An association between a virus and a specific human disease can be suggested by 1) the use of electron microscopy to visualize a virus in pathological tissue; 2) the presence of a characteristic viral pathological effect; 3) the presence of viral nucleic acid sequences in the diseased cells; 4) the presence of viral antigens in malignant cells; 5) the prevalence of the disease in patients with serologic evidence of infection with the virus or 6) the detection of a unique viral biological activity, such as reverse transcriptase, in pathological samples. The application of any of these techniques to the detection of viruses associated with human malignancies requires information about the structure, antigenic composition, or nucleic acid sequence of the specific virus being screened for. This application proposes the use of a novel assay that detects a biological activity common to many transforming viruses. Conceivably, a broad spectrum of viruses can be detected by this assay in the absence of any specific structural or nucleic acid sequence information. This may facilitate the detection of as yet uncharacterized viruses present in human malignancies. The transforming genes of a broad spectrum of viruses including adenoviruses. SV40, papilloma viruses and HTLV-I encode a transcriptional transactivator. Although these transactivators have no structural homologies with each other there appears to be a functional homology in that they are all capable of transactivating genes containing an adenovirus early promoter. Other viruses known to encode transactivators include pseudorabies virus, other herpesviruses such as HSV and EBV, and HIV. The pseudorabies virus transactivator shares this functional homology with the other viruses whereas the HIV transactivator does not. Additional studies are necessary to determine to what extent the multiple EBV transactivators can regulate expression from the adenovirus early promoters. The experiments proposed in this application are designed to detect the presence of a broad spectrum of viral transactivators in primary cells from patients with a variety of diseases. The hypothesis to be tested is that the presence of any of a broad spectrum of viruses present in these cells will be manifested by the presence of transactivator activity as measured by expression of marker genes linked to an adenovirus early promoter. Preliminary evidence will be presented that indicates that malignant cells from patients with Sezary syndrome, a T cell leukemia, efficiently express marker genes linked to an adenovirus early promoter. The similarities between Sezary syndrome and HTLV-I related leukemia provide an impetus to further characterize these cells and isolate the genes responsible for the transactivation of the adenovirus early promoter. The experiments proposed in the application are designed to extend these observations to other diseases and to detect and ultimately isolate as yet uncharacterized viruses which are associated with human diseases.
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| Strair, R K; Medina, D J; Nelson, C J et al. (1993) Recombinant retroviral systems for the analysis of drug resistant HIV. Nucleic Acids Res 21:4836-42 |
