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Addressing 675 young scientists at last month's 60th Meeting of the Nobel Laureates in Lindau, Germany, zur Hausen presented new findings on TTV. He and de Villiers have identified viral proteins that resemble certain MS auto-antigens in brain lesions of patients with multiple sclerosis. He's also found segments of TTV genomes in many cancer cell lines, including leukemia and Hodgkin's lymphoma lines, with no similar patterns in normal human tissues. He's found relatively high levels of complete TTV sequences in gastrointestinal, breast, lung cancers, as well as in samples of leukemia and myeloma. But the virus is also present at high levels in normal tissues.
Still, in TTV-infected tissues and cell lines, zur Hausen and de Villiers have found evidence of genomic rearrangements, and have linked a specific small region of TTV in cancer cells to truncated host cell genes. Given that studies have also linked TTV to immunosuppression and immunomodulation, chronic inflammation, prevention of apoptosis, and chromosomal aberrations, they suggest that TTV may act as an indirect carcinogen. Unlike human papillomavirus (HPV), which has a direct oncogenic effect on cells, TTV alone may not trigger disease -- but when combined with host factors such as higher levels of pro-inflammatory cytokines, and other diseases such as malaria, that recipe could create problems.
"There is a range of intriguing data on TTV, but a connection has not yet been proven," zur Hausen told The Scientist.
It's right to be cautious, said Mauro Bendinelli of the University of Pisa in Italy, who also studies TTV's potential role in disease. "The mere presence of TTV DNA inside tumor cells means very little or nothing at all, given that the virus is so pervasive," he said. "Thus, the data currently available do not permit us to say anything more than that TTV should be investigated as a possible environmental co-factor in the process of carcinogenesis," Bendinelli said.
First identified in the liver of a hepatitis patient in 1997 by Tsutomu Nishizawa of Jishi Medical School in Tochigi-ken in Japan, TTV is the first virus found in a new class of anelloviruses, and has now been found in many infants and most healthy adults, and in 100 percent of the population in certain geographical areas. This makes it more difficult to study because it is difficult to find normal controls for comparison, according to James Lawson, a virologist at the University of New South Wales in Australia, who focuses on HPV and breast cancer.
But it is precisely these challenges that attracted zur Hausen to TTV. "This virus fascinated me due to its ubiquitous nature, its presence in the hematopoietic system, and its remarkable heterogeneity." His experience with Epstein-Barr virus, as well, suggested to him that these ubiquitous viruses could, under certain circumstances, wreak havoc.
Indeed, TTV mutates relatively easily, as zur Hausen demonstrated in a Journal of Virology paper, in which he isolated multiple TTV genotypes from the spleen of one Hodgkin's disease patient. Given its susceptibility to genetic modification, the virus may mutate to express proteins similar to the host's, zur Hausen reasoned. "Such sequences, which have been found in asthma and rheumatoid arthritis as well as MS patients, may lead to autoimmune reactions," he said.
Technical issues also make TTV a challenge to study, said Bendinelli. "It is very difficult to culture, and animal models are lacking." Bendinelli has found that elevated levels of TTV variants may be preferentially associated with severe forms of certain diseases in which inflammation is an important component, such as asthma in children and some rheumatic diseases in adults, and TTV helps increase proinflammatory cytokines. "We don't know what the consequences are of long-term TTV infection, but it is my impression that viruses can do damage to hosts by keeping levels of inflammation high so that any other pathogen can also add to the harm," Bendinelli said. Claudia Figueiredo of the Oswaldo Cruz Institute in Rio de Janeiro, Brazil is also among the scientists pursuing the TTV-cancer link.
"I am fully convinced that viruses that cause so pervasive, persistent and highly productive infections as the anelloviruses should not be too easily dismissed as a potential cause of damage to human health," said Lawson. However, "extremely low viral load in some cancers, the latency period between infection and cancer, the rarity of cancer following common infection, the influence of co-factors such as hormones and genetic susceptibility, and problems with lab techniques with detecting viral sequences are some issues we deal with to build a case for causality," he said.
Zur Hausen is used to long odds, and skepticism from others. In the early 1980s, when he was pursuing his hypothesis that HPV can cause cervical cancer, many colleagues thought he was misguided. In 2008, that research earned him the Nobel Prize in Physiology or Medicine.
Related stories:
[7th September 2009]
[6th October 2008]
[16th October 2009]
[Comment posted 2012-02-02 21:11:53]
Mark - LINK
[Comment posted 2010-09-06 04:48:43]
Although I read the very interesting article by Vicky Brower almost three weeks ago, I decided to wait till today before replying to the idea that TTV may be a bona-fide cancer-causing virus. In the last week, Elsevier published the on-line version of our editorial, which discusses of viruses possibly linked to prostate carcinoma (PCa) {Rovigatti, #5891}. In this way, I have at least one recently published article on this subject: unknown or candidate human cancer viruses. Among candidate cancer-causing viruses for prostate carcinoma, we didn?t discuss TTV, because it is not considered a likely possibility in Pca {Rovigatti, #5891}. Likewise, the associations discovered so far between TTV and other human malignancies seem to be indirect and explainable by higher levels of inflammation in several diseases in general and cancer in particular.
Unfortunately, Brower?s editorial appears without any publication as yet of hard-data and of molecular mechanisms on the hypothetical role of TTV cancer-causal role (by Zur Hausen or others). However, particularly the catching title and the last sentences may give the readers the impression that there is good evidence indeed for TTV as a cancer-causing virus. The last paragraph on the endurance of Zur Hausen after his discovery of the HPV association with cervical cancer in the early ?80s is just a character description of Prof. Zur Hausen and an opinion of a TTV-cancer link. It doesn?t necessarily implies or tells us something ?without hard and published data- about the reality of such an association and of the cancer-causing nature of TTV. However, most of the readers? comments so far seemed to go that way and even further (association with schizophrenia, all illnesses have infectious origins, etc.).
This brings to mind the announcement on the front page of the New York Times in 1998 of the discovery of angiostatin and endostatin by Judah Folkman?s group: both compounds dramatically shrink experimental tumours, by cutting blood supplies. However, in the same New York Times front-page, Jim Watson went commenting: ?Judah?s going to cure cancer in two years time?. Unfortunately, cancer has not been cured as yet neither by Folkman nor by others, although Avastin (bevacizumab) has extended the lives of certain types of colon cancer patients by approximately five months.
In science, precision in defining problems and experimental results is essential. I believe, that the best assessment of TTV role in human cancer was given, in the article by Vicky Brower , by Mauro Bendinelli (with whom I rarely agree). He said: "The mere presence of TTV DNA inside tumor cells means very little or nothing at all, given that the virus is so pervasive". Pervasiveness of TTV is one of the problems, the others are: 2. presence in healthy subjects and 3. lack of a clear carcinogenic mechanism and 4. epidemiological data.
1. Pervasiveness, i.e. the presence of TTV in the great majority of invividuals, seems to be irreconcilable with the most accepted models of carcinogenesis: that cancer onset is probably associated with a new infection. This is particularly true in the field of leukemia and lymphomas, which was extensively reviewed by Zur Hausen and De Villiers and the issue is strongly related to epidemiological data (see point 4). Even the ontogeny of such an infection clearly indicates a rapid acquisition of this virus infection in newborns and infants, so that by one year of age 100% of humans appear to be infected by TTV. Even double or triple infections are rather common, reaching similar levels at one year. In this sense, TTV appears to be more an obligate parasite of H. sapiens, with a role similar to E. coli in intestinal infections, rather than a cancer-causing virus.
2. Presence in healthy subjects. In order to find or hypothesize any association with TTV (or any viral infection), it would be essential to identify the virus only in affected individuals. Indeed, this is one of the four Koch?s postulates, even after ?revision? or ?correction? and this is also a logical requirement for an aetiological agent. However, this is obviously not true for TTV, since it is present in 100% individuals (previous point). Even numerous attempts to associate presence or higher frequency of TTV infection with disease (for example, liver disease) have failed. In a recent report from Russia, TTV was detected in over 90% of 512 very healthy athletes, with titers over 103.
3. Lack of demonstrated carcinogenic mechanisms. For any disease and particularly for cancer, a mechanism for disease onset should be hypothesized, which should be plausible and demonstrable/falsifiable through experimentation. For example, in the above mentioned association between prostate carcinoma (PCa) and a newly detected gamma retrovirus (XMRV), the initial discovery was followed by several articles describing the integration sites of XMRV in PCa and a mechanism of ?promoter-insertion? has been proposed. A carcinogenic mechanism ?so called ?target cell conditioning model?- proposed by Zur Hausen/De Villiers in a paper published in 2005 (in the journal International Journal of Cancer) involved genetic instability and the possibility that TTV induced chromosomal translocations: however, no data were presented in that paper nor later on. Switch to a different virus Furtermore, in a later article published in 2009 (still in IJC) without De Villiers as co-author, Zur Hausen changed the ?target cell conditioning model?, by switching to a different virus: not TT virus anymore but a PAPOVA virus. It is not completely clear (from reading the article) why he chose a different candidate, since direct evidence is missing for either of them, but obviously, carcinogenic mechanisms are well known for Papova viruses on the basis of their inactivation through their T antigens of essential cellular regulators such as p53 and pRB. Zur Hausen also underlines previous work in which replication-defective Papova viruses (SV40) were shown to become highly transforming: therefore his model now includes a ?defective? but still unknown (=not discovered yet) Papova virus.
4. Epidemiological Data and Previous Models for Leukaemia/Lymphoma. In both the 2005 and 2009 papers, Zur Hausen (with De Villiers in 2005) emphasizes the importance of previous epidemiological data for understanding the origins of human leukaemia/lymphoma in connection to TT or papova virus. Two major models are discussed in both papers: Kinlen?s and Greaves models. Previously (in 2004 and before) we had also emphasized the possibility that today?s leukaemia models could be explained by a viral infection: the virus we proposed was isolated from a cancer-cluster, such as the ones considered in Kinlen?s model, and is called MFV (also discussed in our recent paper).
Leo Kinlen observed dramatic increases in leukaemia incidence in aggregates or excesses of cases associated in space and time (also called cancer-clusters). His model considers a population or group -typically segregated and previously unexposed to a relatively common infectious agent (unknown, called Agent X)- when becomes exposed to such X Agent through migration. For example, when a group of migrants from a densely populated city or town migrates to a sparsely populated area: the immigrants will carry with themselves such an X Agent, toward which they have built immunity (herd immunity), but the autochthonous population will be completely susceptible to Agent X, in view of their lacking immunization. According to Kinlen, such mechanism could explain the presence of leukaemia/lymphoma excesses (cancer clusters) often documented in UK, US and elsewhere.
Melvin Greaves focused initially his research on leukaemia in homozygous vs heterozygous twins, characterized by specific chromosomal translocations (such as MLLs and Tel-AML-1), which typically affect transcription factors. Homozygous twins display in certain types of leukaemia but not in others (for example in the infant leukaemia with MLL rearrangements) identical breakpoints, thus suggesting that an initial rearrangement occurred in utero and then pre-leukemic cells spread to the homozygous twin through placental anastomoses. Presence of such prenatal translocations was confirmed by the study of blood collected at birth through Guthrie?s cards. According to Greaves, this phenomenon could also explain the diagnosis of twin cases up to 9 years apart, if a second event could be the actual and final trigger of the disease: in his model, the second event is most likely infectious in nature, but not necessarily linked to a specific agent (Agent X as in Kinlen?s model): it could correspond to any stress to the immune system. Logical consequence of the model was the study of the presence of specific translocations at time of birth on Guthire?s card: these are present with frequencies 100 times higher than actual leukaemia cases, once more indicating the logical need for a second or triggering event.
In the 2005 and 2009 papers Zur Hausen suggested that the infectious agent responsible for either Kinlen?s model (Agent X) or Greaves model 2nd hit is either TTV (2005) or a Papova Virus (2009) through the ?target cell conditioning model?, which was accordingly modified in the 2009 version. To the contrary, starting from 1988, we have proposed that the responsible agent is MFV, a virus, which was indeed isolated from a cancer cluster of paediatric tumours (2004) and which is also described in the recently published paper in connection to prostate cancer. As I have emphasized in this ?rather long- response to Vicky Brower?s interesting editorial, what surprises in Zur Hausen proposal for TTV as candidate is: 1. pervasiveness of TTV infection; 2. presence of TTV in perfectly healthy subjects; 3. lack of hard data on mechanism of carcinogenesis: for example, no experiment so far has induced leukaemia or cancer with TTV in experimental animals (as we have done with MFV in mice and rats); 4. lack of epidemiological data, which could provide a reasonable basis for TTV in cancer-clusters or in population-mixing episodes.
Finally, the mind-changing between the 2005 (with De Villiers) for TTV and the 2009 (alone) for Papova Virus is also surprising, in view of this new reconsideration in 2010, again for TTV, according the editorial. This flip-flopping (also surprising that it was not picked-up before but most people don?t read entire scientific articles) doesn?t add credibility to the TTV involvement in leukaemia/lymphoma.
[Comment posted 2010-08-19 09:10:54]
"Lactoferrin probably exerts its effect at the level of viral adsorption"
A high level of iron in the body DISALLOWS lactoferrin from stopping the virus bacteria or fungus AT the door.
?We recently found that bovine lactoferrin (bLF), a milk glycoprotein belonging to the iron transporter family, prevented hepatitis C virus
(HCV) infection in human hepatocyte PH5CH8 cells, that are susceptible to HCV infection, and demonstrated that the anti-HCV activity of bLF was due to the interaction of bLF and HCV.?
These two articles explain it.
?Reuters March 2, 2007 ? Findings from a study of Olympic wrestlers indicate that hepatitis B is found in the sweat of infected individuals, and so sweating might be a way that the virus could be passed between participants in contact sports.?
?20 May 02 Starving the bacteria that cause body odour of the iron they need to grow may soon arm deodorants with an extra stink-stopping weapon.?
?Efficient iron withdrawal has the potential to provide the basis for new fungal growth control strategies.?
?Researchers Demonstrate That Toenail Fungus and Athlete?s Foot Spread From Person to Person?
Picolinic acid is an iron chelator.
"A Novel Topical Antiviral Agent, PCL-016 (Picolinic Acid), Inhibits Adenovirus Replication in the Ad5/NZW Rabbit Ocular Model"
"Relation between virulence and resistance to lactoferrin"
"Intracellular Chelation of Iron by Bipyridyl Inhibits DNA Virus Replication"
[Comment posted 2010-08-18 22:53:11]
When it comes to therapies of cancer (or viral infections or chronic inflammation) the timing of treatment may indeed be pivotal in determining which way an immune response is driven - successfully or unsuccessfully - for the individual.
[Comment posted 2010-08-18 17:47:13]
[Comment posted 2010-08-18 17:12:44]
[Comment posted 2010-08-18 12:09:25]
[Comment posted 2010-08-18 11:57:51]
[Comment posted 2010-08-18 11:47:15]
All diseases are tied to infectious agents.
But just think about it... our genome is comprised of multiple segments (infectious agents or parts of ) that evolved from the earlist life form.