New virus behind cancer, MS?

Nobel Laureate linkurl:Harald zur Hausen;http://nobelprize.org/nobel_prizes/medicine/laureates/2008/hausen.html has a hunch, and he's gathering the data to support it.

Harald zur Hausen
Image: Wikimedia commons

For the past decade, zur Hausen and linkurl:Ethel-Michelle de Villiers,;http://www.dkfz.de/en/tumorvirus-charakterisierung/index.html his scientific partner and wife, are studying a little-known, single-stranded DNA virus -- Torque teno virus (TTV). Preliminary evidence is suggesting it may be an indirect cause or co-factor in certain multi-factorial diseases, including cancer and autoimmune diseases.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 linkurl:Mauro Bendinelli;http://rheumatology.oxfordjournals.org/cgi/content/extract/46/5/885 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 linkurl:James Lawson,;http://notes.med.unsw.edu.au/medweb.nsf/page/resinterestsshowperson?OpenDocument&StaffID=8700008 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 linkurl:isolated multiple TTV genotypes;http://www.ncbi.nlm.nih.gov/pubmed/15220423 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 linkurl:inflammation is an important component,;http://www.ncbi.nlm.nih.gov/pubmed/12858422 such as linkurl:asthma;http://www.ncbi.nlm.nih.gov/pubmed/16136454 in children and some rheumatic diseases in adults, and TTV helps linkurl:increase proinflammatory cytokines.;http://www.ncbi.nlm.nih.gov/pubmed/19765789 "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.
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[16th October 2009]