microbiology 26 (1999) 227^232 G., Weiss, R.A., Gazzard, B., Bosho¡, C. and Gotch, F. (1999) Identi¢cation of human herpesvirus 8-speci¢c cytotoxic T-cell responses. J. Virol. 73 (in press). [17] Ensoli, B., Gendelman, R., Markham, P., Fiorelli, V., Colombini, S., Ra¡eld, M., Cafaro, A., Chang, H.K., Brady, J.N. and Gallo, R.C. (1994) Synergy between basic ¢broblast growth factor and HIV-1 Tat protein in induction of Kaposi's sarcoma. Nature 371, 674^680. [18] Albini, A., Soldi, R., Giunciuglio, D., Giraudo, E., Benelli, R., Primo, L., Doonan, D., Salio, M., Camussi, G., Rockl, W. and Bussolino, F. (1996) The angiogenesis induced by HIV-1 Tat protein is mediated by the Flk-1/KDR receptor on vascular endothelial cells. Nature Med. 2, 1371^1375. [19] Coursaget, P. and Mun¬oz, N. (1999) Vaccination against infectious agents associated with human cancer. In: Infections and Human Cancer (Newton, R., Beral, V. and Weiss, R.A., Eds.), pp. 355^381. Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY. [20] Weiss, R.A. (1998) Xenotransplantation. Br. Med. J. 317, 931^934. FEMSIM 1123 17-11-99