The Mystery TT Virus--What Is It?

For this article, Leslie Pray interviewed Isa Mushahwar, consultant and retired distinguished research fellow and director of the Virus Discovery Group, Abbott Laboratories, North Chicago, Ill. Data from the Web of Science (ISI, Philadelphia) show that Hot Papers are cited 50 to 100 times more often than the average paper of the same type and age. I.K. Mushahwar et al. J.C. Erker, A.S. Muerhoff, T.P Leary, J.N. Simons, L.G. Birkenmeyer, M.L. Chalmers, T.J. Pilot-Matias, S.M. Dexai, "Molecular and biophysical characterization of TT virus: Evidence for a new virus family infecting humans," Proceedings of the National Academy of Science, USA, 96:3177-82, March 16, 1999. (Cited in 128 papers) In 1997, a group of Japanese scientists discovered a novel virus in a patient hospitalized for an acute illness that was treated as hepatitis. But because the patient's disease was not caused by any of the known hepatitis viruses, the researchers speculated that they had discovered a new kind of hepatitis virus, which they named TT virus, or TTV.1 Since then, however, accumulating evidence strongly suggests that TTV is not hepatitis-related. Instead, it appears to be a very common, widespread, nonpathogenic virus. Most hepatitis cases are caused by one of the five main hepatitis viruses, A-E, "but in the U.S. alone, it is estimated that there are 68,000 cases of post-transfusion hepatitis of unknown etiology still taking place among blood recipients," says Isa Mushahwar, who served as distinguished research fellow and director of the Virus Discovery Group, Abbott Laboratories, North Chicago, Ill., until his retirement in April. Mushahwar is now a consultant for the group, which was established in 1993 to look for a new hepatitis virus to account for all the unexplained cases of hepatitis. Because of its speculated causal link to hepatitis, TTV quickly became the object of intense scrutiny for Mushahwar and his colleagues. They were the first research team to reveal the virus' complete nucleotide sequence, circular nature, and certain biochemical and biophysical characteristics. They found that even though the new virus shares some structural similarities with viruses in the Parvoviridae and Circoviridae families, its biophysical characteristics and genomic makeup are sufficiently different to have its own new viral family, the Circinoviridae, named after the Latin circinatio, which means "the describing of a circle." Their results are presented in this Hot Paper. Following publication, and similar results from another research group, who independently sequenced the virus and published a few months later,2 a slew of TTV research activity began. Based on these initial studies, TTV's prevalence was estimated to be "about two to three percent in the normal population, anywhere you look," says Mushahwar. TTV appeared to occur even among healthy individuals uninfected with hepatitis, raising doubts about any causal link to the disease. TTV's possible association with hepatitis was made even more tenuous by the realization that the initial PCR assays used to detect the virus were flawed, so "the literature was jammed with an underestimation of the frequency of these viruses," Mushahwar says. In a follow-up study to their Hot Paper,3 he and his colleagues "optimized PCR methods for detection of TTV and found, to our amazement, that 33 percent of the volunteer blood donors are infected with it. The virus is ubiquitous." In another PCR-improved study by Japanese researchers, TTV was detected in 92 percent of the general population.4 The fact that it is prevalent among healthy individuals suggests, according to Mushahwar, that it is not only ubiquitous but nonpathogenic as well. "There are a lot of healthy people carrying this virus," he says, "which raises the question: 'What are these viruses doing in humans and not causing any disease?'" The clinical significance of TTV remains unclear. There is a small chance that a variant or subspecies of the virus could cause disease.3 But it's more likely, says Mushahwar, that TTV is simply a harmless endosymbiont. Its nonpathogenic nature is the most interesting and important aspect of TTV's biology thus far, he says. "It is a possibility that through extensive mutation, TTV was rendered to be nonpathogenic over many generations. However, at present, mutual adaptation is the best possible explanation for the existence of endosymbionts. The host and the virus adapt mutually to each other, perhaps because the immune system is not capable of mounting an immune response to these viruses." In addition to TTV, there have been just six other new viruses discovered since 1989, Mushahwar says. But he suspects that researchers will continue to discover other ubiquitous, nonpathogenic viruses as the "very delicate and very sensitive molecular biology techniques being developed to look for viruses" are perfected. Meanwhile, Abbott's discovery group is no longer studying TTV, according to Mushahwar. Their goal, after all, is to find a new hepatitis virus. Leslie Pray can be contacted at lpray@nasw.org. References 1. T. Nishizawa et al., "A novel DNA virus (TTV) associated with elevated transaminase levels in a posttransfusion hepatitis of unknown etiology," Biochemical and Biophysical Research Communications, 241:92-7, 1997. 2. H. Miyata et al., "Identification of a novel GC-rich 113-nucleotide region to complete the circular, single-stranded DNA genome of TT virus, the first human Circovirus," Journal of Virology, 73:3582-6, 1999. 3. T.P. Leary et al., "Improved detection systems for TT virus reveal high prevalence in humans, non-human primates and farm animals," Journal of General Virology, 80:2115-20, 1999. 4. K. Takahashi et al., "Very high prevalence of TT virus (TTV) infection in general population of Japan revealed by a new set of PCR primers," Hepatology Research, 12:233-9, 1998.

The Mystery TT Virus--What Is It?

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