Discussion in 'Fibromyalgia Main Forum' started by simonedb, Jul 19, 2010.

  1. simonedb

    simonedb Member

    Retroviral sequences related to human T-lymphotropic virus type II
    in patients with chronic fatigue immune dysfunction syndrome
    (Epstein-Barr virus syndrome/infectious mononucleosis/myalgic encephalomyelitis/polymerase chain reaction/in situ hybridization)
    The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104 by Hilary Koprowski, November 13, 1990

    Chronic fatigue immune dysfunction syndrome
    (CFIDS) is a recently recognized illness characterized by
    debilitating fatigue as well as immunological and neurological
    abnormalities [Straus, S. E. (1988) J. Inf. Dis. 157, 405412].
    Once thought to be caused by Epstein-Barr virus, it is now
    thought to have a different but unknown etiology. We evaluated
    30 adult and pediatric CFIDS patients from six eastern states
    for the presence of human T-lymphotropic virus (HTLV) types
    I and II by Western immunoblotting, polymerase chain reaction,
    and in situ hybridization of blood samples. The majority
    of patients were positive for HTLV antibodies by Western
    blotting and for HTLV-II gag sequences by polymerase chain
    reaction and in situ hybridization. Twenty nonexposure healthy
    controls were negative in all assays. These data support an
    association between an HTLV-ll-like virus and CFIDS.
    The chronic fatigue immune dysfunction syndrome (CFIDS)
    is characterized by hematologic, neurologic, and neuromuscular
    abnormalities (1-5). Once called chronic Epstein-Barr
    virus syndrome, this disease may be related or identical to
    myalgic encephalomyelitis, Iceland disease, and epidemic
    neuromyasthenia (6).
    Several immunologic abnormalities have been documented
    in CFIDS patients (7-10). These abnormal immune patterns
    may represent primary immunologic defects or appear secondary
    to chronic infection. Although several viruses have
    been associated with CFIDS, including herpesviruses (11-13)
    and enteroviruses (14), the ubiquitous nature of these agents
    has hampered identification of any one as the etiologic agent.
    We examined adult and pediatric CFIDS patients for evidence
    of human retroviruses, human T-lymphotropic virus
    (HTLV) types I and II. For comparison, we also tested
    healthy age- and sex-matched controls who were household
    or casual contacts of these patients and healthy people who
    had no history of or exposure to CFIDS. All samples were
    coded and the investigators "blinded."

    Subjects. The first cohort consisted of 10 adults and 2
    teenagers from a North Carolina referral practice drawn from
    six eastern states. All patients met established criteria for
    CFIDS (1) and 4 of the patients were severely affected and
    largely homebound. The second cohort consisted of 19 children
    (<18 years of age) from rural upstate New York, where
    they were part of a CFIDS epidemic in 1985 (15). Of these 19
    children, 13 with mild to moderate symptoms were clustered
    in four families. Six children were not from family clusters.
    Three of these had severe symptoms and were homebound
    for more than 6 months.
    Healthy age- and sex-matched exposure controls were
    recruited from among people in North Carolina and New
    York who had either sexual or casual contacts with the
    patients. Blood samples from 20 healthy nonexposure controls
    were obtained in the Philadelphia area: 10 from adults
    and 10 from umbilical cords of newborns. All adult donors
    and mothers of newborns denied symptoms of CFIDS and
    exposure to CFIDS patients.
    All patients and controls were Caucasian and denied histories
    of blood or gamma globulin transfusions, intravenous
    drug abuse, and male homosexuality. None of the pediatric
    patients was known to be sexually active and no evidence of
    sexual abuse was observed. Sera from all patients and
    controls were tested by the American Red Cross (Philadelphia)
    and found negative for human immunodeficiency virus
    (HIV) antibodies and hepatitis B antigen.
    Patients' and exposure controls' heparinized blood samples
    were coded by the referral clinicians and the investigators
    were blinded. Each patient and exposure control was
    bled two or three times over 2 years, depending on patient
    consent. The nonexposure controls were processed and
    coded by a single person, who was not involved in the
    experiments. In all experiments, these control samples were
    interspersed with samples from patients and exposure controls.
    Western Immunoblot. Serum or plasma was tested for
    antibodies to HTLV-I and -II by Western blotting (16).
    Density gradient-purified HTLV-I from MT-2 cells was generously
    provided by V. Kalyanaraman (Advanced Biosciences,
    Kensington, MD) and used as antigen source in all
    Western immunoblots. Positive control sera were from
    HTLV-I-infected tropical spastic paraparesis patients. Negative
    control sera were from healthy donors from Philadelphia.
    Strips were scored according to criteria ofthe American
    Red Cross: positive samples must contain antibodies to
    products of at least two viral genes, including gag.
    DNA Extraction. After proteinase K digestion, DNA was
    extracted semiautomatically in a nucleic acid extractor (model
    340A; Applied Biosystems) (ref. 17, pp. 916-919). DNA
    from HTLV-I- and -II-infected cell lines was extracted using
    a second machine. DNA samples were aliquoted, used once
    for polymerase chain reaction (PCR), and discarded.
    PCR. To reduce the risk of laboratory contamination of the
    PCR, all reactions were carried out in a study-dedicated
    room. PCR was performed as described (18). Reaction-in CFIDS patients and controls. Lane 1, typical reactivity of serum
    from a patient with tropical spastic paraparesis; lanes 2-5, adult
    cohort; lanes 6-9, pediatric cohort; lanes 10 and 11, typical pattern
    of nonexposure controls. The molecular mass of viral proteins was
    determined by comigration of purified proteins (14.3 kDa to 200
    mixture controls without DNA and with noninfected cellular
    DNA (U-937 monocytic cells) were included with every PCR.
    Oligonucleotides were synthesized and HPLC-purified on
    a 5-15% acetonitrile gradient in 50 mM triethylamine/acetic
    acid, pH 7.0, by the Wistar DNA synthesis facility. Amplified
    DNA was stored at -20°C until use. The template capability
    of purified DNA was verified by performing a PCR using
    /3-globin primers (19).
    Southern Blot Hybridization. Reaction products (25 ,ul)
    were electrophoresed in 1.2% agarose gels and capillaryblotted
    onto Nytran filters (Schleicher & Schuell). The filters
    were prehybridized as described (ref. 17, pp. 944-955).
    Oligomer probes were 5'-end-labeled to a specific activity of
    6-8 x 106 cpm/pmol and hybridized as described (17) at
    37°C. The filters were exposed to Kodak XAR film for 5-7
    days at -70°C.
    In Situ Hybridization. Cells expressing RNA homologous
    to HTLV-I and HTLV-II were detected by in situ hybridization
    using 35S-labeled RNA antisense probes specific for
    the 5' region of both viruses. HTLV-I and HTLV-II gag
    subclones from MT-2 and Mo-T, respectively, were inserted
    into the pSP64 Sac I site and transcribed as reported (20). The
    RNA transcripts averaged 0.5 kilobase in length and were
    hybridized at 1-2 x 108 dpm/ml at 50°C on 4% paraformaldehyde-
    fixed activated peripheral blood mononuclear cells
    (PBMCs). The cells were centrifuged onto glass slides and
    then autoradiographed for 4-8 days (16).

    HTLV Serum Antibodies. We tested sera for evidence of
    human retroviral infection by Western immunoblotting
    against purified HTLV-I. By American Red Cross criteria,
    50% of adult and 61% of pediatric CFIDS patients were
    positive, while none of the 20 nonexposure control sera was
    reactive. Typical patterns of reactivity are shown in Fig. 1.
    Several CFIDS sera show distinct reactivity to both HTLV
    gag and env gene products. CFIDS samples in lanes 2, 3, and
    6-9 (Fig. 1) were scored positive, while those in lanes 4 and
    5 were negative. The two negative sera (lanes 10 and 11) are
    representative ofthe pattern seen with nonexposure controls.
    HTLV Proviral Sequences. Since Western blots suggested
    that a proportion of CFIDS patients may have been exposed
    to HTLV, we examined their peripheral blood cells for
    HTLV-I- and -II-specific proviral sequences by PCR. We
    selected and synthesized a series of oligonucleotides to use as
    primers and probes specific for the gag and tax regions of
    both HTLV-I and -II (Fig. 2).
    The results of amplification and Southern blotting for
    HTLV-I gag are shown in Fig. 3. Although a strong signal
    was observed from MT-2 DNA, all CFIDS patients and
    controls were negative. Identical results were observed using
    HTLV-I tax primers (data not shown).
    In contrast, when the same samples were analyzed for an
    HTLV-II gag region, products of the appropriate size (identical
    to that in Mo-T) were seen in a majority of adult (Fig. 4A)
    and pediatric (Fig. 4B) CFIDS patients. Several exposure
    controls in both cohorts were also found to contain the same
    HTLV-II gag region as CFIDS patients. These same primers
    did not amplify any hybridizable product from the blood of 10
    healthy infants or 10 healthy adults (Fig. 4 C and D).
    (Although shown here in a separate autoradiogram for illustration,
    these controls were routinely interspersed with patient
    samples and found negative when assayed.) Despite the
    lack of amplification of the HTLV-II gag region in the
    nonexposure controls, the DNA from these samples was a
    competent template for PCR, since a region of f3-globin was
    routinely amplified using specific primers (Fig. 4E). All
    patients were negative for the HTLV-II tax amplified prodof DNA from Mo-T and was detected in only one exposure
    control (data not shown). The PCR experiments are summarized
    in Tables 1 and 2.
    Retroviral mRNA Detection. To determine whether the
    HTLV-II gag region amplified by PCR of patients' DNA was
    part of a functional gene, we evaluated the expression of
    HTLV mRNA in PBMCs by in situ hybridization using gag
    transcripts from both HTLV-I and -II. Fig. 5 shows the typical
    pattern of reactivity seen with HTLV-II gag RNA probe. The
    analysis of adult samples is summarized in Table 3.

    We have presented evidence for HTLV-II-like infection of
    blood cells from CFIDS patients and, to a lesser extent, from
    some people who closely associate with them. More than
    50% of samples from 31 patients contained antibodies to at
    least two viral gene products by Western blot analysis. Since
    serologic assays using HTLV-I-derived antigens cannot distinguish
    between HTLV-I- and -II-specific antibodies, the
    positive Western blots may be directed toward either virus
    (21). Because purified HTLV-I was used as the antigen, it is
    unlikely that the antibodies were detecting cellular antigens
    shed from the infected MT-2 cells. This is further substantiated
    by patient reactivity to proteins with the molecular
    weights reported for HTLV-I and -II antigens. The pronounced
    reactivity to gag (p19 and p24) and env (gp45-46) in
    cycles of PCR amplification and Southern blot hybridization, DNA
    from adult (A) and pediatric (B) CFIDS patients and exposure
    controls. Mo-T (HTLV-II) DNA from 200 pg to 2 ,jg without carrier
    DNA is shown hybridized in lanes 1-3; HTLV-I DNA in lane 4. (C
    and D) Cord blood DNA and DNA from nonexposed adults were
    amplified and hybridized as described. In C: lane 1, 4bX174 DNA;
    lane 2, reagents only; lane 3, U-937 DNA; lane 4, buffer control; lanes
    5-14, cord blood DNA; lanes 16-19, Mo-T (HTLV-II) DNA from 2
    .g to 200 pg without carrier DNA. In D: lane 1, 4X174 DNA; lanes
    2-11, DNA from blood of healthy nonexposure adults; lanes 12-17,
    cord blood DNA; lanes 19, 21, 23, and 25, Mo-T (HTLV-H1) DNA
    from 2 pg to 2 ng without carrier. (E) Amplification of 8-globin DNA
    of adult and pediatric nonexposure controls. Lane 1, OX174 DNA;
    lanes 2-4, reagent controls; lanes 5-10, DNA from cord blood; lanes
    11-20, peripheral blood of adults. Gel was stained with ethidium
    positive patients suggests exposure to a virus closely related
    or identical to either HTLV-I or -II.
    The frequency of these antibodies in CFIDS patients
    compared with healthy, noncontact controls suggests exposure/
    infection with an HTLV-like agent rare in healthy
    noncontact people. Some adult CFIDS patients in the study
    were from the southeastern United States, where HTLV-I
    infections are more frequent, but the reported incidence of
    HTLV seropositivity in blood donors there is only 0.05%
    (22). More important, the pediatric patients reside in rural
    upstate New York, where population studies have shown that
    the HTLV seropositivity rate approaches zero (22).
    Although polyclonal upregulation of antibodies to other
    viruses has been reported in CFIDS, this mechanism is
    unlikely with respect to HTLV (23). These antibodies appear
    to be directed exclusively to viruses to which the majority of
    the population has been exposed. Polyclonal B-cell activation
    would not be expected to induce antibodies to a virus the
    patients had never encountered.
    To detect the presence of proviral HTLV in blood cells of
    CFIDS patients, we amplified specific regions ofHTLV-I and
    HTLV-II by PCR. None of the CFIDS patients' blood
    samples contained detectable HTLV-I gag sequences. In
    contrast, DNA from at least two separate bleedings was
    positive for the HTLV-II gag subregion in 83% of adult and
    72% of pediatric CFIDS patients. None of the HTLV regions
    examined was amplified from DNA of 20 nonexposure controls.
    If this gag gene is a segment of a complete provirus, the
    retrovirus is probably not prototypic HTLV-II (24), since we
    did not amplify an HTLV-II tax region in CFIDS patients that
    is found in Mo-T. The reported sequence variability among
    HTLV-II isolates, not seen with isolates of HTLV-I, supports
    this hypothesis (25).
    We confirmed these findings on the adult CFIDS samples
    by demonstrating that 7 out of 10 HTLV-II gag-positive
    samples by PCR had cells expressing HTLV-II gag mRNA.
    Moreover, the detection of viral mRNA in these cells dem-onstrates that the HTLV-II gag is a functional gene. Although
    the gag mRNA-positive cells were rare (10-2 to 10-4)
    as compared with the productively infected T-cell line Mo-T,
    similar frequencies of PBMCs expressing retroviral niRNA
    have been reported for HIV-infected individuals (20).
    The HTLV-II-like region we have amplified in CFIDS
    DNA probably is not a homologous endogenous gene or
    ubiquitous virus for several reasons. First, endogenous genes
    are present in all nucleated cells of a positive individual and
    can be detected by Southern blot hybridization of genomic
    DNA without the need for prior amplification, as was neces-Scale used to score samples: ++++, 100-50% positive cells;
    + + +, 50-1% positive cells; + +, 1-0.1% positive cells; +, 1-0.01%
    positive cells; -, <0.01% positive cells.
    sary in this study. Second, a GenBank search (August 8, 1990)
    for homology and sequence position of the HTLV-II gag
    primer pairs against primate endogenous genes and all known
    viruses revealed no possible amplification of a 409-bp sequence
    except for HTLV-II gag. Among the viruses excluded
    by this search were herpes simplex viruses 1 and 2, Epstein-
    Barr virus, cytomegalovirus, poliovirus, human herpesvirus 6,
    and known endogenous human retroviruses, including one
    shown'to have a degree of homology to HTLV (26).
    The correlation between the'presence of serum antibodies
    to HTLV and detectable' HTLV-II-like gag DNA or RNA in
    CFIDS patient blood was high but not universal. Of 13
    pediatric patients positive by PCR, 10 were Western blotpositive.
    Of 10 adult PCR-positive patients, 5 had positive
    Western blots. The lower frequency of antibody-positivity in
    adults is compatible with the reported incidence of cellmediated
    anergy in adult CFIDS (27). Alternatively, antibody-
    negative patients may reflect latency of the retroviruslike
    gene. In fact, of 6 Western blot-negative CFIDS adults,
    HTLV-II gag mRNA could not be detected in 4. Conversely,
    of 6 Western blot-positive adult patients, 5 expressed
    HTLV-II gag mRNA.
    The clinical histories of these CFIDS patients do not reveal
    behavioral or genetic factors usually associated with retroviral
    infection. Yet our data suggest' that not only are these
    HTLV-II-like genes and HTLV-reactive antibodies associated
    with CFIDS in patients but that samples from a significant
    proportion of their nonsexual contacts are positive.
    Because this study was not designed to address the issue of
    transmissibility of the agent, conclusions regarding its communicability
    would be premature. However, the epidemiology
    of some CFIDS cases suggests horizontal, casual transmission,
    as in the epidemics at Lake Tahoe, Nevada (23), and
    Lyndonville, New York (15).'Herberman and colleagues (28)
    have reported that natural killer (NK) cell abnormalities
    found in CFIDS patients are observed in some healthy
    contacts of the patients, but not in healthy, nonexposure
    controls (28).
    Although our data support an association between an
    HTLV-like agent and CFIDS, we cannot, as yet, define the
    agent's role in the disease process. Rather than an etiologic
    agent, it may be a benign secondary infection to which
    immunologically compromised patients are susceptible. Alternatively,
    it may be one of two viruses that, when coinfecting
    the same hematopoetic cells, induce immune dysfunction. In
    any case, biological characterization of this agent and its role
    in the pathogenesis of CFIDS awaits its isolation.
    We thank Dr. Robert Gallo (National Institutes of Health) for the
    HTLV-I- and -II-positive T-cell lines MT-2 and Mo-T; Dr. V.
    Kalyanaraman (Advanced Biosciences, Kensington, MD) for his gift
    of purified HTLV-I, Dr. Premkumar Reddy (Wistar) for the HTLV-I
    RNA probe, and Dr. Abbas Vafai (University of Colorado, Denver)
    for the HTLV-II RNA probe. We are indebted to Drs. Lawrence
    Seidman and Morton Valow (Philadelphia) for the umbilical cord
    blood. Advice and helpful discussion was provided by Drs. Rick
    Mettus and Alagarsamy Srinivasan (Wistnr). The technical assistance
    of Ms. Susan Dorman is appreciated. We thank Mrs. Eva Davis
    for preparation of the manuscript. This work was supported by
    National Institutes of Health Grant NS11036 and grants from the
    Pioneer Foundation and the CFIDS Association.
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    [This Message was Edited on 07/19/2010]
    [This Message was Edited on 07/19/2010]
    [This Message was Edited on 07/23/2010]
  2. quanked

    quanked Member

    I wonder why it was so difficult to copy and paste.

    The study is all Greek to me. I am hoping some fine mind will reduce the content of the study down to and understandable summary. It will not be my mind, that is for sure : )
  3. simonedb

    simonedb Member

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    Reddy EP, Sandberg-Wollheim M, Mettus RV, Ray PE, DeFreitas E, Koprowski H.

    Science. 1989 Jan 27;243(4890):529-33. Erratum in: Science 1989 Oct 6;246(4926):246.
    PMID: 2536193 [PubMed - indexed for MEDLINE]
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    11.Molecular cloning of human T-cell lymphotrophic virus type I-like proviral genome from the peripheral lymphocyte DNA of a patient with chronic neurologic disorders.

    Reddy EP, Mettus RV, DeFreitas E, Wroblewska Z, Cisco M, Koprowski H.

    Proc Natl Acad Sci U S A. 1988 May;85(10):3599-603.
    PMID: 2897123 [PubMed - indexed for MEDLINE]Free PMC ArticleFree text
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    12.HTLV-I and chronic nervous diseases: present status and a look into the future.

    Koprowski H, DeFreitas E.

    Ann Neurol. 1988;23 Suppl:S166-70.
    PMID: 2450520 [PubMed - indexed for MEDLINE]
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    13.Human immune response to monoclonal antibody administration is dose-dependent.

    Sears HF, Bägli DJ, Herlyn D, DeFreitas E, Suzuki H, Steele G, Koprowski H.

    Arch Surg. 1987 Dec;122(12):1384-8.
    PMID: 3689113 [PubMed - indexed for MEDLINE]
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    14.Association of human T-lymphotropic viruses in chronic neurological disease.

    DeFreitas E, Saida T, Iwasaki Y, Koprowski H.

    Ann Neurol. 1987 Feb;21(2):215-6. No abstract available.
    PMID: 3030191 [PubMed - indexed for MEDLINE]
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    15.HTLV-I infection of cerebrospinal fluid T cells from patients with chronic neurologic disease.

    DeFreitas E, Wroblewska Z, Maul G, Sheremata W, Ferrante P, Lavi E, Harper M, di Marzo-Veronese F, Koprowski H.

    AIDS Res Hum Retroviruses. 1987 Spring;3(1):19-32.
    PMID: 2887183 [PubMed - indexed for MEDLINE]
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    16.Human antibody induction to the idiotypic and anti-idiotypic determinants of a monoclonal antibody against a gastrointestinal carcinoma antigen.

    DeFreitas E, Suzuki H, Herlyn D, Lubeck M, Sears H, Herlyn M, Koprowski H.

    Curr Top Microbiol Immunol. 1985;119:75-89. Review. No abstract available.
    PMID: 2867860 [PubMed - indexed for MEDLINE]
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    17.Human anti-idiotype antibodies in cancer patients: Is the modulation of the immune response beneficial for the patient?

    Koprowski H, Herlyn D, Lubeck M, DeFreitas E, Sears HF.

    Proc Natl Acad Sci U S A. 1984 Jan;81(1):216-9.
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    18.Abrogation of tumor rejection by trypan blue.

    Kreider JW, Bartlett GL, DeFreitas E.

    Cancer Res. 1978 Apr;38(4):1036-40.
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  4. bigmama2

    bigmama2 New Member

    thank you for posting this info. we appreciate it!!! it will be very interesting to see how xmrv pans out, and also the possible connection to elaine defr. work.

    spacee- i have a post for you on cfs board. (didnt want to hijack this one.) oh , and i am so sorry your sister "wont hear a word about CFS". that is wrong, and sad.


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