1. HHV-6 News

Sept 21, 2008

CFS Researcher John Martin links Chronic Fatigue Syndrome and Autism

24-7PressRelease - Burbank, CA, June 27, 2008

A natural therapy that activates the alternative cellular energy (ACE) pathway has been developed by the Institute of Progressive Medicine and is available for extended clinical studies in patients with various illnesses, including autism. Qualified parents of autistic children are being offered the opportunity to participate in these studies by acting as clinical investigators within the Institute of Progressive Medicine. According to Dr. W. John Martin, MD, PhD. founder of the Institute of Progressive Medicine, the increasing incidence of autism is attributed to a relatively silent epidemic of an infectious disease process affecting adults that, in pregnant women, can cause brain damage of the fetus leading to the subsequent development of autism. He firmly believes the infectious agents are "stealth adapted" viruses that lack the antigenic components normally targeted by the cellular immune system. "There has been an over emphasis on some of potential triggering factors of an autism breakdown," stated Dr. Martin, "rather than pursuing the fundamental cause of autism; seeking a truly effective therapy ;and most importantly, trying to prevent autism from developing in a susceptible, stealth adapted virus infected child."

The current treatment protocol is predicated upon the underlying postulate that autism is primarily caused a congenitally acquired, persisting, non-inflammatory viral infection that can not be effectively controlled by the immune system. Dr. Martin has proposed and has now proven that the body has an auxiliary defense mechanism beyond the immune system, which can suppress the cell damaging effects of viruses, including those that are stealth adapted. This protection can be increased by activating the ACE pathway using products termed enerceuticals. Some of these products work well if placed against the body and illuminated with an ultraviolet-A light.

The autism related studies using a light stimulated enerceutical medical device are being coordinated, in part, by Mr. BJ McKelvie, the co-producer of the autism anthem song "I'm in Here." "We have begun to see remarkable improvements in the treated children" commented Mr. McKelvie. "It is time to move forward with much more extensive clinical testing and for this we need parent participation. With a well coordinated effort, we can potentially achieve at least a 50% improvement in the intellectual and social functioning of children labeled as being autistic. This has occurred with my own son immediately after beginning the therapy."

While still investigational, the studies also hold promise as a potential approach to preventing autism from occurring in children born to mothers presumptively infected with a stealth adapted virus. "Maintaining an active ACE pathway during the first few years of life may help virus infected infants resist some of the suspected triggers of an autistic breakdown in interpersonal communication" commented Dr. Martin. "A major challenge for public health authorities is to stop denying the existence of stealth adapted viruses, some of which clearly originated from African green monkey simian cytomegalovirus (SCMV) contamination of earlier batches of live polio virus vaccines."

More information on this topic is available at www.s3support.com or my sending an e-mail to s3support@mail.com Parent enrollment procedures for the autism study can be viewed at the web site www.iminhere.ca or obtained by contacting Mr. BJ McKelvie via e-mail to bj@iminhere.ca

About Inst. of Progressive Medicine

The Institute of Progressive Medicine is a non-profit public charity headquartered in Burbank CA. It's nationwide team of investigators is seeking simple yet effective method of disease prevention and therapy that can help empower the public and not be restricted by their lack of profitability to the medical system or by political considerations of the public health authorities and many of the existing major patient support groups. Telephone (626) 616-2868.

24-7PressRelease/ - BURBANK, CA, April 04, 2007

The talk began with an overview of the history of poliomyelitis and the development of polio vaccines. It identified several missteps in this process including the decision to use freshly cultivated kidney cells from monkeys, rather than a well characterized cell line, for vaccine production. The issue of SV40 contamination of vaccines produced in kidney cells of rhesus monkeys led to a switch in 1961 to the use of African green monkeys. In 1972 it was realized that African green monkey kidney cell cultures were commonly contaminated with simian cytomegalovirus (SCMV). Industry and the Food and Drug Administration (FDA) chose not to make this information public arguing that many millions of doses had been used without signs of an acute CMV illness. The possibility of SCMV causing chronic illness was seemingly not considered even though other viruses were known at the time to become latent in the body.

In 1991, Dr. Martin isolated a cell damaging virus from a patient with chronic fatigue syndrome (CFS). The virus was shown to be an atypical CMV and to have been derived from SCMV. The FDA and the Centers for Disease Control and Prevention (CDC) were notified of this finding with the clear inference that the virus probably came from a contaminated polio virus vaccine. The virus causes a severe illness in cats without evoking any inflammatory reaction, the usual hallmark of an infectious disease. Dr. Martin reasoned that the virus had possibly lost or mutated the relatively few viral genes that provide the major target antigens for the cellular immune response. He drew the analogy to a terrorist who avoids homeland security by not wearing military insignia. The terrorist can still cause extensive damage, as can viruses that go unseen by the cellular immune system. Dr. Martin introduced the terms "stealth" and "stealth adapted" to characterize a generic grouping of viruses lacking components for effective immune recognition. Many patients with complex neurological and psychiatric diseases were shown by blood cultures to be infected with stealth adapted viruses, some of which were unequivocally derived from SCMV. As predicted, DNA sequencing of the stealth SCMV confirmed the loss or mutation of the three viral genes that code for the dominant cytomegaloviral antigens normally targeted by the cellular immune system.

The FDA and CDC were unwilling or unable to accept the concept of stealth adaptation and have seemingly been hesitant to criticize vaccines. By 1998, however, the decision was made to switch from using live polio virus vaccines (Sabin type) back to formalin inactivated polio vaccine (Salk type). Finally in 2002, FDA examined older lots of polio virus vaccines for DNA of SCMV. Three of 8 lots from the mid-1970's clearly contained SCMV DNA. More extensive and similarly positive results were obtained in British studies on their vaccines.

Human CMV is the most common infectious cause of infant deaths in the United States, exceeding that of infant AIDS (400 versus less than 50). Moreover, CMV is a common cause of mental retardation and/or hearing and visual impairment, with an estimated 8,000 children affected annually. Congenital CMV has been linked to several cases of autism. It is negligence that the FDA and CDC have not followed up on the finding of SCMV DNA contamination of licensed vaccines, and to have not screened some of these children to determine if their CMV is always of human and never of simian origin. FDA has simply argued that they could not culture virus from these old vaccines and yet, for proprietary reasons, can not provide the contaminated vaccines for independent virus culture studies.

Dr. Martin has reported isolating stealth adapted viruses from autistic children. Congenital infection is consistent with the biochemical evidence of neurological damage at birth in children who subsequently become autistic. A viral infection can cause the diverse symptoms seen in autistic children and can explain some of the illnesses seen in other family members, including mothers. An underlying viral infection would also be expected to predispose an individual to heightened susceptibility to various toxins and to be influenced by various nutritional and genetic factors.

Dr. Martin expressed criticism of the "business of autism" with the selling of products and services at excessive profits, performance of irrelevant laboratory tests, and the hyping of various supposed therapies. Few specialists are well qualified to address autism as a potentially infectious disease of the brain. Unfortunately, some practitioners are also engaging in financial kickbacks with little regard for rigorous science and clinical validation.

In spite of the absence of an effective immune response, the body is able to counter stealth adapted viruses through an alternative cellular energy (ACE) pathway. Indeed, autism can be simplified to a problem of insufficient cellular energy for optimal brain functioning. Various natural products with ACE activity are available for clinical trails.

In summary, Dr. Martin expressed his strong belief that i) stealth adapted viruses exist and can explain the increasing incidence of many types of diseases including autism. ii) The body has an auxiliary defense mechanism that extends beyond the immune system that can provide cellular energy for healing. iii) Enhancing the alternative cellular energy (ACE) pathway will be useful in the prevention and therapy of autism. Additional information on the talk and copies of the presented slides are available at http://www.s3support.com E-mail enquires are welcome at s3support@mail.com

About The Institute of Progressive Medicine The Institute of Progressive Medicine is a Public Charity. Its faculty includes members with expertise in infectious diseases.

Kent Heckenlively of Age of Autism on John Martin and the Stealth viruses in Autism.

September 11, 2008

Autism Causes: Virus Weaves Itself into the DNA Transferred from Parents to Babies

University of Rochester Medical Center

Parents expect to pass on their eye or hair color, their knobby knees or their big feet to their children through their genes. But they don’t expect to pass on viruses through those same genes.

New research from the University of Rochester Medical Center shows that some parents pass on the human herpes virus 6 (HHV-6) to their children because it is integrated into their chromosomes. This is the first time a virus has been shown to become part of the human DNA and then get passed to subsequent generations. This unique mode of congenital infection may be occurring in as many as 1 of every 116 newborns, and the long-term consequences for a child’s development and immune system are unknown.

“At this point, we know very little about the implications of this type of infection, but the section of the chromosome into which the virus appears to integrate is important to the maintenance of normal immune function,” said Caroline Breese Hall, M.D., professor of Pediatrics and Medicine at the University of Rochester Medical Center, and author of the study which publishes in Pediatrics this month. “With further study, we hope to discern whether this type of infection affects children differently than children infected after birth.”

HHV-6 causes roseola, an infection that is nearly universal by 3 years of age. The typical roseola syndrome produces several days and up to a week of a high fever and may have variable other symptoms including mild respiratory and gastrointestinal symptoms. With roseola, just as the fever breaks, the child may briefly develop a rash. A congenital infection of HHV-6 – or one that is present at birth – produces high levels of virus in the body but scientists (doctors) do not know whether it produces any developmental or immune system problems.

Some congenital infections can cause serious problems in fetuses. If a mother contracts cytomegalovirus (CMV) while pregnant, her fetus is at risk of hearing or vision loss, developmental disabilities and problems with the lungs, liver and spleen. Some of those health problems don’t show up until months or years after birth. HHV-6 virus is a closely related virus to CMV, and the congenital infection rate of CMV is similar to that of congenital HHV-6 – about 1 percent. However, this research shows that a congenital HHV-6 infection differs greatly from a congenital CMV infection in that it is often integrated into the chromosomes of the baby rather than passed through the placenta.

“This is the first time a herpes virus has been recognized to integrate into the human genome. To think that it’s actually a part of us – that’s really fascinating,” said Mary Caserta, M.D., associate professor of Pediatrics at the University of Rochester Medical Center and one of the paper’s authors. “This opens up a whole new realm of exploration.”

Of 254 children enrolled in this study between July 2003 and April 2007, 43 had congenital HHV-6 infections based on cord blood samples. Of 211 children without congenital infection, 42 were children who acquired an HHV-6 infection during the study. Of the infants who had congenital infections, 86 percent of them (37) had the virus integrated into their chromosomes. Only six of the congenitally infected babies were infected by the mother through the placenta .

Children who had integrated HHV-6 had higher levels of virus in the body than those who were infected through the placenta. HHV-6 DNA was found in the hair of one parent of all children with integrated virus with available parental samples (18 mothers and 11 fathers), which means the children acquired the integrated infections through their mother’s egg or father’s sperm at conception. The virus’s DNA was not found in hair samples of parents of children who were infected after birth.

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This study is part of a series of ongoing studies on children with HHV-6 infections at the University’s Golisano Children’s Hospital at Strong. This study was funded by grants from the National Institute of Child Health and Development and, in part, by grants from the General Clinical Research Center, the National Center for Research Resources, the National Institutes of Health and the HHV-6 Foundation.

July 9, 2008

Patent suggests a potential animal model for HHV-6 infection that may link AIDS, CFS, MS, autism and many other serious medical problems

Note: the following is United States Patent 20060130161 which can be found at http://www.freepatentsonline.com/y2006/0130161.html

Provided are non-human animal model systems for viral pathogenesis of neurodegeneration, autoimmune demyelination, and autoimmune diseases such as diseases of the central ]nervous system, including multiple sclerosis (MS), and diabetes. Such non-human animal model systems may be suitably employed for the study of diseases such as MS and diabetes and for the identification and characterization of candidate therapeutic compounds and compositions for the treatment of such diseases. Also provided herein are markers and methods for the detection, in patients susceptible to autoimmune disease, of autoimmune diseases of the central nervous system such as progressive multifocal leukoencephalopathy (PML) following treatment with one or more therapeutic agent as exemplified herein by the therapeutic agent natalizumab. Exemplary animal model systems comprise marmosets infected with a herpesvirus such as HHV6-A and HHV6-B, transgenic mouse and zebrafish animal model systems wherein the transgene encodes CD46, and methods for monitoring the risks of patients having MS, diabetes and other auto-immune disorders treated with anti-adhesion molecules such as natalizumab.

Inventors:

Genain, Claude (Mill Valley, CA, US) Application Number: 11/248499 Publication Date: 06/15/2006 Filing Date: 10/12/2005 View Patent Images: Images are available in PDF form when logged in. To view PDFs, Login or Create Account (Free!) Referenced by: View patents that cite this patent Export Citation: Click for automatic bibliography generation Assignee: CARANTECH, INC. (Mill Valley, CA, US) Primary Class: 800/14 International Classes: A01K67/027 Attorney, Agent or Firm: SPECKMAN LAW GROUP PLLC (1201 THIRD AVENUE, SUITE 330, SEATTLE, WA, 98101, US) Claims: What is claimed is:

  1. A non-human animal model system for multiple sclerosis (MS) said non-human animal model system comprising a monkey and a herpesvirus wherein said monkey is infected with said herpesvirus.

  2. The non-human animal model system of claim 1 wherein said monkey is selected from the group consisting of a marmoset, a New World monkey, and an Old World monkey, wherein said monkey is susceptible to infection with said herpesvirus.

  3. The non-human animal model system of claim 2 wherein said marmoset is C. jacchus.

  4. The non-human animal model system of claim 1 wherein said herpesvirus is selected from the group consisting of HHV6-A and HHV6-B.

  5. The non-human animal model system of claim 1 wherein a single exposure of said monkey to said herpesvirus triggers and/or increases the severity of a central nervous system inflammatory disease.

  6. The non-human animal model system of claim 1 wherein more than one exposure of said monkey to said herpesvirus triggers and/or increases the severity of a central nervous system inflammatory disease.

  7. The non-human animal model system of claim 5 or claim 6 wherein said central nervous system inflammatory disease is multiple sclerosis.

  8. The non-human animal model system of claim 1 wherein one or more exposure of said monkey to said herpesvirus, other herpes virus, or other virus triggers and/or increases the severity of other inflammatory diseases or malignancies of the central or peripheral nervous systems and neuromuscular junction selected from the group consisting of paraneoplastic syndromes and cerebellar degenration, limbic encephalitis, opsoclonus myoclonus, subacute sclerosing panencephalitis (SSPE), PML and other diffuse or focal leukodystrophies (early and late onset), acute and chronic polyneurpathies and polyradiculopathies, acute disseminated encephalomyelitis, myopathy, myasthenia gravis, Guillain Barre, miller-Fisher syndrome, Eaton Lambert syndrome, CNS vasculitis, sarcoidosis and neurosarcoid, Rasmussen's disease, paraneoplastic sensory neuropathy, CNS lymphoma, high and low grade oligodendroglioma and glioblastoma, glioblastoma multiformis, optic nerve glioma and meningioma, ependymoma and medulloblastoma.

  9. The non-human animal model system of claim 1 wherein one or more exposure of said monkey to said herpesvirus or another virus results, triggers, and/or increases severity of other neurological disorders of unknown cause that include an inflammatory component selected from the group consisting of narcolepsy, chronic fatigue syndrome, stiff man syndrome, and autism in children.

  10. The non-human animal model system of claim 1 wherein one or more exposure of said monkey to said herpesvirus triggers and/or increases the severity of an inflammatory disease and/or autoimmune disorder selected from the group consisting of diabetes, arthritis, anemia, lupus, pemphigus, thyroiditis, glomerular or intersticial nephritis, cardiomyopathy, myositis, dermatomyositis, hepatitis, and ulcerative colitis.

  11. The non-human animal model system of claim 1 wherein said animal model system is suitable for the identification of factors mediating the direct toxicity of said herpesvirus towards a cell type selected from the group consisting of oligodendrocytes, astrocytes, and brain cells.

  12. A transgenic mouse model system, comprising a transgene encoding CD46 and a herpesvirus, wherein said mouse is infected with said herpesvirus.

  13. The transgenic mouse model system of claim 12 wherein said herpesvirus is selected from the group consisting of HHV6-A and HHV6-B.

  14. The transgenic mouse model system of claim 12 wherein said transgene encoding CD46 is ubiquitously expressed in vivo.

  15. The transgenic mouse model system of claim 12 wherein said transgene encoding CD46 is expressed in vivo in a tissue selected from the group consisting of brain, spinal cord, and peripheral nerve.

  16. The transgenic mouse model system of claim 12 wherein a single exposure of said transgenic mouse to said herpesvirus triggers and/or increases the severity of a central nervous system inflammatory disease.

  17. The transgenic mouse model system of claim 12 wherein more than one exposure of said transgenic mouse to said herpesvirus triggers and/or increases the severity of a central nervous system inflammatory disease.

  18. The transgenic mouse model system of claim 16 or claim 17 wherein said central nervous system inflammatory disease is multiple sclerosis.

  19. The transgenic mouse model system of claim 12 wherein one or more exposure of said mouse to said herpesvirus triggers and/or increases the severity of an inflammatory disease and/or autoimmune disorder selected from the group consisting of diabetes, arthritis, anemia, lupus, pemphigus, thyroiditis, glomerular or interstitial nephritis, cardiomyopathy, myositis, dermatomyositis, hepatitis, and ulcerative colitis.

  20. The transgenic mouse model system of claim 12 wherein said model system is suitable for the identification of factors mediating the direct toxicity of said herpesvirus towards a cell type selected from the group consisting of oligodendrocytes, astrocytes, and brain cells.

  21. The transgenic mouse model system of claim 20 wherein said factor is selected from the group consisting of CD4+ T-cells and CD8+ T-cells.

  22. A non-human animal model system for the study of brain or spinal cord atrophy and degeneration in a disease affecting basal ganglia and gray matter said disease being selected from the group consisting of Alzheimer's disease, Parkinson's disease, Lewy body disease, Lafora disease, chorea and athetosis, Huntington's disease, and amyotrophic lateral sclerosis (Lou Gherig's disease).

  23. A non-human animal model system for the study of the interaction between a virus and a primate immune system wherein said primate is selected from the group consisting of a human and a non-human.

  24. A non-human animal model system for the study of the interactions between virus pairs wherein said virus pairs are selected from the group consisting of: (a) HHV6-A and HHV6-B; (b) HHV6-A and CMV; (c) HHV6-A and EBV; (d) HHV6-A and VZV; (e) HHV6-A and HHV8; (f) HHV6-A and HIV; (g) HHV6-A and HTLV; and (h) any one of HHV6-A, HHV6-B, CMV, EBV, VZV, and HHV8 and HIV.

  25. An experimental system for the study of the potential of a candidate compound for reducing the severity of a disease, said experimental system comprising a herpesvirus infected non-human animal; wherein said disease is selected from the group consisting of a demyelinating disease, a neurodegenerative disease, and multiple sclerosis; and wherein said reduction in the severity of said disease is determined by measuring an inhibition of viral replication and/or transcription.

  26. An experimental system comprising a mammal selected from the group consisting of a monkey, a wild-type mouse, an EAE mouse, and a CD46 transgenic mouse; wherein said experimental system permits the testing of soluble CD46 (complement receptor) as a therapeutic agent.

  27. A composition comprising a CD46 selected from the group consisting of (a) a soluble CD46, (b) a cell associated CD46, and (c) an artificial delivery system associated CD46; wherein said composition is effective in reducing the severity of a disease selected from the group consisting of multiple sclerosis and/or other autoimmune and immune-mediated inflammatory diseases of the brain or other target organs; wherein said soluble CD46 is produced in recombinant form, as a full-length polypeptide or as a truncated variants; and wherein said artificial delivery system is either a liposome or a vesicle.

  28. The composition of claim 27 wherein said composition is effective in the treatment of a neurodegenerative disorder and/or a tumor.

  29. An experimental system for the study of a potential vaccine therapeutic for reducing the severity of a disease, said experimental system comprising a herpesvirus infected animal; wherein said disease is an autoimmune and/or neurodegenerative disease.

  30. The experimental system of claim 29 wherein said disease is multiple sclerosis.

  31. The experimental system of claim 29 wherein said herpesvirus is HHV6.

  32. A non-human animal model system for the early detection of an autoimmune and/or neurodegenerative disease prior to detectable disease onset in a patient.

  33. The non-human animal model system of claim 32 wherein said patient is a child or teenager.

  34. One or more methods for detection of certain antibodies against viruses such as, but not limited to HHV6 in serum, namely conformational and not limited to protein antigens, by means of fluorescence activated cell sorting analysis or other method where a detection tag is used to reveal presence of an antibody bound to its target antigen on the cell surface, or in other presentation where it resembles its native conformation.

  35. Methods as above valued in their capacity to identify subjects where an active destructive process linked or concomitant to HHV6 replication and activity is ongoing, in order to initiate early treatment in these subjects and prevent full development of disease such as MS, chronic fatigue syndrome and other disorders.

  36. A flow cytometric method for detecting in a pateint a viral infection comprising the step of detecting a virus-specific immunoglobulin responses wherein said virus is selected from the group consisting of HHV6, HHV7, HHV8, CMV, EBV, HSV, JC, BK, and SV40.

  37. The methods of claims 34-36 where measurements of antibodies or in vitro cellular responses are used a biomarkers to predict individual risk for developing multiple sclerosis.

  38. The method of claim 37 wherein the presence of said antibodies is predictive of a risk for developing a CNS disorder.

  39. The method of claim 37 wherein the presence of said antibodies is predictive of a risk for developing an autoimmune disorder selected from the group consisting of diabetes, arthritis, anemia, lupus, pemphigus, thyroiditis, glomerular or interstitial nephritis, cardiomyopathy, myositis, dermatomyositis, hepatitis, and ulcerative colitis.

  40. An experimental system for the identification of genes responsible for the development of an autoimmune and/or neurodegenerative disease following exposure to a herpesvirus, said experimental system employing a technique selected from the group consisting of a gene expression array, proteomics, metabonomics, and metabolonics.

  41. An experimental system for the identification of genes responsible for the development of a detrimental autoantibody response that may lead to autoimmune and/or neurodegenerative disease following exposure to a herpesvirus, said experimental system employing a technique selected from the group consisting of a gene expression array, proteomics, metabonomics, and metabolonics.

  42. An experimental system for the identification of genes responsible for the development of a beneficial autoantibody response (neutralizing antibody against virus) that may prevent development autoimmune and/or neurodegenerative disease following exposure to a herpesvirus, said experimental system employing a technique selected from the group consisting of a gene expression array, proteomics, metabonomics, and metabolonics.

  43. A method for identifying a compound effective in reducing the severity of herpesvirus-mediated toxicity in the model system of claim 1 or claim 12 comprising the steps of (a) administering to said model system a candidate compound and (b) determining whether said herpesvirus-mediated toxicity is reduced in severity.

  44. A method for evaluating the therapeutic value of compounds or other intervention that antagonize the development of detrimental autoantibodies as described in claim 1.

  45. A method for evaluating the therapeutic value of compounds or other intervention that favor the development of beneficial autoantibodies as described in claim 1.

  46. A methods and model system to evaluate the therapeutic value of compounds or intervention that alter the immune system via its cellular responses in the way to either antagonize detrimental autoantibodies or favor beneficial ones.

  47. The method of claim 31 wherein said herpesvirus-mediated toxicity is correlative of a neurodegenerative disease selected from the group consisting of multiple sclerosis, Parkinson's disease, Alzheimer's disease, and cerebellar degeneration.

  48. A method for detecting HHV-6 mediated cellular toxicity in a patient sample said method comprising the step of assaying cell death wherein said patient sample is selected from the group consisting of a CNS sample, a blood sample, and a CSF sample.

  49. A flow cytometric method for assessing the risk of a patient developing a exhibit virus-related and cancerogenic complications following an immunotherapeutic treatment regimen, said method comprising the step of measuring an absolute CD3+CD8+ cell count, an absolute CD19+ counts, a relative proportion of CD19+ cells, and a CD19+/CD3+ ratio, wherein a reduction in CD3+CD8+ cell counts, an increase in absolute CD19+ counts, an increase in the relative proportion of CD19+ cells, and an increase in CD19+/CD3+ ratio indicates an increase the risk that a patient will exhibit virus-related and cancerogenic complications.

  50. The flow cytometric method of claim 49 wherein said immunotherapeutic treatment regimen comprises a step of administering to said patient an antibody therapeutic selected from the group consisting of natilizumab, muromonab-CD3, abciximab, rituximab, daclizuniab, basiliximab, palivizumab, infliximab, trastuzumab, gemtuzumab, alemtuzumab, ibritumomab, adalimumab, omalizumab, tositumomab-I131, efalizumab, cetuximab, and bevacizumab.

  51. A non-human animal model system for diabetes, said non-human animal model system comprising a monkey and a herpesvirus wherein said monkey is infected with said herpesvirus.

  52. The non-human animal model system of claim 51 wherein said monkey exhibits a blood glucose level of between about 200 mg/dl and 2,000 mg/dl.

Description: CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. § 119(e) to U.S. Provisional Patent Application No. 60/618,277, filed Oct. 12, 2004, and to co-pending U.S. Provisional Patent Application No. 60/720,676, filed Sep. 26, 2005, each of which is incorporated herein by reference in its entirety. GOVERNMENT SUPPORT

Certain aspects of the presently disclosed inventions were developed with support from a National Multiple Sclerosis Society Pilot Grant No. PP0916. The Government may have certain rights to some aspects of those inventions. BACKGROUND OF THE INVENTION

  1. Technical Field of the Invention

The present invention relates generally to viral pathogenesis and autoimmune diseases such as diseases of the central nervous system, including multiple sclerosis (MS), and diabetes. More specifically, provided herein are non-human animal model systems for viral pathogenesis of neurodegeneration and autoimmune demyelination. Such animal model systems may be suitably employed for the study of MS and for the identification and characterization of candidate therapeutic compounds and compositions for the treatment of MS. Also provided herein are markers and methods for the detection, in patients susceptible to autoimmune disease, of autoimmune diseases of the central nervous system such as progressive multifocal leukoencephalopathy (PML) following treatment with one or more therapeutic agent as exemplified herein by the therapeutic agent natalizumab.

  1. Description of the Related Art

Multiple Sclerosis (MS) designates a group of heterogeneous, immune-mediated chronic demyelinating disorders of the central nervous system (CNS) affecting 350,000 Americans and over 1 million individuals worldwide. MS affects women twice as often as men, and thus also represents a significant women's health issue. Pathologically, MS is characterized by plaques of perivascular infiltration comprised of mononuclear cells and macrophages, accompanied by concentric destruction of the myelin sheaths (demyelination), death of oligodendrocytes, proliferation of astrocytes, and axonal damage. Lassmann, Multiple Sclerosis 4:93-98 (1998); Raine, Multiple Sclerosis and Chronic Relapsing EAE: Comparative Ultrastructural Neuropathology , in Multiple Sclerosis: Pathology, Diagnosis and Management 413-460 (Hallpike et al. eds., 1983); and Trapp et al., The New England Journal of Medicine 338:278-285 (1998).

The etiology of MS is unknown; however, strong circumstantial evidence suggests that MS is an autoimmune disorder arising in a genetically susceptible host under the pressure of environmental triggers. Hohlfeld, Brain 120:865-916 (1997) and Oksenberg et al., Pathogenesis of Multiple Sclerosis: Relationship to Therapeutic Strategies , in Multiple Sclerosis: Advances in Clinical Trial Design, Treatment and Future Perspectives 14-46 (Goodkin et al. eds., 1996). To a large extent, our current knowledge of the factors that may participate in the pathogenesis of MS lesions is based on observations of experimental allergic encephalomyelitis (EAE), an autoimmune disorder that is produced in laboratory animals by sensitization with antigens of CNS myelin. Martin et al., Ann. Rev. Immunol. 10:153-187 (1992); Miller et al., Immunol. Today 15:356-361 (1994); and Wekerle et al., Ann Neurol 36:S47-S53 (1994).

In contrast to the often-stereotyped illnesses encountered in the many models of EAE, the clinical phenotype of human MS can be benign or rapidly disabling, with variable courses including relapsing, remitting, or progressive forms. This heterogeneity of clinical presentation most likely reflects complex influences of environment and/or inherited genetic factors, and may correlate with distinct neuropathological subtypes as suggested by recent analyses of biopsy and autopsy material that showed specific patterns of lesions with various proportions of inflammation, demyelination, and oligodendrocyte and axonal pathology. Lassmann, Multiple Sclerosis 4:93-98 (1998); Lucchinetti et al., Ann. Neurol. 47:707-717 (2000); and Storch et al., Ann Neurol 43:465-471 (1998). Effector mechanisms of tissue damage in CNS autoimmunity include direct toxicity of infiltrating T cells, secretion of pro-inflammatory cytokines, antibody-mediated toxicity, and complement and macrophage activation (reviewed in Brosnan et al., Brain Pathol 6:243-257 (1996)).

A viral etiology has been long suspected for MS based on epidemiologic studies (Kurtzke, Clin. Microbiol. Rev. 6:382-427 (1993); Kurtzke et al., Neurology 36:307-328 (1986)) and circumstantial evidence of CNS demyelinating diseases that occur in the context of infection with neurotropic viruses (Gilden et al., Multiple Sclerosis 2:179-183 (1996); Stohlman et al., Brain Pathol 11:92-106 (2001); Raine, in Textbook of Neuropathology 627-714 (Davis et al., eds. 1997a)). A popular hypothesis is that infections may trigger molecular mimicry, a phenomenon by which T cells of the immune system recognize a viral peptide that is the mimic of a peptide of myelin (direct mimicry). CNS invasion by T cells following viral infection, whether due to mimicry or to clear the acute infestation, may also damage the myelin and/or neurons, through either direct cytotoxicity to cells harboring the virus or production of pro-inflammatory products that create a toxic environment within the CNS and activation of macrophages or microglia (bystander damage). This in turn may trigger secondary immune attacks against exposed CNS antigens (Stohlman et al., Brain Pathol 11:92-106 (2001)).

The association between certain viral infections or vaccinations (for example measles, varicella zoster, vaccinia, Epstein Barr virus (EBV), HTLV-I) and cases of acute disseminated encephalomyelitis, encephalitis or myelitis is well recognized. It is also widely perceived that viral infections may trigger MS attacks. Higher antibody titers against neurotropic viruses are reported for MS serum or cerebrospinal fluid (CSF) compared to controls (Johnson et al., N Engl J Med 310:137-141 (1984); and Johnson, Ann Neurol 36:S54-S60 (1994)). The presence of an antigen-driven, CNS restricted immune response in MS and in infections of the CNS is supported by findings of specific oligoclonal bands in patients' CSF (Tourtelotte et al., Neurology 30:240-244 (1980)), and the more recent demonstration of clonal expansion of specific B cell immunoglobulin gene rearrangements (Baranzini et al., J. Immunol. 163:5133-44 (1999); Owens et al., An. Neurol. 43:236-243 (1998); Colombo et al., J. Immunol. 164:2782-2789 (2000); and Qin et al., J. Clin. Invest. 102:1045-1050 (1998)). In contrast to oligoclonal bands that, in CNS infections, are directed against viral antigens (Gilden et al., Multiple Sclerosis 2:179-183 (1996)), the specificity of oligoclonal bands in MS has not been established. It has, however, recently been suggested that they may react to some component of Epstein-Barr virus (Cepok et al., J Clin Invest 115:1352-60 (2005)). The number of viruses that have been incriminated in MS pathogenesis is constantly growing, and in fact interferon (IFN)-β was first tried as a treatment for MS owing to its anti-viral activity.

One difficulty in establishing direct relationships between viral exposures and MS is that appropriate in vivo experimental systems for validation of such associations are lacking. Examples of virus capable of inducing acute or chronic demyelinating disease include canine distemper virus, the JHM strain of mouse hepatitis virus, murine Semliki Forest virus, sheep Visna, caprine arthritis-encephalitis virus, SV40 in macaque monkeys, Theiler's murine encephalomyelitis virus (TMEV) (Johnson, Ann Neurol 36:S54-S60 (1994)), and lymphocytic choriomeningitis virus (LCMV) (Evans et al., Journal of Experimental Medicine 184:2371-84 (1996)). Viral proteins can also be expressed in the CNS of transgenic mice, which renders the animals susceptible to infection (Evans et al., Journal of Experimental Medicine 184:2371-84 (1996)). Disease pathogenesis varies between these models, and may include a component linked to viral persistence (monophasic disease), or secondary CNS inflammation and destruction not associated with virus infestation. Infection of mice with TMEV produces a gastroenteritis, which is rapidly cleared. Only inbred susceptible strains subsequently develop an unrelenting and severe progressive demyelinating disease with what is believed to be bystander damage to myelin. Stohlman et al., Brain Pathol 11:92-106 (2001) and Dal Canto et al., Microscopy Research and Technique 32:215-29 (1995). Infection of mice with LCMV produces a cytotoxic, CD8+ mediated response that directly destroys CNS cell targets. It is important to understand that although these models have provided the first (and only existing) insights into the relationships between autoimmune CNS demyelination and viral infections, they are still insufficient for proving direct association of MS with any of the viruses that ubiquitously infect humans without adverse consequences. CNS complications of TMEV infections are under the restrictive control of genetic influence and it is difficult to extrapolate their mechanisms to outbred human populations. Many of these disease models require intracranial injection of viruses in neonatal animals, an artificial situation that similar to EAE does not mimic natural exposure of humans to pathogens.

Immunization of Callithrix jacchus ( C. jacchus ) marmosets with whole human white matter, and myelin/oligodendrocyte glycoprotein (MOG) in adjuvant produce chronic, relapsing-remitting disorders of mild to moderate clinical severity which are reminiscent of typical forms of human MS. The neuropathology of acute C. jacchus EAE consists of large concentric areas of primary demyelination, macrophage infiltration, astrogliosis, and death of oligodendrocytes. Massacesi et al., Ann. Neurol. 37:519-530 (1995); Genain et al., Immunol. Reviews 183:159-172 (2001); and Brok et al., Immunol Rev 183:173-185 (2001). Ultrastructural features of myelin breakdown are similar in marmoset EAE and human MS, suggesting common mechanisms of myelin destruction. Genain et al., Immunol. Reviews 183:159-172 (2001) and Raine et al., Ann Neurol 46:144-160 (1999). Remyelination occurs in chronic EAE.

C. jacchus marmosets are small animals (350-400 gm), yet serial paraclinical and laboratory studies, such as peripheral blood reactivity to myelin antigens, CSF sampling, and in vivo magnetic resonance imaging (MRI) can be obtained. Genain et al., Proc. Natl. Acad. Sci. USA 92:3601-3605 (1995); Genain et al., Methods: a Companion to Methods in Enzymology 10:420-434 (1996); Jordan et al., AJNR Am. J. Neuroradiol. 20:965-976 (1999); and Hart et al., Am. J. Pathol. 153:649-663 (1998). As an outbred species, marmosets exhibit a very broad immunologic repertoire against myelin antigens, which is similar to humans. In addition to whole myelin and MOG, susceptibility to myelin basic protein (MBP), MBP-derived peptides, and proteolipid protein (PLP) has been demonstrated. Genain et al., Immunol. Reviews 183:159-172 (2001). Diverse epitope recognition and T cell receptor β chain utilization are seen in the encephalitogenic repertoires against myelin proteins. Genain et al., J. Clin. Invest. 94:1339-1345 (1994); Uccelli et al., Eur. J. Immunol. 31:474-479 (2001); Villoslada et al., Eur. J. Immunol. 31:2942-2950 (2001); and Mesleh et al., Neurobiol Dis 9:160-172 (2002). C. jacchus are unique primates for studies of autoimmunity because these monkeys are born as naturally occurring bone marrow chimeras. While sibling pairs or triplets are genetically distinct, they share, and are tolerant to, each other's bone marrow-derived cell populations, which permits adoptive transfer of T cell clones. Genain et al., J. Clin. Invest. 94:1339-1345 (1994); Villoslada et al., Eur. J. Immunol. 31:2942-2950 (2001); and Watkins et al., Journal of Immunology 144:3726-3735 (1990).

The MS-like lesion in C. jacchus is mediated by a complex interplay between cellular and humoral responses to myelin. MOG has been shown to be a target for demyelinating antibodies. Genain et al., J. Clin. Invest. 96:2966-2974 (1995). Importantly, pathogenicity of MOG-specific autoantibodies has also been demonstrated in selected cases of human MS. Genain et al., Nat Med 5:170-175 (1999). C. jacchus shares a very high degree of homology with humans for myelin and immune system genes. The recent cloning of MOG-specific marmoset immunoglobulin genes has revealed similarity of gene usage and epitope recognition between marmosets and humans. von Büdingen et al., Immunogenetics 53:557-563 (2001) and von Büdingen et al., Proc. Natl. Acad. Sci. USA 99:8207-8212 (2002).

Human herpesvirus (HHV)6 has been implicated in the etiology of multiple sclerosis (MS), based on detection of HHV6 DNA in MS plaques and serum, presence of anti-HHV6 reactivity in MS-affected individuals, and reports of encephalitis or encephalomyelitis associated with this virus. Epidemiological studies indeed suggest that viruses or other environmental factors may trigger MS or influence its course. As for other viruses, however, evidence for a direct link of causality between HHV6-A and disease pathogenesis has been lacking.

The two HHV6 variants (HHV6-A and HHV6-B) show capability to infect a wide range of human and primate host cells. HHV6-B causes exanthema subitum, a mostly benign febrile illness in children. A cellular receptor for HHV6 has been recognized as the membrane cofactor protein (CD46). CD46 is a ubiquitous receptor promiscuous to other microbes and herpesviruses including measles, and belongs to a family of complement receptor proteins. High levels of soluble CD46 are observed at early stages of MS—a finding also interpreted as evidence for a role of HHV6 infection in relapses.

HHV6 is a herpesvirus that possesses a 159 kbp to 170 kbp long genome with 7 gene blocks common to all Herpesviridae, a group of genes found only in β-herpesviruses (ORFs U2 to U14) and genes specific to the Roseolavirus genus (ORFs U15 to U25). Three genes, U22, U83 and U94, are specific for HHV6 (not HHV7). HHV6-B contains 119 ORFs in comparison with 110 for HHV6-A. Dockrell, J Med Microbiol 52:5-18 (2003). Despite being very similar, the two HHV6 variants have very different cell tropism and disease manifestations, which support the concept that they are different herpesviruses.

HHV6-B causes exanthema subitum in children, or initial exposure may be asymptomatic. Practically all individuals get infected prior to age 2 (Caserta et al., J Pediatr 145:478-84 (2004) and Zerr et al., N Engl J Med 352:768-76 (2005)). HHV6-B is found in a wide variety of tissues, including lymphoid organs, brain, serum and salivary glands. Ablashi et al., J Virol Methods 21:29-48. (1988); Levy et al., Lancet 335:1047-1050 (1990); Levy et al., Virology 178:113-121 (1990) and Lusso et al., Baillieres Clin Haematol 8:201-23 (1995)).

HHV6-A has a particular tropism for the CNS and skin. This variant has so far rarely been isolated or detected in children with primary HHV6 infection, and is not clearly associated with any infectious illness in healthy populations. HHV6 persists in latent or replicative states throughout life, and actively replicates in salivary glands (variant B). Secondary infection by HHV6 is usually silent except in immuno-compromized patients. Dockrell, J Med Microbiol 52:5-18 (2003) and Campadelli-Fiume et al., Emerg Infect Dis 5:353-366 (1999). Antibodies against HHV6-A are found in most of the general population, and steadily persist through life before declining in older subjects. Levy, Lancet 349:558-563 (1997).

The CD46 cellular HHV6 receptor (Santoro et al., Cell 99:817-827 (1999)) is expressed ubiquitously, including in CNS, but only in humans and certain higher mammals and primates, which explains the narrow range of species that can be infected with this virus. CD46 binds to the C3b and C4b proteins and inactivates the complement system. Thus, one of its presumed functions is to protect the cells from self-lysis by complement. HHV6 is capable of infecting CD4+, CD8+, NK and γδ T cells, B cells, macrophages, dendritic cells, fibroblasts, epithelial cells and a variety of lymphoid or CNS-derived cell lines. Dockrell, J Med Microbiol 52:5-18 (2003); Campadelli-Fiume et al., Emerg Infect Dis 5:353-366 (1999); and Levy, Lancet 349:558-563 (1997). Both variants infect primary fetal astrocytes, but HHV6-A appears to have a greater neurotropism in vivo. Hall et al., Clin Infect Dis 26:132-137 (1998). Infection in vitro by HHV6 is monophasic and generally followed by decreased cell proliferation and/or cell death. Grivel et al., J Virol 77:8280-9 (2003); Opsahl et al., Brain 128:516-27 (2005); and Smith, et al., J Virol 79:2807-13 (2005). In vivo, HHV6 induces CD4 T cell depletion, as shown in a SCID mouse model implanted with human fetal thymus and liver (Gobbi et al., J Exp Med 189:1953-1960 (1999)), and may contribute to HIV-associated immunosuppression. It is also clear that HHV6 infection interferes with other viruses, including EBV, cytomegalovirus (CMV), and human immunodeficiency virus (HIV) for which either enhancing or suppressing effects have been described. Levy, Lancet 349:558-563 (1997).

The CD46 receptor is shared by a number of pathogens including measles virus, and signaling through this molecule is one of the most potent mechanisms of T cell stimulation and activation. Several isoforms of CD46 that differ by their cytoplasmic domains are expressed in humans, and engagement of these 2 classes of CD46 receptors appears to have opposite consequences on the polarization of the immune response towards Th1 or Th2 phenotypes (Marie et al., Nat Immunol 3:659-66 (2002); Russell, Tissue Antigens, 64:111-8 (2004); and Riley-Vargas et al., Trends Immunol 25:496-503 (2004)).

In vivo, HHV6 induces CD4+ T cell depletion, as shown in a SCID mouse model implanted with human fetal thymus and liver (Gobbi et al., J Exp Med 189:1953-60 (1999) and Gobbi et al., J Virol 74:8726-31 (2000)), and may contribute to HIV-associated immunosuppression (Lusso et al., Immunol Today 16:67-71 (1995b)). It is also clear that HHV6 infection interferes with other viruses, including EBV, cytomegalovirus (CMV), and human immunodeficiency virus (HIV) for which either enhancing or suppressing effects have been described (Levy, Lancet 349:558-63 (1997) and Ablashi et al., J Virol Methods 21:29-48 (1988)). A number of attempts have been made to create models of infection with HHV6 in primates (macaques and chimpanzees), which as in the SCID mouse model primarily support the concept that HHV6-A acts as a cofactor in the simian acquired immunodeficiency syndrome (Lusso et al., J Virol 64:2751-8 (1990) and Lusso et al., AIDS Res Hum Retroviruses 10:181-7 (1994)).

Because >95% of the general population is exposed to the virus during infancy, it is difficult to envision HHV6 infection as a sole cause for MS prevalence (approximately 1:1,000 for Caucasions in the United States) in the absence of additional factors of pathogenesis. One possible scenario that has been proposed to explain the association of MS with viral exposure is that primary infection triggers a silent immune attack on the central nervous system (CNS), which is followed over time by development of CNS-directed autoimmunity. In favor of this hypothesis are findings that the risk of developing MS appears to be acquired early in life, and follows migration patterns to and from geographical areas of low/high prevalence if individuals are moved during their childhood. MS epidemics have also been observed after novel exposure of previously isolated insular populations to foreign environmental factors. Yet, there is still no direct evidence of an association between any viral exposures and common forms of MS.

Of particular relevance to MS are recent observations that both HHV6 variants show capability to modulate T cell inflammatory responses towards Th1 (pro-inflammatory) phenotypes. Mayne et al., J Virol 75:11641-11650 (2001). In addition, a consequence of infection of endothelial cells by HHV6-A appears to be an increase in vascular endothelium permeability. Caruso et al., J Med Virol 67:528-533 (2002). Thus, in keeping with the concept of heterogeneity in MS pathophysiology, it is possible that an association between MS and HHV6 exists for certain clinical or neuropathological subtypes that are yet to be identified. It is, however, premature to conclude that this is sufficient evidence that this virus causes MS, which is commonly regarded as a disease with generalized autoimmune dysregulation; findings of viral DNA, antibody reactivity, or even association with viral infections may indeed represent a consequence of the disease rather than its cause.

An association between HHV6-A and MS was recently suggested by findings of HHV6-B DNA sequences in diseased oligodendrocytes within MS plaques (Challoner et al., Proc. Natl. Acad. Sci. 92:7440-7444 (1995); Opsahl et al., Brain 128:516-27 (2005). These observation however, has not been confirmed by subsequent attempts (Coates et al., Nat Med 4:537-8 (1998)), and could not be formally confirmed by immunohistochemistry. HHV6 DNA has also been found in the brain of normal subjects and in Alzheimer's disease (Luppi et al., J Med Virol 47:105-11 (1995); Lin et al., J Pathol 197:395-402 (2002)). Thus, detection of viral sequences in the CNS is not sufficient for proof of pathogenicity. Serologic studies have reported elevated titers of anti-HHV6-Antibodies in patients with relapsing remitting MS compared to controls (Ablashi et al., Mult Scler 4:490-6 (1998); Sola et al., J Neurol Neurosurg Psychiatry 56:917-9(1993); Soldan et al., Nature Medicine 3:1394-7 (1997)). However, a large number of subsequent studies that examined IgG/IgM reactivity in serum and/or CSF, presence of HHV6 DNA or viral transcripts in serum, CSF and brain, peripheral T cell proliferative responses to HHV6, or virus recovery in culture have not unequivocally confirmed these results. The following reviews provide detailed discussions of the numerous HHV6 association studies that have been performed (Ablashi et al., J Virol Methods 21:29-48 (1988); Ablashi et al., Mult Scler 4:490-6 (1998); Krueger et al., Pathol Res Pract 185:915-29 (1989); Enbom, Apmis 109:401-11 (2001); Moore et al., Acta Neurol Scand 106:63-83 (2002); Krueger et al., Intervirology 46:257-69 (2003); DeRanieri et al., J Sch Nurs 20:69-75 (2004); Dewhurst, Herpes 11 Suppl 2:105A-111A (2004); Fotheringham et al., Herpes 12:4-9 (2005)).

More compelling for an association between HHV6-A and certain forms of CNS demyelination which possibly represent extremes of the spectrum of MS presentations are numerous case reports of encephalomyelitis, and acute and chronic myelitis where a clear relationship between the infection and CNS disease was strongly suggested (Carrigan et al., Neurology 47:145-148 (1996); Mackenzie et al., Neurology 45:2015-7 (1995); McCullers et al., Clin Infect Dis 21:571-6 (1995); Novoa et al., J Med Virol 52:301-8 (1997); Portolani et al., J Med Virol 65:133-7 (2001); Portolani et al., Minerva Pediatr 54:459-64 (2002); Singh et al., Transplantation, 69:2474-9 (2000); Moore et al., Acta Neurol Scand 106:63-83 (2002); Dockrell, J Med Microbiol 52:5-18 (2003); Campadelli-Fiume et al., Emerg Infect Dis 5:353-66 (1999); Gilden et al., Multiple Sclerosis 2:179-183 (1996); Kleinschmidt-DeMasters et al., Brain Pathol 11:440-51 (2001); Ward, Curr Opin Infect Dis 18:247-52 (2005).

In addition to MS and encephalomyelitis, and association with HHV6 exposure and HHV6 reactivity has also been claimed for chronic fatigue syndrome and narcoplepsy. Chronic fatigue syndrome (CFS) is an incapacitating disease of adult of all ages, which shares certain clinical features with MS (the fatigue) and is also likely immune-mediated. Similar to MS, studies of antibody reactivity have been inconsistent in proving a relationship between CFS and HHV6 (Enbom, Apmis 109:401-11 (2001); Ablashi et al., J Clin Virol 16:179-91 (2000); Wallace et al., Clin Diagn Lab Immunol 6:216-23 (1999); Nicolson et al., Apmis 111:557-66 (2003)).

Experimental systems are needed to understand causal relationships between HHV6 infection and the occurrence of CNS inflammatory conditions that mimic human MS. Only the availability of such models will permit studies of causal and time-dependent relationships between infection and CNS disease in a controlled fashion. Thus, there remains a need in the art for experimental systems that permit longitudinal studies following HHV6 exposure in order to characterize the role of this virus in autoimmune CNS demyelination and animal model systems suitable of identifying and characterizing efficacious therapeutics and treatment regimens effective in ameliorating or decreasing the severity of this autoimmune disease. SUMMARY OF THE INVENTION

The present invention addresses these and other related needs by providing, inter alia, non-human animal model systems for viral pathogenesis of neurodegeneration, autoimmune demyelination, and diabetes. Such animal model systems may be suitably employed for the study of multiple sclerosis (MS) and for the identification and characterization of candidate therapeutic compounds and compositions for the treatment of MS.

Animal model systems according to the present invention are correlative of MS disease in humans and, thus, will find a wide range of utilities. Such animal model systems will, for example: (1) provide an opportunity to identify the factors controlling the pathogenesis of CNS autoimmunity following exposure to HHV6; (2) provide a suitable system for identifying and characterizing potentially efficacious therapeutic agents for the treatment of MS disease; (3) provide a suitable system for performing similar investigations and therapeutic testing for additional or alternative neurodegenerative and autoimmune, immune-mediated or infectious and post-infectious human conditions; (4) permit the discovery of biomarkers for the detection of MS; and (5) lead to the development of strategies and/or treatment regimens to remedy HHV6 induced CNS pathology.

Within certain embodiments, the non-human animal is a non-human primate wherein the primate is infected with a herpesvirus. Typically, non-human primates suitably infected with a herpesvirus according to the present invention include monkeys and are selected from the group consisting of a marmoset, a New World monkey, and an Old World monkey, wherein the primate is susceptible to infection with said herpesvirus.

Exemplified herein are non-human primate animal model systems wherein a marmoset ( C. jacchus ) is infected with a herpesvirus. More specifically, presented herein are non-human animal model systems of MS disease that are based upon the in vivo infection of a non-human animal with HHV6. An exemplary animal model of HHV6-induced CNS demyelination has been created in the common marmoset C jacchus , a New World non-human primate that develops spontaneous autoimmunity and is also used in studies of experimental allergic encephalomyelitis.

Captive marmosets are naïve to HHV6, and express a CD46 that is homologous to human CD46, which affords the opportunity, as presented herein, to model the events following initial and subsequent exposures, and to study the consequences of infection. CNS autoimmune demyelination appears associated with repeated exposures of adult marmosets to HHV6-A.

Thus, within certain embodiments are provided C. jacchus marmosets that are infected with a herpes virus, exemplified by one or more HHV6 variants. While infection with HHV6 is monophasic and rapidly lethal to the cells in vitro (HHV6 is capable of inducing apoptosis in CNS glial cells), it is demonstrated herein that a CNS demyelinating disorder follows infection of naïve adult marmosets with HHV6-A. In some instances, it is further demonstrated that certain animals proceed to develop lesions of the gray matter, especially the basal ganglia, and marked brain atrophy. Without wishing to be limited to any particular mode of action, it is believed that this CNS disease is associated with the appearance of T cell reactivity to myelin antigens.

A wide variety of herpesviruses may be suitably employed in the non-human primate animal model systems disclosed herein. Particularly suitable are those herpesviruses that are capable of specifically binding to a CD46 receptor. Exemplified herein are non-human primate animal model systems infected with a herpesvirus selected from the group consisting of HHV6-A and HHV6-B.

Depending upon the precise application contemplated, non-human primates may be infected by a single exposure to a single herpesvirus variant whereby infection of the non-human primate with the herpesvirus triggers and/or increases the severity of a central nervous system inflammatory disease. Alternatively, other applications may require that non-human primates are infected by more than one exposure to a single herpesvirus variant wherein more than one exposure of the non-human primate to said herpesvirus triggers and/or increases the severity of a central nervous system inflammatory disease. Further provided are non-human primate animal model systems wherein a primate is infected with one or more exposure to more than one herpesvirus variant. Particularly suitable to the non-human primate animal model systems presented herein are herpesvirus variants selected from the group consisting of HHV6-A and HHV6-B.

Non-human primate animal model systems of the present invention are suitably employed for studying disease mechanisms and for identifying and characterizing candidate therapeutics for a number of diseases of the central nervous system, in particular inflammatory and demyelinating diseases of the central nervous system. Exemplified herein are non-human primate animal model systems of multiple sclerosis. Within relates aspects, exposures of a non-human primate with one or more herpesvirus variant may further trigger and/or increases the severity of other inflammatory diseases or malignancies of the central or peripheral nervous system and neuromuscular junction.

For example, exposure of a non-human primate to one or more herpesvirus may trigger and/or increase the severity of a disease selected from the group consisting of a paraneoplastic syndrome and cerebellar degeneration, limbic encephalitis, opsoclonus myoclonus, subacute sclerosing panencephalitis (SSPE), progressive multifocal leukoencephalopathy (PML) and other diffuse or focal leukodystrophies (early and late onset), acute and chronic polyneurpathies and polyradiculopathies, acute disseminated encephalomyelitis, myopathy, myasthenia gravis, Guillain Barre, miller-Fisher syndrome, Eaton Lambert syndrome, CNS vasculitis, sarcoidosis and neurosarcoid, Rasmussen's disease, paraneoplastic sensory neuropathy, CNS lymphoma, high and low grade oligodendroglioma and glioblastoma, glioblastoma multiformis, optic nerve glioma and meningioma, ependymoma, and medulloblastoma.

Alternative aspects of the present invention provide that exposure of a non-human primate to one or more herpesvirus may trigger and/or increase the severity of a neurological disorder comprising an inflammatory component selected from the group consisting of narcolepsy, chronic fatigue syndrome, stiff man syndrome, and childhood autism.

Still further aspects of the present invention provide that exposure of a non-human primate to one or more herpesvirus may trigger and/or increase the severity of an inflammatory disease and/or autoimmune disorder selected from the group consisting of diabetes, arthritis, anemia, lupus, pemphigus, thyroiditis, glomerular or intersticial nephritis, cardiomyopathy, myositis, dermatomyositis, hepatitis, and ulcerative colitis.

Yet other aspects of the present invention provide non-human primate animal model systems that are suitable for the identification of factors mediating the direct toxicity of one or more herpesvirus and a cell type selected from the group consisting of an oligodendrocyte, an astrocyte, and a brain cell.

Other embodiments of the invention disclosed herein provide non-human animal model systems for the study of brain or spinal cord atrophy and degeneration in a disease affecting basal ganglia and gray matter wherein the disease is selected from the group consisting of Alzheimer's disease, Parkinson's disease, Lewy body disease, Lafora disease, chorea and athetosis, Huntington's disease, and amyotrophic lateral sclerosis (Lou Gherig's disease).

Further embodiments provide non-human animal model systems for the study of the interacti

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