Journal of IiME Volume 3 Issue 1 www.investinme.org Human enteroviruses and chronic infectious disease (continued) subsequent infection with poliovirus is quickly suppressed by the pre-existing anti-poliovirus immunity and the virus infection eradicated. But of course, anti-poliovirus protective immunity does not protect from being infected with a different HEV. Human enterovirus virions are small at 29nm in diameter; said another way, this means about 345,000 viruses would need to be lined up to equal one centimeter. The virus particle consists of an ordered array of 4 capsid proteins that forms an icosahedral structure of incredible beauty. In Figure 1, the reader can see what the coxsackievirus B3 (CVB3) virion would look like were one able to actually see it. This structure was solved with a technique called X-ray crystallography(23) in which X-rays, which are directed through crystals of virus and bent in specific ways, are then interpreted by computer analysis to provide a virus structure. Numerous other images of related enteroviruses can be found by visiting the website of the Institute for Molecular Virology at the University of Wisconsin in Madison WI, USA. The HEV cause a plethora of different human diseases and syndromes, the most important of which are poliomyelitis [now largely, although not entirely, eradicated in the world through use of the vaccines(16)], meningitis and encephalitis, myocarditis, pancreatitis, myositis, and type 1 (insulin dependent) diabetes (T1D)(31). Recent work has also indicated a possible role for HEV in the poorly understood etiology of chronic fatigue syndrome (CFS)(9, 11). Polio, T1D and CFS are noteworthy, in that these diseases are chronic and in the case of polio and T1D, fatal without treatment. Certainly, fatal cases of the other HEV diseases occur as well(28) but as a rule, HEV diseases are deemed to be acute illnesses of relatively low clinical importance because they are so common. Nonetheless, 5-10 million cases of symptomatic HEV infections occur annually in the US alone(27). Group B coxsackievirus infection of the heart Within only a few years after their discovery in Invest in ME (Charity Nr. 1114035) the late 1940s, the group B coxsackieviruses (CVB) were shown to be involved in inflammatory heart disease or myocarditis(6, 12, 32). Because of the ease with which the CVB replicated in mice, an experimental model to study myocarditis was soon available and has been exploited for numerous studies over the years. Once myocardial biopsy techniques became widespread as a clinical assay for the presence of myocarditis(29), researchers became interested in determining how often HEV was associated with myocarditis. These studies have demonstrated that about 15-20% of adult myocarditis cases can be associated with an HEV infection(2). This was carried out in most cases by isolating RNA from very small biopsy samples of the human heart, then analyzing the RNA for the presence of HEV RNA using a variety of techniques. Interestingly, in those adult cases of myocarditis in which the presence of virus was shown by detecting the viral RNA, rarely can an infectious virus be isolated. This is confusing: how can one detect viral RNA and not detect the virus? And indeed, this was a conundrum for many years. Most HEV cause cells in culture to die; this outcome, termed cytopathic effect or cpe, is the result of the virus infecting the cells in culture and killing them in the process of producing the next virus generation. Failure to observe cpe upon inoculating cell cultures with homogenized heart samples, was taken to be evidence that virus qua virus was not present. This goes back to the foregoing discussion, in which the general view of HEV is as a virus that rapidly causes cell lysis (acute disease). As opposed to adult samples, samples of pediatric myocarditic heart tissue generally shows both the presence of cytopathic virus when placed in culture as well as the presence of viral RNA when molecular assays are carried out. We considered the possibility that HEV infections of adult human hearts might generate a population of viruses that have been characterized and termed defective interfering (DI) viruses(10, 13). Although DI Page 24/76
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