Metabolites of the antipsychotic agent clozapine inhibit the replication of human immunodeficiency virus type 1.

Schizophrenia is a serious and often debilitating neuropsychiatric disease of worldwide importance. Current therapy relies on the use of typical antipsychotic medications, which specifically inhibit binding of ligand at the D2 dopamine receptor, and atypical medications which display little activity for this receptor interaction. While atypical antipsychotic agents have been shown to variably inhibit other neuroreceptor-ligand interactions, the exact mechanisms for the therapeutic efficacy of these medications have not been completely defined. Clozapine, an atypical antipsychotic, and nine of its metabolites were studied in vitro for possible antiviral activity against a model of a human neurotropic virus, human immunodeficiency virus type 1 (HIV-1). In an assay for inhibition of virus-induced cytopathic effect (CPE) two metabolites demonstrated antiviral activity (ID50 = 37-85 micrograms/ml) (119-289 microM), while other atypical or novel antipsychotics as well as typical medications had no effect. Based on an ELISA, four chemically similar metabolites inhibited the production of p24, the major internal antigen of HIV (ID50 = 11.6-15.7 micrograms/ml) (38-51 microM). These data suggest that the therapeutic efficacy of some antipsychotics may be due in part to an ability to inhibit viral replication. Antiviral agents may prove to be effective adjuncts in the treatment of schizophrenia.

cDNA cloning of a human homologue of the Caenorhabditis elegans cell fate-determining gene mab-21: expression, chromosomal localization and analysis of a highly polymorphic (CAG)n trinucleotide repeat.

The two most consistent features of the diseases caused by trinucleotide repeat expansion-neuropsychiatric symptoms and the phenomenon of genetic anticipation-may be present in forms of dementia, hereditary ataxia, Parkinsonism, bipolar affective disorder, schizophrenia and autism. To identify candidate genes for these disorders, we have screened human brain cDNA libraries for the presence of gene fragments containing polymorphic trinucleotide repeats. Here we report the cDNA cloning of CAGR1, originally detected in a retinal cDNA library. The 2743 bp cDNA contains a 1077 bp open reading frame encoding 359 amino acids. This amino acid sequence is homologous (56% amino acid identify and 81% amino acid conservation) to the Caenorhabditis elegans cell fate-determining protein mab-21. CAGR1 is expressed in several human tissues, most prominently in the cerebellum, as a message of approximately 3.0 kb. The gene was mapped to 13q13, just telomeric to D13S220. A 5'-untranslated CAG trinucleotide repeat is highly polymorphic, with repeat length ranging from six to 31 triplets and a heterozygosity of 87-88% in 684 chromosomes from several human populations. One allele from an individual with an atypical movement disorder and bipolar affective disorder type II contains 46 triplets, 15 triplets longer than any other allele detected. Though insufficient data are available to link the long repeat to this clinical phenotype, an expansion mutation of the CAGR1 repeat can be considered a candidate for the etiology of disorders with anticipation or developmental abnormalities, and particularly any such disorders linked to chromosome 13.

Release of simian virus 40 virions from epithelial cells is polarized and occurs without cell lysis.

We have investigated the process of release of simian virus 40 (SV40) virions from several monkey kidney cell lines. High levels of virus release were observed prior to any significantly cytopathic effects in all cell lines examined, indicating that SV40 utilizes a mechanism for escape from the host cell which does not involve cell lysis. We demonstrate that SV40 release was polarized in two epithelial cell types (Vero C1008 and primary African green monkey kidney cells) grown on permeable supports; release of virus occurs almost exclusively at apical surfaces. In contrast, equivalent amounts of SV40 virions were recovered from apical and basal culture fluids of nonpolarized CV-1 cells. SV40 virions were observed in large numbers on apical surfaces of epithelial cells and in cytoplasmic smooth membrane vesicles. The sodium ionophore monensin, an inhibitor of vesicular transport, was found to inhibit SV40 release without altering viral protein synthesis or infectious virus production.