Sidney A. Houff

Involvement of JC Virus–Infected Mononuclear Cells from the Bone Marrow and Spleen in the Pathogenesis of Progressive Multifocal Leukoencephalopathy

PROGRESSIVE multifocal leukoencephalopathy (PML), a subacute demyelinating disease resulting from infection of oligodendrocytes by JC virus, occurs almost exclusively in immunocompromised patients....

Chlordecone intoxication in man 1. Clinical observations

Industrial overexposure to chlordecone, an organochlorine insecticide, caused tremor in 76 of 148 exposed workers. Chlordecone was absorbed through oral, respiratory, and dermal routes, the last possibly the most significant. Epidemiology of this incident disclosed low-level, wide spread environmental exposure of man to chlordecone. In 23 workers with chronic chlordecone intoxication, tremor was associated with opsoclonus, pleuritic pain and arthralgia. No seizures were reported. The site of action of chlordecone on the central nervous system is unknown. It concentrates inhuman adipose and hepatic tissue but is not biodegradable, either in humans or elsewhere in nature.

Multiple sclerosis in twins

We studied 30 sets of twins in whom one or both was suspected of having multiple sclerosis (MS). In 24 pairs, a firm clinical diagnosis was made on each twin. Among these 24 pairs, 6 of 12 monozygotic twins were concordant for clinical MS, compared with 2 of 12 dizygotic twins.Of those over the age of 50, two of three monozygotic pairs were concordant, but neither of the two dizygotic twin pairs were concordant. Because ascertainment was primarily through public announcement, this series may be biased in favor of twins concordant for MS. The individuals within monozygotic concordant twin pairs exhibited wide differences in severity and age at onset of disease; the more recently affected twin tended to have a lower cerebrospinal fluid (CSF) IgG and a higher IgM level. Although the frequency of HLA-B7 and Dw2 in this twin population was high, the HLA makeup did not differ appreciably between concordant and discordant MS twins. Furthermore, the two DZ-concordant twins were HLA-nonidentical. Unexplained neurologic signs were found in three asymptomatic twins, and a high proportion of clinically normal twins had abnormalities of CSF immunoglobulins. These latter findings suggest a high incidence of subclinical MS in this population.

Progressive multifocal leukoencephalopathy: lessons from AIDS and natalizumab

Abstract The dramatic increase in the incidence of progressive multifocal leukoencephalopathy (PML) that occurred as a consequence of the AIDS pandemic and the recent association of PML with the administration of natalizumab, a monoclonal antibody to α4 integrin that blocks inflammatory cell entry into the brain, has stimulated a great deal of interest in this previously obscure viral demyelinating disease. The etiology of this disorder is JC virus (JCV), a polyoma virus, observed in 80% of the population worldwide. Seroepidemiological studies indicate that infection with this virus typically occurs before the age of 20 years. No primary illness owing to JCV infection has been recognized and the means of spread from person to person remains obscure. Following infection, the virus becomes latent in bone marrow, spleen, tonsils and other tissues. Periodically the virus reactivates during which time it can be demonstrated in circulating peripheral lymphocytes. The latter is significantly more commonly observed in immunosuppressed populations than that in normal subjects. Despite the large pool of people infected with JCV, PML remains a relatively rare disease. It is seldom observed in the absence of an underlying predisposing illness, typically one that results in impaired cellular immunity. A variety of factors are likely responsible for the unique increase in frequency of PML in HIV infection relative to other underling immunosuppressive disorders. Preliminary data suggests that natalizumab appears to distinctively predispose recipients to PML relative to other infectious complications. Studies in these populations will be invaluable in understanding the mechanisms of disease pathogenesis.

JC Virus Antibody Status Underestimates Infection Rates

JC virus (JCV) seropositivity is a risk factor for progressive multifocal leukoencephalopathy (PML) in patients on natalizumab. Accordingly, the JCV serological antibody test is of paramount importance in determining disease risk.

Neurological complications of herpes simplex virus type 2 infection.

Herpes simplex virus type 2 (HSV-2) infection is responsible for significant neurological morbidity, perhaps more than any other virus. Seroprevalence studies suggest that as many as 45 million people in the United States have been infected with HSV-2, and the estimated incidence of new infection is 1 million annually. Substantial numbers of these persons will manifest neurological symptoms that are generally, although not always, mild and self-limited. Despite a 50% genetic homology between HSV-1 and HSV-2, there are significant differences in the clinical manifestations of these 2 viruses. We herein review the neurological complications of HSV-2 infection.

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.

Interactions between c-Jun, Nuclear Factor 1, and JC Virus Promoter Sequences: Implications for Viral Tropism

ABSTRACT The infectious cycle of the human polyomavirus JC (JCV) is ultimately regulated in cellular nuclei at the level of viral protein expression and genomic replication. Such activity is prompted by interactions between variant nucleotide sequences within the JCV regulatory region (promoter) and cellular transcription factors that bind specific DNA consensus sites. In previous work we identified an NF-1 class member, NF-1X, as a critical transcription factor affecting the JCV cellular host range. Within variant JCV promoters, as well as other viral and cellular promoters, adjacently located NF-1 and AP-1 consensus sites are often found. The close proximity of these two binding sites suggests the opportunity for interaction between NF-1 and AP-1 proteins. Here, by electrophoretic mobility shift assays, we show temporal and dose-dependent interference by an AP-1 family member, c-Jun, upon NF-1 proteins binding an NF-1 consensus site derived from JCV promoter sequence. Moreover, as demonstrated by protein-protein interaction assays, we identify specific binding affinity independent of DNA binding between NF-1X and c-Jun. Finally, to compare the binding profiles of NF-1X and c-Jun on JCV promoter sequence in parallel with in vivo detection of viral activity levels, we developed an anchored transcriptional promoter (ATP) assay. With use of extracts from JCV-infected cells transfected to overexpress either NF-1X or c-Jun, ATP assays showed concurrent increases in NF-1X binding and viral protein expression. Conversely, increased c-Jun binding accompanied decreases in both NF-1X binding and viral protein expression. Therefore, inhibition of NF-1X binding by c-Jun appears to play a role in regulating levels of JCV activity.

A rapid method for in situ hybridization for viral DNA in brain biopsies from patients with AIDS.

Brain biopsy is often necessary in the diagnosis of neurological complications found in AIDS patients. We describe here a rapid method of tissue preparation and in situ DNA hybridization for detecting JC virus DNA in frozen brain biopsy sections which allows the diagnosis of progressive multifocal leukoencephalopathy to be established on the day of surgery. Once the diagnosis is established, therapeutic and management decisions can be made more easily. The commercial availability of biotinylated probes for several of the DNA viruses most frequently encountered in brain infections of AIDS patients will provide wide application of these techniques to patient management.

Suppressor cell activity in multiple sclerosis

Patients with multiple sclerosis and matched controls were tested for lymphocyte stimulation response and induction of suppressor cell activity in response to concanavalin A (Con A) and antigens from axolemma or myelin. Of 17 stable patients, 6 failed to have a suppressor cell response activated by one of these brain cell antigens. Among the patients who lacked these suppressor responses, five had lymphocyte stimulation responses to the same antigens. All matched controls except for one had suppressor cell responses to these antigens, and none responded with a positive cellular immune reaction. We found no difference in lymphoproliferative responses to Con A in patients and controls. The level of suppressor cell activity induced by Con A in the stable MS patients varied but did not differ significantly from that of controls.