Human Cancers and Viruses: A Hypothesis for Immune Destruction of Tumours Caused by Certain Enveloped Viruses Using Modified Viral Antigens.

Introduction

• Burkitts lymphoma (1) and nasopharyngeal carcinoma and the Epstein Barr virus (EBV)(2)
• Carcinoma of the cervix and herpes virus type 2 (HV2) (3) and more recently the human papilloma virus (HPV) (4)
• Kaposi's sarcoma and the cytomcgalo-virus (CMV) (5)
• Primary liver cancer and hepatitis B virus (HPV) (6.7)
• More recently the human T-cell leukaemia and the human T-Cell leukaemia virus (HTLV 1) (8).

The evidence linking the above viruses to these malignant tumours has come partly from epidemiological studies and partly from molecular biology. Epidemiological studies have shown a higher incidence of the tumour concerned in social groups or in geographical areas of high viral cndcmicity than in those of low viral endemicity. The incidence of primary liver cancer for example, is 50 times higher in Africa and Asia where the prevalence of the hepatitis B antigen is higher than in North America and Northern Europe where this antigen is low (7). Scrocpidemiology has also shown significantly higher antibodies or viral antigen in tumour patients than in normal controls living in the same areas.

At the molecular level the Epstein-Barr virus has transformed normal lymphocytes in vitro into cells that have all the characteristics of Burkitt Lymphoma cells (9), and the viral genome has been detected in tumour cells (10) further supporting the direct involvement of the virus in this tumour.

Although these tumour viruses are indeed involved in the malignant transformation of (lie affected cells, given the high endemicity of the viruses in the various Communities concerned, and (lie relative absence of malignant tumours in most of those whoa have had contact with the virus, it can he readily admitted that other additional factors in the host or (tae environment must play a determinant role in those who eventually develop malignant tumours. Such factors would include for example, the presence of aflatoxin or alcoholism in association with hepatitis I3 in liver cancer (11) or the presence of endemic malaria with the Epstein Barr Virus in Burkitt's lymphoma (12).

These other factors notwithstanding, understanding the relationship of the viruses to the host is indispensable for the proper understanding of these tumours.

Given the complexity of the problem and the great volume of publications on cancer and viruses, a simplified approach will hopefully attempt to perceive the common thread running through this complex problem which could, in turn, sheet new light on it.

The tumour viruses

1. They all persist in a latent or overt forms in the body for long periods, sometimes for life, and
2. They all possess viral envelopes.

A proper understanding of how the above 2 characteristics are related to each other and to the host could throw new light on the subject of viruses and malignant tumours. Such information is indispensable for formulating action that is directed at eliminating malignant tumours caused by them.

The persistence of the viruses in the body

The quality of effectiveness of the antibodies produced in a body depends on one or both of the following 2 factors:

1. The competence of the immune system of tile host.
2. The nature of the antigens provoking them.

It should be recalled in passing, that immunity to the hepatitis A virus infection, a non-enveloped virus for example, is effective and those who survive the initial infection eliminate the virus from the body completely. In contrast, those with hepatitis B virus infection, an enveloped virus, frequently have persistence of the virus.

The viral envelope

The DNA viruses in the above group develop, as ' is well known, in the nucleus of the infected cell and acquire their envelopes from the inner lamella of the nuclear membrane of the infected cell (13). The complete viruses leave the cell with their envelopes in place.' Specific surface viral antigens, mostly glycoproteins, are attached to the surface of the envelope.

The HTLV 1, an RNA virus, in keeping with the development of retro-viruses, acquires its envelope by budding from the cell surface membrane. Specific surface viral antigens made of glycoproteins, are also attached to, or ,project from, the surface of the viral envelope.

In both the DNA and RNA viruses, the envelope which has the same-basic form, is made of phospholipoproteins which are derived, as was indicated above, from the host cell. Being of host cell origin, the viral envelope is itself non-antigenic. However, in carrying (tie specific surface antigens of the virus, the envelope becomes part of the antigenic complex which the viral surface presents to the immune system of the body. It is this antigenic complex-host lipoproteins in the envelope plus specific surface antigens-which determines tile immune response of the body.

The presence, of the envelope modifies the specific surface antigens

The antigenic complex described above is interpreted by the host immune system as partly self because the envelope is of host origin. The virus, using the envelope, has thus effectively 'disguised' itself and has induced or misled the immune system into considering it, with its surface antigens as partly self.

If the immune response, humoral or cell-mediated, were to destroy tike antigenic complex is constituted, it would also do serious harm to those host cell elements, whether infected or not, from which the envelope was derived. This would constitute a serious auto-immune disease.

To avoid such serious damage, the immune system produces instead 'compromise' Antibodies which in order not to destroy its own cells, do not also destroy the virus (these compromise antibodies nevertheless cause some degree of auto-immunity which can be demonstrated in various ways in many such patients).

Thus the virus, using the non-antigenic lipoproteins of the envelope as a kind of disguise tins 'blackmailed' die immune system into producing a compromise, and therefore ineffective, response thereby ensuring its survival in the body. Disguise and blackmail have been the modus operandi of these enveloped viruses. The foregoing over-simplified account provides the elements of a hypothesis for ridding the body of the above enveloped viruses and eventually of the malignant tumours caused by them.

Hypotheses

Whilst viral nucleic acids are, infective and call cause viral multiplication when introduced into the cell, the natural infectivity of the enveloped viruses vis a vis the cell, is abolished when it is deprived of its envelope. It should then act as a simple antigenic material.

Verification of the hypothesis should lead to several useful applications in practice. Before considering such possible applications however, it is necessary to answer two possible theoretical objections to the hypothesis.

Possible objections to the hypotheses

It will be recalled that Freund's complete adjuvants were widely used in immunology in die 1950-1970s to enhance the antigenicity of various protein antigens. These adjuvants were made partly from lipid extracts of the tubercle bacillus, paraffin and oils of various kinds. How these adjuvants worked in the body was never very clear. What was clear however, was that without being antigenic themselves, they nevertheless enhanced the antigenicity of those antigens with which they were introduced into experimental animals or patents.

The lipoproteins on the viral envelope are lipids also and can also be expected to have an adjuvant or enhancing effect on the specific surface antigens on the viral envelope, and this should provoke strong antibodies.

Yet the hypothesis proposes instead that the lipoproteins of the envelope modify and reduce the antigenicity of the specific surface antigens which in turn provoke weak or ineffective antibodies. The reason for this is that the lipids of the envelope are of host origin and not foreign to the body as was the case with the crude adjuvants of 4-5 decades ago. By associating the host lipoproteins with its surface antigens The virus has transformed antigens which should have been enhanced and so eliminated into antigens that are 'tolerated' by the immune system. There is a useful message for transplantation immunologists hidden somewhere in this simple but effective viral disguise of its foreign antigens.

The second possible objection to the hypothesis concerns the new immune response that is expected when the viral core, shorn of its envelope, is re-introduced into the host. Why, it could be asked, should the immune system react anew to an antigen with which it has apparently been in contact previously?

In the synthesis of the above enveloped viruses and indeed of all such viruses, defective particles are frequently produced consisting of naked cores of or empty envelopes only. Such defective cores, by that very fact, are different from the cores of complete enveloped viruses, otherwise they would not have been defective. Also, when complete enveloped viruses degenerate and die, as they eventually must, they release damaged or degenerating cores. These defective or degenerated cores, (HBc, HBc and the antibodies to them are sometimes found, for example, in primary liver cancer associated with hepatitis B virus (14)) will continue to be produced for as long as viral synthesis and degeneration continue.

These defective or degenerating cores are clearly different, in some very small but important detail, from the intact core of a complete virus and their respective antigenicities must clearly be different also. Since there is no natural mechanism for artificially dissolving the viral envelope in vivo, it can be assumed that the immune system of the host has never had any previous contact with the normal core of a complete virus. The viral core obtained in vitro must therefore constitute a truly new antigen for the host capable, when re-introduced into the body, of provoking a completely new immune response which should eliminate the core of the complete enveloped virus from the body-which is the only part of the virus worth eliminating.

In the light of the foregoing it should now be interesting to examine the consequences cf the elimination of the intact viral core on the corresponding malignant tumour.

The malignant tumour Several malignant tumours caused by envelop viruses have been shown to contain the corresponding viral genome on the tumour cells, zur Hausen al (10) as stated above, have shown, for example the EBV DNA in biopsies of Burkitt's tumour an anaplastic carcinoma of the nasopharynx.

If antibodies to the EBV, have been unable to clininate the EBV from Burkitt's lymphoma patients because of the 'blackmailing' presence of the viral envelope, it is not surprising that the same andbod should be unable, for the same reason, to act again the viral DNA present in the tumour cells.

The new uncompromised immune response provoked by the intact viral core as indicated above should eliminate that core of genome in the envelope virus and whatever else it may be. This would elude the viral genome on the tumour cell which will in consequence, be destroyed as well. This immune destruction should also include all other non-malignant cells that carry the viral genome. In the case primary liver cancer associated with the hepatitis virus for example, this could include non cancer( virally infected liver cell. Unless adequate measure are taken, the immune destruction of the tumour can therefore lead to serious consequences in such patients. In contrast, cancer of the cervix, with the herp type 2 infection or even the more recent HPV linked to the cervix and lower genital tract, should give excellent results.

Conclusion

Simple and effective vaccines based on the same principle should of course, be used to prevent infections in healthy persons or animals by enveloped viruses and the chronic diseases and malignant tumours induced by them. This should bring great benefits to animal and human health.