1. HHV-6 News
March 10, 2010
HHV-6 Inserts Itself into Telomeres
Researchers have found "clear evidence that the virus can insert its DNA specifically into telomeres - structures at the ends of each chromosome that play key roles in both aging and cancer." http://www.physorg.com/news187282554.html
This is yet more evidence suggest HHV-6 may belong in a class by itself like African Swine Fever Virus. Robert Gallo, the so-called discoverer of HHV-6 insists that HHV-6 is not African Swine Fever Virus.
Click here to see a research paper on the homology of HHV-6 and African Swine Fever Virus.
August 10, 2009
Is Robert Gallo one step closer to admitting that HHV-6 is the real AIDS virus? This new paper could ultimately turn everything about HIV, HHV-6 and AIDS upside down.
Evolution of SIV toward RANTES resistance in macaques rapidly progressing to AIDS upon coinfection with HHV-6A
"Progression to AIDS is often associated with the evolution of HIV-1 toward increased virulence and/or pathogenicity. Evidence suggests that a virulence factor for HIV-1 is resistance to CCR5-binding chemokines, most notably RANTES, which are believed to play a role in HIV-1 control in vivo. HIV-1 can achieve RANTES resistance either by phenotypic switching from an exclusive CCR5 usage to an expanded coreceptor specificity, or by the acquisition of alternative modalities of CCR5 usage. An infectious agent that might promote the evolution of HIV-1 toward RANTES resistance is human herpesvirus 6A (HHV-6A), which is frequently reactivated in HIV-1-infected patients and is a potent RANTES inducer in lymphoid tissue."
Angélique Biancotto1, Jean-Charles Grivel1, Andrea Lisco, Christophe Vanpouille, Phillip D Markham, Robert C Gallo, Leonid B Margolis and Paolo Lusso
Retrovirology 2009, 6:61doi:10.1186/1742-4690-6-61
http://www.retrovirology.com/content/6/1/61
June 9, 2009
Will the new think tank mentioned in the press release below acknowledge the link between AIDS, CFS and HHV-6?
Experts Launch Think Tank for Mystery Disease
(MMD Newswire) June 8, 2009 -- Ten leading scientists in Europe have formed a Think Tank for ME and will hold their first meeting on the 13th of June. They want to initiate an effective research effort to find the secret behind the mystery disease that cripples an increasing number of lives.
Myalgic Encephalomyelitis, often referred to as Chronic Fatigue Syndrome (CFS), is a disease which affects at least one million individuals in the US, and an even greater number in Europe. Despite the large number of people affected, there is a lack of serious large-scale research initiatives focused on the disease. The number of patients is rapidly increasing but healthcare personnel lack knowledge about existing research and possible treatments.
Last year's winner of the Nobel Prize in Medicine, Professor Luc Montagnier of France, says, "Scientists have already uncovered a lot about ME, but this information does not reach professional healthcare personnel, and the disease is still not taken seriously. It is about time this changes." Montagnier, one of the discoverers of the HIV-virus, is a supporter of the Think Tank, but is unable to join the first meeting due to his demanding schedule.
Treatable Disease Ten internationally recognized scientists, many of them prominent leaders in their respective fields of research, have decided to do something about it. They have come together in a Think Tank to promote cooperation among scientists from various disciplines and to stimulate intense focus on innovative and creative research. The first meeting is set in Stavanger, Norway on the 13th of June.
"There are more than 5000 research papers which show that ME has an organic basis with abnormalities in the immune, nervous and gastrointestinal systems and that it is influenced by genetic and environmental factors," states Professor Kenny De Meirleir of Belgium. "Despite these findings, it has been close to impossible to initiate large-scale research to verify these facts and observations. We will never be able to treat ME properly if we do not initiate this type of research."
Using new biotechnological techniques, much of the underlying pathophysiology of the disease has been unmasked. Several treatable clinical entities have been discovered, but this information does not reach healthcare personnel. The result is that patients remain undiagnosed and untreated for years with something that might be fully treatable. This is a huge drain on the economy, as the estimated socio-economic costs for Europe are estimated to be €20 billion annually.
Educate Professionals An important part of the Think Tank's mission is to spread knowledge about the disease. The incidence of ME and the impact on public health are actually higher than that of other better researched conditions like Multiple Sclerosis and HIV. Research shows that ME can be a very disabling chronic disorder which often diminishes patients' quality of life to levels lower than that of cancer, MS, HIV and lupus.
Professor Ola Didrik Saugstad of Norway states, "There is a total lack of knowledge and understanding about this disease in the healthcare system. We wish to use our knowledge to educate and train doctors, therapists and other healthcare personnel so they can better understand how to manage an ME-patient."
New in ME The Think Tank meetings are the brainchild of a new organization, European Society for ME (ESME). This society will focus on organizing research and educating professionals in the field of ME.
"Until now ME organizations have been patient-based and only focused on the needs of the patients, so this is something completely new and unique. We are a group of professionals who want to stimulate new research in the field of ME and to help doctors and healthcare personnel to stay informed about the latest developments in diagnosing and treating ME-patients," says ESME board member Mrs. Catherine Miller-Duhen.
January 8, 2009
UC Davis M.I.N.D. Institute study shows California's autism increase not due to better counting, diagnosis
January 7, 2009 (SACRAMENTO, Calif.) — A study by researchers at the UC Davis M.I.N.D. Institute has found that the seven- to eight-fold increase in the number children born in California with autism since 1990 cannot be explained by either changes in how the condition is diagnosed or counted — and the trend shows no sign of abating.
Published in the January 2009 issue of the journal Epidemiology, results from the study also suggest that research should shift from genetics to the host of chemicals and infectious microbes in the environment that are likely at the root of changes in the neurodevelopment of California’s children.
“It’s time to start looking for the environmental culprits responsible for the remarkable increase in the rate of autism in California,” said UC Davis M.I.N.D. Institute researcher Irva Hertz-Picciotto, a professor of environmental and occupational health and epidemiology and an internationally respected autism researcher.
Hertz-Picciotto said that many researchers, state officials and advocacy organizations have viewed the rise in autism's incidence in California with skepticism.
The incidence of autism by age six in California has increased from fewer than nine in 10,000 for children born in 1990 to more than 44 in 10,000 for children born in 2000. Some have argued that this change could have been due to migration into California of families with autistic children, inclusion of children with milder forms of autism in the counting and earlier ages of diagnosis as consequences of improved surveillance or greater awareness.
Hertz-Picciotto and her co-author, Lora Delwiche of the UC Davis Department of Public Health Sciences, initiated the study to address these beliefs, analyzing data collected by the state of California Department of Developmental Services (DDS) from 1990 to 2006, as well as the United States Census Bureau and state of California Department of Public Health Office of Vital Records, which compiles and maintains birth statistics.
Hertz-Picciotto and Delwiche correlated the number of cases of autism reported between 1990 and 2006 with birth records and excluded children not born in California. They used Census Bureau data to calculate the rate of incidence in the population over time and examined the age at diagnosis of all children ages two to 10 years old.
The methodology eliminated migration as a potential cause of the increase in the number of autism cases. It also revealed that no more than 56 percent of the estimated 600-to-700 percent increase, that is, less than one-tenth of the increased number of reported autism cases, could be attributed to the inclusion of milder cases of autism. Only 24 percent of the increase could be attributed to earlier age at diagnosis.
“These are fairly small percentages compared to the size of the increase that we’ve seen in the state,” Hertz-Picciotto said.
Hertz-Picciotto said that the study is a clarion call to researchers and policy makers who have focused attention and money on understanding the genetic components of autism. She said that the rise in cases of autism in California cannot be attributed to the state’s increasingly diverse population because the disorder affects ethnic groups at fairly similar rates.
“Right now, about 10 to 20 times more research dollars are spent on studies of the genetic causes of autism than on environmental ones. We need to even out the funding,” Hertz-Picciotto said.
The study results are also a harbinger of things to come for public-health officials, who should prepare to offer services to the increasing number of children diagnosed with autism in the last decade who are now entering their late teen years, Hertz-Picciotto said.
“These children are now moving toward adulthood, and a sizeable percentage of them have not developed the life skills that would allow them to live independently,” she said.
The question for the state of California, Hertz-Picciotto said, will become: 'What happens to them when their parents cannot take care of them?'
“These questions are not going to go away and they are only going to loom larger in the future. Until we know the causes and can eliminate them, we as a society need to provide those treatments and interventions that do seem to help these children adapt. We as scientists need to improve available therapies and create new ones,” Hertz-Picciotto said.
Hertz-Picciotto and her colleagues at the M.I.N.D Institute are currently conducting two large studies aimed at discovering the causes of autism. Hertz-Picciotto is the principal investigator on the CHARGE (Childhood Autism Risk from Genetics and the Environment) and MARBLES (Markers of Autism Risk in Babies-Learning Early Signs) studies.
CHARGE is the largest epidemiologic study of reliably confirmed cases of autism to date, and the first major investigation of environmental factors and gene-environment interactions in the disorder. MARBLES is a prospective investigation that follows women who already have had one child with autism, beginning early in or even before a subsequent pregnancy, to search for early markers that predict autism in the younger sibling.
“We’re looking at the possible effects of metals, pesticides and infectious agents on neurodevelopment,” Hertz-Picciotto said. “If we’re going to stop the rise in autism in California, we need to keep these studies going and expand them to the extent possible.”
The study was funded by grants from the National Institute of Environmental Health Sciences (NIEHS) and by the M.I.N.D. Institute.
In 1998, dedicated families concerned about autism helped found the UC Davis M.I.N.D. (Medical Investigation of Neurodevelopmental Disorders) Institute. Their vision? Experts from every discipline related to the brain working together toward a common goal: curing neurodevelopmental disorders. Since that time, collaborative research teams at the M.I.N.D. Institute have turned that initial inspiration into significant contributions to the science of autism, fragile X syndrome, Tourette's syndrome, learning disabilities and other neurodevelopmental disorders that can limit a child's lifelong potential.
January 5, 2009
High Levels of Inflammatory Markers in Chronic Fatigue Syndrome Patients Signal Increased Risk of the Many Other Illnesses Involving Inflammation, Such as Diabetes & Cardiovascular Disease
by Emory University News Release December 18, 2008
"Data from this study suggest that people suffering with these and other symptoms of CFS are likely to have a physical cause for their difficulties, even when a clear-cut medical diagnosis cannot be found" - and face increased risk for illnesses with more definitive tests & treatments.
A new study conducted by researchers from Emory University and the Centers for Disease Control and Prevention (CDC) shows that individuals with chronic fatigue syndrome (CFS) have increased blood levels of the inflammatory chemicals known to increase risk for developing illnesses ranging from cardiovascular disease and dementia to diabetes and cancer. The results of the study, published in the journal Brain, Behavior and Immunity are available on line* [no abstract available].
There has been debate over the years regarding the role played by the immune system in disorders like CFS and fibromyalgia. Such disorders have no known cause but ravage people's lives with symptoms such as fatigue, pain, sleep disturbance and troubles with thinking and memory.
"Data from this study suggest that people suffering with these and other symptoms of CFS are likely to have a physical cause for their difficulties, even when a clear-cut medical diagnosis cannot be found," says Charles L. Raison, MD, lead author on the study and clinical director of the Mind-Body Program in the Department of Psychiatry and Behavioral Sciences at Emory University School of Medicine.
The study also showed that inflammation is not specific for CFS and so doesn't hold much promise as a diagnostic tool for CFS, Raison explains.
"We don't know where the increased inflammation is coming from in the patients with CFS symptoms in our study, and although depression has been associated with increased inflammation, in our study it did not account for the increased inflammation in individuals with CFS or who almost met criteria for CFS."
"Given these observations, the simplest way to think about these findings is that people with increased inflammation - from whatever source - are more likely than others to develop a range of symptoms that frequently lead to a diagnosis of a condition such as CFS or fibromyalgia," says William C. Reeves, MD, co-investigator of the study and chief of the Chronic Viral Diseases Branch of the Centers for Disease Control and Prevention (CDC).
Reeves emphasizes that study results may have health implications. "Because even mild increases in inflammatory markers such as c-reactive protein (CRP) have been shown to predict the later development of many serious illnesses, we might do better to see conditions such as chronic fatigue syndrome as way stations on the road to diagnosable medical illnesses rather than as a discreet disease state in its own right."
Prior studies have shown that chemicals like CRP are produced by inflammatory processes that can cause symptoms of CFS. Those studies have often been confounded by a variety of factors, such as small patient groups, recruiting patients and comparison subjects from very different populations and not carefully looking for the presence of medical and psychiatric disorders that are also associated with increased inflammation.
'We have attempted to address the shortcomings of previous studies by recruiting patients and control subjects from the same large, population-based sample of individuals, and carefully screening for the presence of conditions such as depression that frequently co-occur with CFS, and that might skew findings," says Raison.
The Study
To examine the relationship between CFS and inflammation, study investigators measured blood levels of CRP and white blood cells in 457 individuals recruited as part of a larger study on the prevalence of CFS in metropolitan, urban and rural Georgia.
Individuals in the study underwent extensive evaluations to identify medical and psychiatric conditions and to identify illnesses that are currently considered sufficient to explain fatigue and other symptoms that exclude an individual from being able to receive a CFS diagnosis.
In addition to these assessments, all individuals in the study were diagnosed either as having CFS, as having symptoms of CFS but not meeting full criteria for the disorder, or as being well.
The researchers found that subjects with CFS had higher levels of CRP than did well individuals and also had higher scores on an inflammatory factor that included both CRP and white blood cell levels.
Subjects who had CFS symptoms, such as fatigue, pain, sleep disturbance and cognitive complaints, but who did not meet full CFS criteria, also had higher levels of CRP and the inflammatory factor than did well individuals and had higher levels of white blood cell levels.
Additionally, researchers found that subjects who had symptoms but did not meet full CFS criteria had numerically higher levels of inflammation than did subjects with CFS; however, these differences were not significantly different.
Other factors associated with increased inflammation in the study population as a whole included depressive symptoms, being overweight, and being a female. Researchers found that inflammation was strongly associated with reported disability from physical symptoms in the population as a whole, but was not associated with disability from mental symptoms such as anxiety.
Jin-Mann S. Lin, PhD, from the Chronic Viral Diseases Branch of the CDC also contributed to this study.
Dr. Raison is on the speaker's bureau for Wyeth, Lilly and Schering Plough. He has served on advisory boards for Wyeth, Lilly, Schering Plough and Centocor and is a consultant for eGenHealth.
Funding for this study was provided by the Centers for Disease Control and Prevention (CDC).
- Reference: "Association of peripheral inflammatory markers with chronic fatigue in a population-based sample," Brain, Behavior and Immunity, published online Dec. 2008, DOI:10.1016/j.bbi.2008.11.005
http://www.prohealth.com/library/showarticle.cfm?LIBID=14199
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:
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.
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.
The non-human animal model system of claim 2 wherein said marmoset is C. jacchus.
The non-human animal model system of claim 1 wherein said herpesvirus is selected from the group consisting of HHV6-A and HHV6-B.
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.
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.
The non-human animal model system of claim 5 or claim 6 wherein said central nervous system inflammatory disease is multiple sclerosis.
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.
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.
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.
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.
A transgenic mouse model system, comprising a transgene encoding CD46 and a herpesvirus, wherein said mouse is infected with said herpesvirus.
The transgenic mouse model system of claim 12 wherein said herpesvirus is selected from the group consisting of HHV6-A and HHV6-B.
The transgenic mouse model system of claim 12 wherein said transgene encoding CD46 is ubiquitously expressed in vivo.
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.
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.
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.
The transgenic mouse model system of claim 16 or claim 17 wherein said central nervous system inflammatory disease is multiple sclerosis.
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.
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.
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.
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).
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.
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.
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.
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.
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.
The composition of claim 27 wherein said composition is effective in the treatment of a neurodegenerative disorder and/or a tumor.
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.
The experimental system of claim 29 wherein said disease is multiple sclerosis.
The experimental system of claim 29 wherein said herpesvirus is HHV6.
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.
The non-human animal model system of claim 32 wherein said patient is a child or teenager.
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.
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.
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.
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.
The method of claim 37 wherein the presence of said antibodies is predictive of a risk for developing a CNS disorder.
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.
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.
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.
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.
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.
A method for evaluating the therapeutic value of compounds or other intervention that antagonize the development of detrimental autoantibodies as described in claim 1.
A method for evaluating the therapeutic value of compounds or other intervention that favor the development of beneficial autoantibodies as described in claim 1.
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.
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.
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.
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.
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.
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.
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
- 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.
- 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 inf