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Brain Damage in Stealth Virus Infected Children
W. John Martin, M.B., B.S., Ph.D.
Abstract
Atypically structured, vacuolating cytopathic stealth viruses exist and can induce multi-system illnesses, including severe brain disease. DNA sequencing studies on an African green monkey simian cytomegalovirus (SCMV)-derived stealth virus has heightened concerns for the potential devastating effects of stealth viruses on living organisms. The prototype stealth virus has lost the major antigenic targets for recognition by cytotoxic T lymphocytes. More impressively, it has captured, amplified and mutated both cellular and bacterial genetic sequences. The term "viteria" has been introduced for viruses containing bacterial sequences. Stealth viruses have been cultured from babies born to infected mothers and from children with a variety of neurological, psychiatric, allergic and neoplastic diseases. The cytopathic changes seen in stealth virus cultures correlate well with the vacuolating cellular damage observed on histological sections of brain tissues obtained on biopsy and on autopsy. Studies to combat the spread of stealth viruses and to effectively treat those already infected are clearly warranted. Additional information is available from the internet at www.ccid.org
Poliovirus Vaccine Contamination
One of society's highest obligations is the protection of its children. Vaccine programs provide a proven method for childhood disease prevention. The safety of such programs has been entrusted to vaccine manufacturers and to government regulatory agencies. Although widely touted as the major medical triumph of the 20th century, the development of viral vaccines has elements of less than stellar performance. The discovery in 1960 of live SV-40 virus contamination in formalin-treated poliovirus vaccine, produced in kidney cells cultures from rhesus monkeys, did not lead to an immediate recall of the contaminated vaccines. Rather, the production method was switched to the use of kidney cells from the less well characterized African green monkeys. This switch in monkey species was soon followed by the decision to forgo formalin inactivation by using a weakened (attenuated) live strain of poliovirus (1). Persisting concerns regarding contaminating viruses in the live poliovaccine led in 1972 to a joint study between the vaccine manufacturer and the United States Food and Drug Administration (FDA). Kidney cultures from all 12 monkeys tested grew African green monkey simian cytomegalovirus (SCMV). Only 4 of the SCMV isolates were detectable using the regular methods for virus detection (2). No changes in testing methodology were imposed, nor was the scientific community alerted to the findings. An explanation that was subsequently offered was that information about the study was deemed to be proprietary. The results of this earlier study were, however, not even conveyed to FDA scientists who, in 1977, notified the Director of the FDA's Bureau of Biologics that certain poliovaccine lots contained unexplained non-cellular DNA; and were, therefore, potentially virally contaminated.
The issue of SCMV contamination of poliovirus vaccines was again raised with the FDA in May 1995. I was then working as a virologist at the University of Southern California. I had developed tissue culture methods that clearly indicated the presence of atypical viruses in patients with complex neurological diseases (3-7). The viruses were striking in that they failed to evoke an inflammatory reaction in the patients from whom they were isolated. They were termed stealth viruses on this basis, and seemingly they lacked target antigens for recognition by the body's cellular immune system. Sequencing studies on a stealth virus strongly suggested it had originated from SCMV. Several meetings with FDA and Center for Disease Control and Prevention (CDC) officials pointed to their unwillingness to allow any outside review of vaccine safety procedures. For example, a simple request to review histological slides of neurological tissue of monkeys inoculated with poliovaccine was refused, again on the basis that it was proprietary information. Noteworthy was the admission that the vaccines were routinely tested in rhesus monkeys because African green monkeys commonly show evidence of neurological disease. Moreover, even in rhesus monkeys, the vaccine was said to induce considerable neurological damage, although less than that induced by non-attenuated poliovirus.
The actual SCMV-related sequence data were published in a respected virology journal in July 1995 (8). The article aroused the interest of anti-vaccine consumer groups. Through the efforts of one of these groups, I was invited to attend a vaccine safety meeting of the Institute of Medicine, National Academy of Sciences (9). The open meeting held on November 6, 1995 was followed the next day by an "executive session." I was later informed that several Industry-connected individuals at this meeting were "furious" that I was allowed to speak. A "watered down" account of what I said subsequently appeared in the official report of the meeting.
Some insight into the lack luster nature of the existing regulatory system was provided by several brief interchanges with Government and other officials during the last several years. For example, I was asked whether formalin treatment would inactivate stealth viruses. My response was that I did not know. The chairman of the National Immunization Advisory Committee suggested the advocacy of a split protocol in which both formalin inactivated and live attenuated poliovaccine would provide the necessary time window for the manufacturer of the inactivated vaccine to develop the stocks required for a complete switch. True to his suggestion, the official switch to inactivated vaccine is scheduled for January 2000. Of course, those "in the know" would have already switched to the inactivated vaccine. An FDA reform bill was being considered by Congress in 1997. I suggested that the bill include the provision that "If a safety issue is identified in the regulation of a biological product, then Industry would waive its proprietary protection so that the information could be made available to the scientific community." The suggestion was well received by the counsel for the House Commerce Committee. It was soon dropped, however, when support was not forthcoming from Industry, FDA or the American Medical Association (AMA). In speaking with an AMA lobbyist, I understood they "would not want the public to know that their doctors were not in the knowledge loop." I once asked industry personnel involved in poliovaccine production whether they were still encountering SCMV in poliovaccine production lots. After some hesitation that disappeared as we all identified ourselves as parents, the straightforward answer was "not infrequently." Armed with this information I again requested an FDA official to please use modern techniques, such as the polymerase chain reaction (PCR), to screen poliovaccine lots for SCMV. "We would not know what to do with a positive result" was his answer.
Sequencing Studies on the SCMV-Derived Stealth Virus
Continued sequencing of the prototype SCMV-derived stealth virus have helped substantiate the original suggestion that stealth adapted viruses lack the critical target antigens for cellular immune recognition (10-11). The virus has a fragmented viral genome (11). While the various fragments cover extensive regions of a typical cytomegalovirus, it is missing sequences that correspond to the known major viral antigens targeted by anti-cytomegalovirus cytotoxic T lymphocytes. Other regions of the cytomegaloviral genome are unevenly distributed, with certain viral genes being markedly over represented. When multiple copies of a gene were identified, it was not uncommon to see minor sequence differences indicating an "error-prone" replication process (10-11).
An overview of the viral sequence data is that approximately two-thirds of the clones contain sequences that correspond to cytomegaloviral genes (10). Where direct comparisons could be made, the genetic sequences matched more closely to rhesus monkey cytomegalovirus than to human cytomegalovirus. Even closer homology could be shown between the stealth virus and the limited known sequences of SCMV. The data are unequivocal that the virus had originated from an SCMV and hence from a poliovaccine (8,10-11).
The question that arose was how could such a fragmented viral genome, lacking certain viral genes while over expressing other viral genes, retain and/or regain its ability to be cytopathic for cells. A partial answer to this question came from analyses of the genes that did not correspond to those of a cytomegalovirus. Several genes were apparently directly incorporated from infected cells. These genes frequently contained short stretches of highly reiterated cellular sequences (12). One set of cellular genes was particularly noteworthy. They corresponded to three copies of a gene that encode a chemokine (13). While the cellular DNA for this gene contain introns, the assimilated genes were lacking introns and had, therefore, been 'captured" as RNA sequences. This finding provided direct evidence for reverse transcription (that is RNA to DNA) in the reconstruction of cytopathic stealth viruses. This process was consistent with the error-prone replication of the stealth virus. Among the cellular genes identified within the stealth virus, were also genes with potential oncogenic (cancer causing) activity (13). This finding highlighted ongoing observations that stealth adapted viruses were being repeatedly detected in both children and adults with various cancers (14 and unpublished observations).
An additional challenging observation was the finding that some of the incorporated sequences had clearly been captured from bacteria (15). The bacterial genes covered a wide range of metabolic functions that could enhance bacterial growth (16). This observation was soon followed by the detection of atypical bacteria within the flora of stealth virus infected patients. Moreover, infectious agents could be released from such bacteria and cause cytopathic effects when transferred to human and to animal cells. The presence of bacterial sequences within viruses infectious for human and animal cells represents a novel life form that has been termed viteria. The prospect exists for metabolically empowered bacteria to establish an increasing presence within nature with potentially devastating biological consequences. The notion that viteria represents "Nature's biological weapons program" is not too far fetched. Information concerning the existence of viteria and their potential Public health consequences was conveyed to CDC, FDA, NIH and the US Congress. Responses are still being awaited from these agencies.
Viteria: An Explanation for Serological and Molecular Findings of Multiple Pathogens in Adults and Children with Chronic Fatigue and Related Illnesses
The recombination of viral, bacterial and cellular genes within broadly infectious viteria could help explain much of the confusion surrounding the cause of chronic fatigue like illnesses in adults, children and household pets. Depending upon the focus of the research, various investigators have ascribed these illnesses to different types of pathogens. Some of the early reports relied upon high antibody titers to Epstein-Barr virus (a type of herpesvirus). Others have noted antibodies reactive with human herpesvirus-6, human herpesvirus-7, human T lymphotropic virus, parvovirus, Borna virus, modified endogenous retroviruses, enteroviruses, including poliovirus, and hepatitis C viruses (17-25). Using molecular techniques, data have been obtained suggesting the presence of mycoplasma species, Chlamydia, Rickettsiae, Brucella and even Borrelia bacteria (26-30). These data are consistent a broad family of viteria that have, and are continuing to, capture, amplify and mutate viral, cellular, bacterial and even fungal genes. Among the cellular/viral genes are likely to be genes encoding the reverse transcriptase of endogenous retroviruses. Although, infection can pass between individuals, including human: animal transmissions, via infected bacteria, the primary brain associated illness is viral not bacterial. The apparent clinical benefits that may occur following antibiotic therapy are potentially explainable by the known capacity of certain antibiotics to modulate chemokine mediated viral activation and replication.
Viteria Detection Systems
The molecular diversity of viteria has helped underscore the value of tissue culture as a primary detection assay. In a relatively straightforward procedure, cells from patients are incubated with normal human and/or animal fibroblasts. The cultures are observed for the development of a vacuolating cytopathgic effect (CPE). For controls, blood samples are obtained from healthy blood donors. None of the controls are expected to yield a positive CPE. In contrast, stealth virus infected patients will typically yield a clearly positive culture. Once established, the cultures can be screened using various immunological and molecular based assays. In particular, cells undergoing CPE will typically stain with polyclonal antisera reactive with various herpesviruses. Similarly, low stringency polymerase chain reaction (PCR) will typically yield multiple products that can be isolated, cloned and sequenced. Semi-quantitative cultures can also be used to assess efficacy of various therapies including chemokine modulating agents and anti-viral drugs. It is also appropriate to screen the bacterial flora of infected individuals for atypical bacteria. If necessary, these can be treated directly using antibiotics and probiotics.
Clinical Studies
During the last decade, I have written several clinical articles describing stealth virus infected patients with complex illnesses. The patients have included children with autism, adults with psychotic disease and several individuals with chronic fatigue/fibromyalgia syndrome. Many of the articles had been summarily dismissed when submitted to major medical journals. The suggestion of a linkage to vaccine use or of community wide epidemics has been unsettling to many reviewers. Still the work has appeared in peer reviewed publications and has been presented at various meetings (31-36). For example, a recent publication (36) described a stealth virus infected child whose illness began in 1997 as a behavioral problem. It took over seven months before the illness was attributed by his parents, both of whom were physicians, to brain damage. Even then a qualified neurologist was unable to detect impaired motor or sensory functions. Yet magnetic resonance imaging (MRI) confirmed extensive sub-cortical brain damage. A brain biopsy showed marked vacuolating/spongiform change. The child's clinical condition progressively deteriorated. He was examined at several major medical centers where it was wrongly concluded that he had a genetic disease from which he would soon die. He was shown to be stealth virus infected by tissue culture and significantly improved with ganciclovir therapy, although he still had major residual deficits. In spite of several courses of anti-viral therapy, with and without steroids, he subsequently succumbed to overt cerebral swelling and herniation.
Other fatal cases have included a young adult initially diagnosed as having a psychotic illness. Four years into this illness, she had an acute exacerbation with coma and massive brain damage (32). Her cerebrospinal fluid grew out a stealth virus closely related to that of the prototype SCMV-derived virus. Another patient with a fatal illness and positive CSF findings died with evidence of a cerebral vasculitis (33).
Virally infected newborn children have variously presented with an acute viral-like syndrome with hepatomegaly, thrombocytopenia, choroid plexus hemorrhage or with more subtle changes comprising unexplained seizure activity and/or delayed neurological development. At least one child, born to a mother with a chronic fatigue like illness, died from a sudden infant death syndrome, two weeks following routine vaccination. Young children have presented with autism, attention deficit and hyperactivity, learning and other behavioral disorders. The association of stealth virus with autism was clearly established in controlled double blind studies. Whereas none of 19 control blood samples tested positive, 13 of 18 children with autism yielded repeated positive stealth virus cultures.
Other culture positive clinical groups have included in-patients in psychiatric institutions, cancer patients, including essentially 100% of patients diagnosed with multiple myeloma, auto-immune illnesses, including systemic lupus erythematosus, rheumatoid arthritis and multiple children diagnosed as having chronic fatigue syndrome. With all of these illnesses, stealth viral infection is viewed as a major contributing factor, complicated by the overlay of auto-immune, allergic and/or neoplastic processes.
Conclusions
An essential theme of this presentation is the apparent lack of responsiveness on the part of those entrusted with the nation's Public Health. While it can be argued that adults need to compete for allocated resources applied to various illnesses, it is difficult to understand the indifference shown to health issues affecting children. Where is the concern that a biopsy-proven childhood viral infection was not recognized at major medical centers? Where is the interest in the many other children who have tested positive for stealth viruses? Why the lack of discussion about possible brain damage causing national tragedies such as school shootings, and the increasing prevalence of autism, attention deficit, asthma and sudden infant death syndrome? Are stealth virus infected patients populating our psychiatric institutions, allergy clinics and even our cancer wards? The world and, in particular, its children appear to be at risk for stealth adapted viruses. The contribution of vaccines to the formation and dissemination of these viruses should be an open topic for scientific discussion. This is not occurring with those presently in charge of overseeing the safety of the Nation's immunization program.
References
1. Paul JR. A history of poliomyelitis. Yale University Press, New Haven, 1971.
2. Unpublished documentation.
3. Martin W.J. Viral infection in CFS patients. in "The Clinical and Scientific Basis of Myalgic Encephalomyelitis Chronic Fatigue Syndrome." Byron M. Hyde Editor. Nightingale Research Foundation Press. Ottawa Canada pp 325-327, 1992.
4. Martin WJ, Zeng LC, Ahmed K, Roy M. Cytomegalovirus-related sequence in an atypical cytopathic virus repeatedly isolated from a patient with chronic fatigue syndrome. Am J Pathol. 1994;145:440-51.
5. Martin WJ. Stealth viruses as neuropathogens. CAP Today. 1994 ;8:67-70.
6. Martin WJ, Glass RT. Acute encephalopathy induced in cats with a stealth virus isolated from a patient with chronic fatigue syndrome. Pathobiology. 1995;63:115-8.
7. Martin WJ. Stealth virus isolated from an autistic child. J Autism Dev Disord. 1995;25:223-4.
8. Martin WJ. Presentation to the Institute of Medicine Meeting on Vaccine Safety, November 6th, 1995. Web site www.ccid.org
9. Martin WJ, Ahmed KN, Zeng LC, Olsen J-C, Seward JC, Seehrai IS. African Green Monkey Origin of the Cytopathic 'Stealth Virus' Isolated from a Patient with Chronic Fatigue Syndrome, Clin Diag Virol 1995; 4: 93-103.
10. Martin WJ. Stealth adaptation of an African green monkey simian cytomegalovirus. Exp Mol Pathol. 1999;66:3-7.
11. Martin WJ. Genetic instability and fragmentation of a stealth viral genome. Pathobiology. 1996;6:9-17.
12. Martin WJ. Cellular sequences in stealth viruses. Pathobiology. 1998;66:53-8.
13. Martin WJ. Melanoma growth stimulatory activity (MGSA/GRO-alpha) chemokine genes incorporated into an African green monkey simian cytomegalovirus-derived stealth virus. Exp Mol Pathol. 1999; 66:15-8.
14. Gollard RP, Mayr A, Rice DA, Martin WJ. Herpesvirus-related sequences in salivary gland tumors. J Exp Clin Can Res.1996;15: 1-4.
15. Martin WJ. Bacteria-related sequences in a simian cytomegalovirus-derived stealth virus culture. Exp Mol Pathol. 1999; 66:8-14.
16. Martin WJ. Viteria: Bacterial sequences in animal and human viruses. J Degenerative Diseases 1999;1:7-10.
17. Jones JF Epstein-Barr virus and the chronic fatigue syndrome: a short review. Microbiol Sci 1988;5:366-9.
18. Di Luca D, Zorzenon M, Mirandola P, Colle R, Botta GA, Cassai E. Human herpesvirus 6 and human herpesvirus 7 in chronic fatigue syndrome. J Clin Microbiol 1995;33:1660-61.
19. Jacobson SK, Daly JS, Thorne GM, McIntosh K. Chronic parvovirus B19 infection resulting in chronic fatigue syndrome: case history and review. Clin Infect Dis 1997 ;24:1048-51.
20. Behan PO, Behan WM, Gow JW, Cavanagh H, Gillespie S. Enteroviruses and postviral fatigue syndrome. Ciba Found Symp 1993;173:146-54.
21. Bruno RL, Creange SJ, Frick NM. Parallels between post-polio fatigue and chronic fatigue syndrome: a common pathophysiology? Am J Med 1998 ;105:66S-73S.
22. DeFreitas E, Hilliard B, Cheney PR, Bell DS, Kiggundu E, Sankey D, Wroblewska Z, Palladino M, Woodward JP, Koprowski H. Retroviral sequences related to human T-lymphotropic virus type II in patients with chronic fatigue immune dysfunction syndrome. Proc Natl Acad Sci U S A 1991;88:2922-6.
23. Holmes MJ, Diack DS, Easingwood. RA, Cross JP, Carlisle B. Electron microscopic immunocytological profiles in chronic fatigue syndrome. J Psychiatr Res 1997;31:115-22.
24. Nakaya T, Takahashi H, Nakamur Y, Kuratsune H, Kitani T, Machii T, Yamanishi K, Ikuta K. Borna disease virus infection in two family clusters of patients with chronic fatigue syndrome. Microbiol Immunol 1999;43:679-89.
25. Barkhuizen A, Rosen HR, Wolf S, Flora K, Benner K, Bennett RM Musculoskeletal pain and fatigue are associated with chronic hepatitis C: a report of 239 hepatology clinic patients. Am J Gastroenterol
1999;94:1355-60.
26. Vojdani A, Choppa PC, Tagle C, Andrin R, Samimi B, Lapp CW. Detection of Mycoplasma genus and Mycoplasma fermentans by PCR in patients with ChronicFatigue Syndrome. FEMS Immunol Med Microbiol 1998;22:355-65.
27. Chia JK, Chia LY. Chronic Chlamydia pneumoniae infection: a treatable cause of chronic fatigue syndrome. Clin Infect Dis 1999;29:452-3.
28. Penttila IA, Harris RJ, Storm P, Haynes D, Worswick DA, Marmion BP. Cytokine dysregulation in the post-Q-fever fatigue syndrome. QJM 1998 ;91:549-60.
29. Ottenweller JE, Natelson BH, Gause WC, Carroll KK, Beldowicz D, Zhou XD, LaManca JJ. Mouse running activity is lowered by Brucella abortus treatment: a potential model to study chronic fatigue. Physiol Behav 1998;63:795-801.
30. Gaudino EA, Coyle PK, Krupp LB. Post-Lyme syndrome and chronic fatigue syndrome. Neuropsychiatric similarities and differences. Arch Neurol 1997; 54:1372-6.
31. Martin WJ. Detection of RNA sequences in cultures of a stealth virus isolated from the cerebrospinal fluid of a health care worker with chronic fatigue syndrome. Case report. Pathobiology. 1997;65:57-60.
32. Martin WJ. Simian cytomegalovirus-related stealth virus isolated from the cerebrospinal fluid of a patient with bipolar psychosis and acute encephalopathy. Pathobiology. 1996;64:64-6.
33. Martin WJ. Stealth viral encephalopathy: report of a fatal case complicated by cerebral vasculitis. Pathobiology. 1996;64:59-63.
34. Martin WJ. Severe stealth virus encephalopathy following chronic-fatigue-syndrome-like illness: clinical and histopathological features. Pathobiology. 1996;64:1-8.
35. Martin WJ, Anderson D. Stealth virus epidemic in the Mohave Valley. I. Initial report of virus isolation. Pathobiology. 1997;65:51-6.
36. Martin WJ, Anderson D. Stealth virus epidemic in the Mohave Valley: Severe vacuolating encephalopathy in a child presenting with a behavioral disorder. Exp Mol Pathol. 1999; 66:19-30.
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