MIMM 466 – Lecture 5
Viruses and hematology: A quest for a cause-effect relationship
Host and milieu
The following are some viruses that have been linked to blood diseases
• EBV and epidemiologic studies
Human T-lymphotropic virus 1 linked to some leukemia
• HTLV-3 alias HIV
• Immunosuppression and cancer:
- Generally linked with chronic viral infection
- Host, immune control and virus
• New strategy for patient management
• 1909: Ellerman and Bang in Copenhagen transmitted leukemia in chicken through cell – free, filtered
extract suggested infectious etiology
They take liquids from the tumor of a chicken. They were able to induce tumors into other
chickens by giving them this liquid even though it was filtered and the liquid itself did not contain
any tumor cells
• 1911: Rous USA transmission of chicken sarcoma by use of filtrates
• 1973: Diamandopoulos simian virus (SV40) can induce leukemia in certain experimental conditions
• Oncogenic virus can promote malignancies in several animals
Can induce cell growth by anti-apoptosis, BCL2…
EBV and lymphoma
• 1952: Denis Burkitt described specific childhood lymphoma in Uganda, closely related to malaria
Rare tumor in the lymph node by the jaw. Only in the wet parts of Africa, where there are lakes and
ponds for mosquitoes to grow. They found that the people that were taking preventive measures
against mosquitoes, they didn’t have this tumor. The link with malaria was really strong that initially
they thought that the tumor was a manifestation of malaria. But in reality, it is not due to malaria
• 1965: Epstein and Barr through EM discovered herpes virus particles in Burkitt lymphoma: EBV or HHV-4
• EBV associated with nasopharingal carcinoma, gastric carcinoma, HL, B cell lymphoma in
• However: 90% of adults worldwide are seropositive for EBV: genetic or environment factor
Almost all of has have been infected with that virus, but we did not get a tumor. So there must be
another factor, like genetics or the environment, in the development of the tumor
The virus is a necessity to get the tumor, but it is not sufficient. The cause and effect chain is more
Parvovirus B19 and malignancies
• 1975 Cossart, in Australia, discovered the virus in well B19 of a large series of microplates- Hence,
• Parvoviruses, genus erythrovirus
• Childhood rash called fifth disease or erythema infectiosum
• Pure red cell aplasia or pancytopenia
In some cases with people that have blood disease, there can be total aplasia where the formation of WBC and platelets are blocked. This is easily reversible by treatment with Ig, IgG.
• Symptomatic in person with impaired hematopoiesis
In healthy individuals, you might get a little sick but that is all. Those that have a sickle cell, blood
disease which is chronic anemia, if you get the virus you may get aplastic anemia for a few months.
If you are not treated, you can die from lack of RBCs.
If you already have a blood disease, it is likely that you will develop a more sever type of anemia
• 2001: Persistent B19 infection and ALL??
Mucosa-associated lymphoid tissue NHL (MALT) bacteria not virus
• Arise from a prolonged lymphoid proliferation in the mucosa
Occur in people with chronic inflammation. This causes persistent immune activation, causing
• Chronic gastritis, Helicobacter pillory- a famous cause
• Remission of local small gastric lymphoma with antibiotic
• 2005: Campilobacter jejuni and small bowel MALT- can cause lymphoma in association. It is not a direct
• 2004: Chlamydia psittaci ocular adnexa NHL- rare case of lymphoma of the eyes, in the glands that
waters your eyes
• 2010: Borrelia burgdorferi and cutaneous NHL
***NHL= Non- Hodgkin’s lymphoma
Viruses are not the only causes of lymphomas.
• Cirrhosis and hepatoma in non-A non-B hepatitis
Originally had no name. It was called non-A non-B hepatitis
• 1996: B cell lymphoma and HCV in Italy. (There are lots of IV drug users. So it has one of the highest
rates of HepC in Europe)
• Cryoglobulimemia and B cell clone: 1-3%
Cryoglobulins are protein that coagulates when it is cold
This is an abnormal protein (single or mixed immunoglobulins) that is in reaction with Hep. C. It is
monoclonal. It is not a cancerous clone but a persistent clone which can lead to lymphoma.
• 2002: Hemine et al, Marginal-zone lymphoma: remission during INF and ribavirine therapy
They found people with a rare case of lymphoma in the spleen. When they treated the patient’s
HepC, in a few patients the lymphoma also disappeared.
- 2013: HepC may help understand the link between lymphoma of cancer because it induces immune
activation mainly in the liver but also in the blood. There are new discoveries that it induces insulin
resistance and cholesterol metabolism. Neuro-cognition and effective curative treatment
Three weeks ago, there was a study introducing a new drug that does not require injection. And all 20
subjects were cured of Hep. C HTLV-1 (Human T-lymphotropic virus-1)
Some people have T cell Lymphoma or leukemia.
Leukemia when it circulates in the blood and lymphoma
when it stays in the tissues or nodes.
HTLV-1 and Adult T-cell leukemia-lymphoma (ATLL)
• 1976: Takatsuki described a distinct entity with
unique geographic distribution and clinical and pathological
features: leukemia, lymphoma, myelopathy
• Distribution: Japan (highest incidence), Carribbean,
Western Africa, South America and Central Asia
Same virus in different host may give different disease
• 1980: Poesz, first retrovirus to cause human disease via Tax protein 1995, Franchini
• 1986: Transmitted like HIV
• 2003: Viral proliferation and immune control
• 2012: We can now measure your viral load. More virus, the more likely you will develop
leukemia/lymphoma. There is a link between having the virus, lack of immune control and the chance of
the survival of the B-cell, and it becoming immortal B-cell lymphoma.
8-9% of our genome is integrated retro virus :D
HTLV-1 virus replication cycle
SKIPPED THE SLIDE
• HIV epidemic: 1981-1983 HIV
Most of our knowledge about immunosuppression and viral lymphoma came from AIDS epidemic
1981: first case
1983- discover of the virus
• Recipients of organ transplants also develop lymphoma
Hard to pin point if the lymphoma is virally caused because there are many causes:
- Presence of chronic viral infections
- Immunosuppressive drugs
HIV infection and the risk of cancer
We have a virus. Now the question is “did HIV lead to cancer or lymphoma?” Answer is No. It is not an oncogenic virus. But if you have HIV and you abstain from treatment you can get Kaposi sarcoma.
• First case report on Kaposi sarcoma (KS) in gay men in New-York City and San Francisco (1981)
• AIDS defining cancer:
- Non-Hodgkin lymphoma (NHL):
- Cervical cancer (HPV)
• Non-AIDS defining cancers:
- Some type of tumors have been found in greater frequency in HIV infected persons
• What cancers are associated with HIV infection, and is the increased risk related to immune function?
• What level of immune deficiency matters? Is there a threshold?
• Does reversing the impairment in immune function lead to decreased cancer risk
If you take this approach, you need to make sure that the decrease cancer risk is due to better
immune function and not because you cured another virus that may have been causing increased
• Does type all type of cancers are associated with immunodeficiency?
• Two possible explanations:
- Confounding by shared lifestyle cancer risk factors
If you smoke or take drugs, that needs to be taken into consideration because the lymphoma
can be associated with these habits.
- A direct effect of HIV, likely through an effect of immune deficiency
- If immune deficiency is responsible, then reversing immune deficiency might decrease cancer risk
Recent increased incidence of cancers in HIV patients
• Increasing survival of patients with HIV might be associated with an increase of traditional cancer
• Aging of the HIV population
Before people with HIV used to die at an earlier age, but due to improvement in treatment there has
been an increased life expectancy. And with age, people get cancer that has nothing to do with
having HIV or not.
• Life style
• Long-term toxicity of ART? (the medication)
• CD4 recovery: When we have HIV, we have a decreased count of CD4. When you get therapy for HIV,
you are supposed to see the restoration of CD4 cell count to normal levels. It can be good for us (in
cancer like Kaposi) but also bad (increase in colon cancer and lung cancer).
- Opportunist cancers
- Traditional cancers?
Incidence of cancers in people with HIV/AIDS compared with immunosuppressed transplant recipients: a
Findings: seven studies of people with HIV/AIDS (n=444172) and five of transplant recipients (n=31977) were
included. For 20 of the 28 types of cancer examined, there was a significantly increased incidence in both
populations. Most of these were cancers with a known infectious cause, including all three types of AIDS-defining cancer, all HPV-related cancers as well as Hodgkin’s lymphoma (HIV/AIDS meta-analysis SIR 11-03, 95% CI8·43-
14·4; transplant 3·89, 2·42-6·26), liver cancer (HIV/AIDS 5·22, 3·32-8·20; transplant 2·13, 1·16-3·91), and stomach
cancer (HIV/AIDS 1·90, 1·53-2·36; transplant 2·04, 1·49-2·79). Most common epithelial cancers did not occur at
InterpretationThe similarity of the pattern of increased risk of cancer in the two populations suggests that it is
immune deficiency, rather than other risk factors for cancer, that is responsible for the increase risk. Infection-
related cancer will probably become an increasingly important complication of long-term HIV infection.
Collect 0.5 million HIV patients and compare to transplant patients. Takes two types of
immunosuppression. One is induced by the medication for the transplant patient and the other by HIV.
The effect of immunosuppression
The incidence in the normal
population is said to be 1.
Increase of EBV related cancers in
both Hodgkin lymphoma and NHL.
Huge increase in Kaposi sarcoma.
Multi step carcinogenesis:
you need the virus and something else, in
this case immunosuppression
HPV related to carcinoma of the
cervix. Transmitted sexually
These stats were then compared to
stats from common epithelial cancers
Common epithelial cancers
There was not much change in the
incidence of normal cancers in the
Immunosuppression leads to the
infection of viral cancers
Sidenote: New studies show Lung cancer is more
increased in HIV and in people with low CD4 cells. Level of immunosuppression and cancer risk
In the case of HIV, it is not about YES or NO, there is a continuum.
- Burkitt median CD4 350-500 (25% EBV)
- Immunoblastic median CD4 50-150 (60% EBV)
- Primary CNS median CD4 10-50 (100% EBV)
Depending on the extent of your immunosuppression, you have different risks
- Median CD4 100-200 (relatively wide interquartile range)
• Hodgkin’s disease
- Median CD4 200-350
• HPV-related cancers
- Any CD4 count
Non-AIDS cancers and CD4: cohort EuroSIDA
Immunosuppression increases incidence even in
non-virally induced cancers
Incidence rates of NHL and KS
When you give good medication, you can control and
decrease the incidence rate of NHL and Kaposi.
1996: they found a good treatment for HIV
NHL after HAART: Australia
HAART: highly active antiretroviral Therapy
decreases the amount of HIV and rebuilds the immune
You see a decrease with better medication Hodgkin lymphoma after HIV: Australia
Better treatment, decrease in lymphoma
Trends in Hodgkin lymphoma and anal cancer
Anal cancer has increased. It is associated with HPV.
Incidence has increased so maybe it has to do with duration of infection and not with immunosuppression.
It might also have to do with the number of subtypes of HPV you are infected with.
Current CD4 count and death from cancer
Even in cancers not known to be linked to virus can be more
frequent in people with low CD4 count