Download Viruses, cancer and aids

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.
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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
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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-
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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.
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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
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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]
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