Subacute sclerosing panencephalitis: isolation of suppressed measles virus from lymph node biopsies.

Measles virus was isolated in mixed cultures of lymph node cells and HeLa cells. The agent was isolated by cocultivation from biopsy specimens of two of five patients with subacute sclerosing panencephalitis. The virus was identified by hemagglutination-inhibition, immunofluorescent, and neutralization tests. Biopsies from controls did not show evidence of measles virus.

Genital herpesvirus hominis type 2 infection: an experimental model in cebus monkeys.

Genital infection with herpesvirus hominis type 2 was established in ten female cebus monkeys. Clinical and laboratory findings in the cebus mimic closely those observed in humans, thus providing an experimental model which may be used in the study of the possible role of genital herpetic infection in cervical cancer and in perinatal and chronic neurological diseases.

Transmission of simian acquired immunodeficiency syndrome (SAIDS) with blood or filtered plasma.

Simian acquired immunodeficiency syndrome (SAIDS), a disease clinically and pathologically similar to acquired immunodeficiency syndrome in humans, was transmitted from diseased rhesus monkeys (Macaca mulatta) to normal monkeys by inoculation with heparinized whole blood or plasma that had been passed through filters of 0.45 micrometer pore size. This suggests that the causative agent is small and most probably a virus. No viruses, however, were isolated by standard cell culture techniques from the blood or filtered plasma which caused SAIDS. Both cellular and humoral immunity were markedly depressed in animals with advanced SAIDS.

Brain tumors in owl monkeys inoculated with a human polyomavirus (JC virus).

Owl monkeys were inoculated intracerebrally, subcutaneously, and intravenously with JC, BK, or SV40 virus. Two of four adult owl monkeys inoculated with JC virus, a human polyomavirus, developed brain tumors at 16 and 25 months after inoculation, respectively. A grade 3 to grade 4 astrocytoma (resembling a human glioblastoma multiforme) was found in the left cerebral hemisphere and brainstem of one monkey. The second monkey developed a malignant tumor in the left cerebral hemisphere containing both glial and neuronal cell types. Impression smears prepared from unfixed tissue of this tumor showed cells that contained polyomavirus T antigen. Virion antigens were not detected. Tumor cells cultured in vitro also contained T antigen but were negative for virion antigen. Infectious virus was not isolated from extracts of this tumor.

A preliminary report on investigation of oncogenic potential of herpes simplex virus type 2 in Cebus monkeys.

A total of 301 female and 133 male Cebus monkeys have been placed under study during a 3-year period. Females are inoculated intradermally into the cervix every 6 months; 225 receive virus and 76 receive control material. More than 50% of the animals were infected on primary inoculation, and a similar percentage was foundon the 1st reinoculation. Males are housed with females at 1:1 to 1:3 ratios. Eighteen % of the males exposed to virus-inoculated females have become infected. To date, a total of 55 pregnancies have produced 14 live births and 8 abortions. The remaining 33 animals are still pregnant. No neonatal herpes simplex virus type 2 infections have been identified. Cytological changes of mild (atypia) to moderate (dysplasia) anaplasia have persisted for 12 to 32 months in 13 herpes simplex virus type 2-infected females. These animals received their 1st inoculation 14 to 50 months ago. Persistent anaplasia has not been found in control animals.

Cellular immune factors associated with mother-to-infant transmission of HIV.

OBJECTIVE: To study a possible correlate of protection in mother-to-infant transmission of HIV infection. In particular, to determine whether lack of HIV-specific T-helper (TH) function as indicated by HIV and non-HIV antigen-stimulated interleukin (IL)-2 production of mother and/or newborn peripheral blood leukocytes (PBL) is associated with mother-to-infant transmission of HIV. METHODS: PBL from 21 HIV-seropositive pregnant women and 23 cord blood leukocytes (CBL) from their offspring were studied for in vitro TH function by IL-2 production in response to HIV and non-HIV antigens. Polymerase chain reaction (PCR) and viral culture assays were performed to determine HIV infection of the infants. RESULTS: PBL from 10 out of 21 (48%) mothers and from eight out of 23 (35%) CBL samples responded to two or more out of five synthetic gp 160 envelope (env) peptides. Three of the 23 (13%) offspring were shown to be HIV-infected by PCR and/or viral culture on follow-up. All three infected infants were from a subset whose CBL did not exhibit env-specific TH immunity. CONCLUSION: Our results demonstrate that fetal T cells can be primed to HIV env determinants in utero, suggest that HIV-specific TH immunity may be protective in newborns, and provide a possible means for identifying newborns who are at risk for HIV infection.

Nutritional studies in the pregnant rhesus monkey--the effect of protein-calorie or protein deprivation on growth of the fetal brain.

Twenty four pregnant nulliparous rhesus monkeys were distributed in three groups. While pregnant, the mothers were fed a diet, adequate in mineral and vitamins, that afforded 4.2 g protein and 100 cal; 1.2 g protein and 100 cal; or 1.2 g protein and 50 cal per kg per day. The fetuses were taken by cesarian section at 156 days gestation (term = 165 days) and the cerebrum and cerebellum were subsequently analysed chemically to assess composition and growth. Analyses revealed no statistically significant changes in protein, DNA, RNA, cholesterol, phospholipid, water, or chloride space of either tissue. The zinc concentration per gram of cerebral tissue or protein was significantly elevated in the low protein low calorie group. These results indicate that the brain of the fetus of this primate is protected during frank protein-calorie restriction of the mother. Moreover it is during this time that the major part of brain development takes place. It is argued that the differences observed after maternal restriction of protein and/or calories in subprimate mammals are not necessarily applicable to the human situation.

Subacute sclerosing panencephalitis in only one of identical twins. A seven-year follow-up.

We report a seven-year follow-up of identical twins, in one of whom subacute sclerosing panencephalitis (SSPE) developed. Primary measles infection occurred simultaneous in both twins at age 4. The affected twin sustained a grade 1 closed head injury within six months of her primary measles infection. At age 13, SSPE was diagnosed following the onset of personality change and myoclonic seizures. Measles antibody level was elevated in the serum and CSF. After remaining in stage 2 for five years, rapid mental and neurological deterioration occurred. Measles antibody level remained elevated, and oligoclonal IgG was present in both serum and CSF. Results of neurological examination as well as virological and immunological tests were normal in the unaffected twin. Besides the occurrence of head injury, factors known to be associated with SSPE were not obviously different in the twins. We have been unable to determine a difference that would easily explain the occurrence of SSPE in only one of two identical twins.

Administration of recombinant human leukocyte alpha 2-interferon in patients with amyotrophic lateral sclerosis.

Recombinant leukocyte alpha 2-interferon (with greater than 98% purity) was evaluated in a pilot treatment in six patients with amyotrophic lateral sclerosis and one patient with slowly progressive postpoliomyelitis motor neuron disease. Interferon, administered subcutaneously in doses of 2 million units three times per week for four months, was ineffective in improving, arresting, or slowing the pace of progression in all the patients who were followed up for ten to 14 months after the end of therapy.

CSF viral antibodies. Evaluation in amyotrophic lateral sclerosis and late-onset postpoliomyelitis progressive muscular atrophy.

Serum and CSF from 48 patients with amyotrophic lateral sclerosis and six patients with late-onset postpoliomyelitis progressive muscular atrophy were investigated for the presence of antibody to poliovirus types 1, 2, and 3, coxsackie viruses B3 and B4, influenza A, measles, rubella, mumps, herpes simplex types 1 and 2, cytomegalovirus, varicella-zoster, and Toxoplasma gondii. These results were compared with those from 53 control patients with neuromuscular disease matched for age, sex, race, and poliovirus vaccine exposure. There was no difference either in distribution of serum or CSF antibody titers or the geometric-mean antibody titers. There was no evidence suggesting the presence of locally produced specific viral antibody within the CNS to any of the agents studied. In particular, there was no serological evidence to suggest an association between persistent infection with any poliovirus type and amyotrophic lateral sclerosis or late-onset postpoliomyelitis progressive muscular atrophy.

Herpesviruses and parkinsonism. Herpes simplex virus types 1 and 2, and cytomegalovirus antibodies in serum and CSF.

Antibodies against herpes simplex virus (HSV) types 1 and 2 and cytomegalovirus (CMV) were assayed with a microindirect hemagglutination (IHA) test in the serum of 67 pairs of patients with Parkinson's disease and controls. Cerebrospinal fluid from 30 pairs was assayed. All patient and control serum was tested with a radioimmunoassay (RIA) for antibodies against HSV type 1 subunit antigens. Serum IHA antibody level against HSV type 1 was increased in patients with Parkinson's disease and RIA antibody levels against the same viral antigen were significantly higher in the patients than controls. Herpes simplex virus type 2 and CMV serum antibodies were equal in the patient and control groups. Most of the CSF samples tested negatively for IHA; small and comparable numbers of the patients and controls had low antibody levels against HSV and CMV antigens.

Human T-lymphotropic virus type I antibodies in the serum of patients with tropical spastic paraparesis in the Seychelles.

Tropical spastic paraparesis (TSP), a chronic myelopathy of unknown etiology, was studied in the Seychelles. Human T-lymphotropic virus type I (HTLV-I) and human immunodeficiency virus antibodies were determined using an enzyme-linked immunosorbent assay and confirmed with an indirect fluorescent antibody test in serum samples of 20 patients with TSP and 16 controls. Test results indicated that 17 patients (85%) and two controls (transverse myelopathy and clinically probable multiple sclerosis) were positive for HTLV-I. Serum samples of nine healthy controls and five with other neurologic diseases were negative for HTLV-I. No serum samples were positive for human immunodeficiency virus. Estimated relative risk for TSP in those subjects whose serum is positive for HTLV-I antibodies is 40. This result is highly statistically significant. Although primarily associated with adult T-cell leukemia and non-Hodgkin's lymphoma, HTLV-I could also be an etiologic agent of TSP.

Measles and canine distemper antibody. Presence in sera from patients with multiple sclerosis and matched control subjects.

Antibody to measles virus and canine distemper virus (CDV) was demonstrated in sera from patients with multiple sclerosis (MS) and from carefully matched control subjects. Elevated measles and CDV antibody titers were found in patients with MS when compared with the matched control subjects. The correlation between the measles and CDV antibody titers was quite high, suggesting that the antibody levels between the two viruses are very closely related. Based on the results of our study and a review of the literature, our conclusion is that the CDV antibody levels in patients with MS and matched control subjects are associated with occurrence of measles virus antibodies.

Coronavirus antibodies in sera from patients with multiple sclerosis and matched controls.

Sera from patients with multiple sclerosis and carefully matched controls were tested for antibodies to three strains of coronavirus. There was no significant difference in the levels of antibody in the patients vs the controls. We conclude that unless the strains of coronaviruses recently reported to have been isolated from patients with multiple sclerosis express important serological differences from those used in these studies, coronaviruses are not associated with the cause of multiple sclerosis.

Micromethod for detection of oligoclonal IgG in unconcentrated CSF by polyacrylamide gel electrophoresis.

A micromethod to detect oligoclonal IgG from 50 microL of unconcentrated CSF was developed by using polyacrylamide gel electrophoresis in sodium dodecyl sulfate (SDS-PAGE). Of 17 patients with multiple sclerosis, oligoclonal bands were demonstrated in 16 instances (94%) by micro-SDS-PAGE and in 13 (76%) by agarose gel electrophoresis. The corresponding figures among 30 patients with optic neuritis were 16 (54%) and five (17%), respectively, and among ten patients with other neurological disease the figures were two (20%) and none, respectively. Thus, micro-SDS-PAGE is more sensitive than agarose gel electrophoresis for detection of oligoclonal IgG. The small volume of unconcentrated CSF that is required enhances the usefulness of this test.

Limitations in the laboratory diagnosis of vertically acquired HIV infection.

At present, the only well-standardized and widely available diagnostic techniques for HIV infection are detection of IgG HIV antibodies and HIV antigen. The antibody detection is sensitive, but is useful only in infants and children older than 15 months because of the presence of maternal antibodies. The utility of HIV antigen testing in neonates and young infants has not been established. A number of sensitive techniques, such as PCR, ELISPOT, and detection of HIV-specific IgM and IgA antibodies, are under development and promise to be very useful in the early diagnosis of vertical HIV infection. However, we will be able to accurately establish the sensitivity or specificity of the individual tests only when we have results of large prospective studies. These studies should compare different diagnostic methods and correlate the results of tests performed sequentially in neonates and young infants with the natural history of their disease process and eventual clinical outcome.

Progressive multifocal leukoencephalopathy: JC virus detection by in situ hybridization compared with immunohistochemistry.

In four cases of progressive multifocal leukoencephalopathy (PML), we compared biotin-labeled DNA:DNA in situ hybridization with peroxidase immunohistochemistry for the detection of JC virus (JCV). The localization of JCV DNA and JCV capsid protein was compared in formalin-fixed, paraffin-embedded brain tissues. Infected oligodendrocytes showed both JCV DNA and JCV protein. However, bizarre astrocytes demonstrated JCV capsid protein less often than JCV DNA. In situ hybridization with a biotinylated probe was as sensitive and specific as immunohistochemistry for diagnosis on formalin-fixed tissue. The presence of both JCV DNA and viral capsid protein in bizarre astrocytes suggests that these cells are neither truly transformed nor permissively infected, but are distinctively altered by JCV.

Polymyositis in an immunodeficiency disease in monkeys induced by a type D retrovirus.

Fifty percent of primates with acquired immunodeficiency caused by a well-characterized type D retrovirus (SAIDS D) developed clinical, laboratory, and histologic features of polymyositis. By use of specific antisera and immunochemical techniques, we found the virus in the lymphoid cells surrounding muscle fibers and invading the endomysia septa. SAIDS D virus was isolated from the involved muscles and infected myotubes of normal muscle in tissue culture. These results suggest that retroviruses, a group of viruses increasingly associated with human diseases, can cause polymyositis with immunodeficiency in nonhuman primates and could play a role in human polymyositis.

CSF "monoclonal" bands in chronic relapsing polyneuropathy.

The characteristics and temporal profiles of cerebrospinal fluid (CSF) and serum immunoglobulin patterns on agarose gel electrophoresis were studied in 47 patients with acute idiopathic polyneuropathy (AIP) and 15 patients with chronic relapsing polyneuropathy (CRP). Nineteen of 47 patients with AIP had transient oligoclonal IgG bands, which disappeared when the neurologic signs subsided. By contrast, 14 of 15 patients with CRP had a "monoclonal" (single) IgG band, which (1) was unchanged on repeated CSF examinations over 18 months, (2) was unaffected by corticosteroid therapy, and (3) did not correlate with the severity or chronicity of the disease. Serum protein patterns and in situ central nervous system IGG synthesis and IgG:albumin index were normal in the CRP patients. The origin of the band and the nature of the putative antigen(s) that the band may be directed against were not identified. Our findings suggest that different immunopathogenic mechanisms may be operating in CRP, compared with AIP. The stable IgG band in CRP may reflect response to a persisting antigenic stimulation and, with further experience, may prove to be of prognostic significance by furnishing early in the illness: (1) a clue to the subsequent course of the disease, and (2) possible guidance on therapeutic decisions.

Multiple sclerosis associated agent (MSAA): failure to confirm an association with multiple sclerosis.

Recent reports indicate that a multiple sclerosis agent (MSAA) has been isolated. This agent was detected in mice by a depression in the percentage of mouse polymorphonuclear neutrophils (PMNs). We attempted to repeat these studies using coded specimens. The test, itself, was extremely variable and difficult to reproduce. In the first study, three of three multiple sclerosis (MS) patients and one of two control patients' specimens showed some PMN depression. In a repeat study of these same samples, one of three MS patients and one of two controls were associated with PMN depression. With a second set of coded specimens, one of four MS patients, one of three patients with neurologic diseases, and none of three controls showed PMN depression. We were unable to confirm the presence of MSAA and conclude that the results were random.