Primary effusion lymphoma (PEL) cells harbor Kaposi's sarcoma-associated herpesvirus (KSHV) episomes and express a KSHV-encoded latency-associated nuclear antigen (LANA). In PEL cells, LANA and KSHV DNA colocalized in dots in interphase nuclei and along mitotic chromosomes. In the absence of KSHV DNA, LANA was diffusely distributed in the nucleus or on mitotic chromosomes. In lymphoblasts, LANA was necessary and sufficient for the persistence of episomes containing a specific KSHV DNA fragment. Furthermore, LANA colocalized with the artificial KSHV DNA episomes in nuclei and along mitotic chromosomes. These results support a model in which LANA tethers KSHV DNA to chromosomes during mitosis to enable the efficient segregation of KSHV episomes to progeny cells.
For the treatment of acyclovir-resistant herpes simplex infection in patients with AIDS, foscarnet has superior efficacy and less frequent serious toxicity than vidarabine. Once the treatment is stopped, however; there is a high frequency of relapse.
To probe the genetic basis of disease specificity of nondefective murine type C viruses, we are constructing recombinants in vitro between molecular clones of Friend murine leukemia virus (Fr-MuLV) and Moloney murine leukemia virus (Mo-MuLV). Fr-MuLV induces erythroleukemias when injected into newborn NFS mice, whereas Mo-MuLV almost invariably induces T-cell lymphomas. We find that a recombinant whose genome is derived primarily from Fr-MuLV but which has 621 nucleotides of Mo-MuLV information at its 3' end induces almost exclusively thymic lymphomas. The sequences derived from Mo-MuLV include 99 nucleotides encoding the carboxyl terminus of Prp15E, the origin of DNA +-strand synthesis, all of the U3 region, and 36 nucleotides of the R portion of the long terminal repeat. When the segment of Mo-MuLV was removed and replaced with the comparable segment from Fr-MuLV, the virus was again erythroblastosis-inducing. These results, in conjunction with studies from other laboratories [Laimins, L. A., Khoury, G., Gorman, C., Howard, B. & Gruss, P. (1982) Proc. Natl. Acad. Sci. USA 79, 6453-6457], suggest that transcriptional signals in U3 may determine tissue tropism and hence influence disease specificity ("targeting") of murine leukemia viruses.
Primary keratinocytes immortalized by human papillomaviruses (HPVs), along with HPV-induced cervical carcinoma cell lines, are excellent models for investigating neoplastic progression to cancer. By simultaneously visualizing viral DNA and nascent viral transcripts in interphase nuclei, we demonstrated for the first time a selection for a single dominant papillomavirus transcription center or domain (PVTD) independent of integrated viral DNA copy numbers or loci. The PVTD did not associate with several known subnuclear addresses but was almost always perinucleolar. Silent copies of the viral genome were activated by growth in the DNA methylation inhibitor 5-azacytidine. HPV-immortalized keratinocytes supertransduced with HPV oncogenes and selected for marker gene coexpression underwent crisis, and the surviving cells transcribed only the newly introduced genes. Thus, transcriptional selection in response to environmental changes is a dynamic process to achieve optimal gene expression for cell survival. This phenomenon may be critical in clonal selection during carcinogenesis. Examination of HPV-associated cancers supports this hypothesis.Cellular responses to growth stimuli or stress quickly result in adaptive chromatin remodeling, leading to alterations in gene expression. Modulations made to optimize cell survival can result in the dysregulation of genes governing cell growth and differentiation and in genomic instability (28), such as those associated with neoplastic progression. In cancers in which cellular proto-oncogene amplification has occurred, higher than normal levels of proto-oncoprotein are observed. Whether this is a result of transcription from all amplified gene copies or from a single locus with increased promoter strength or, alternatively, of mRNA stabilization remains to be elucidated. A superb system for studying genetic and transcriptional alternations associated with neoplastic progression can be found in early and late passages of primary keratinocytes immortalized by high-risk human papillomavirus (HPV) genotypes, in HPV-induced cervical cancers, and in cell lines derived therefrom (73). In such cells, substantial changes have occurred in cellular and viral gene expression relative to that in productively infected, benign condylomata and papillomas. In the present study, we used in situ analytic methods to visualize HPV oncogene expression in individual cells of both experimental model and naturally arising neoplasms and observed striking and unexpected changes accompanying progression.The molecular basis for HPV oncogenesis is predicated on the mechanisms by which these normally benign viruses reproduce themselves. In productive infections, the 8-kb, doublestranded, circular viral DNAs amplify as extrachromosomal nuclear plasmids, and this amplification is restricted to postmitotic differentiated cells of the squamous epithelium. DNA synthesis requires the E2 origin recognition protein and the E1 viral helicase protein, as well as the reactivated host replication machinery. Thus, HPVs e...
Imatinib mesylate administered orally twice daily for AIDS-related KS results in clinical and histologic regression of cutaneous KS lesions within 4 weeks. These promising results demonstrate that inhibition of the c-kit and/or PDGF receptors may represent an effective strategy for treating KS.
Nondefective Friend helper murine leukemia virus (Fr-MuLV) induces primarily erythroleukemias in NFS mice, whereas Moloney murine leukemia virus (Mo-MuLV) induces T cell lymphomas. Using molecular clones of these two viruses, we constructed a recombinant in which a 0.62-kilobase fragment encompassing the U3 region at the 3' end of the Fr-MuLV genome replaced the corresponding region of Mo-MuLV. The recombinant virus obtained by transfection of this clone, whose genome is derived primarily from Mo-MuLV, induces almost exclusively erythroleukemias in NFS mice. This and the previous result of Chatis et al. (Proc. Natl. Acad. Sci. U.S.A. 80:4408 4411), showing that the reciprocal recombinant whose genome is primarily derived from Fr-MuLV induces almost exclusively lymphomas, argue that a strong determinant of the distinct disease specificities of Fr-MuLV and Mo-MuLV lies in this 3' end 0.62-kilobase fragment which contains the putative virus enhancers. To more precisely define this determinant, we have begun to construct recombinants in which smaller 3' end fragments of the Fr-MuLV and Mo-MuLV genomes are exchanged. Analysis of the first such recombinant showed that Fr-MuLV can be converted to a lymphoma-inducing virus in NFS mice by substitution of a 0.38-kilobase fragment encompassing the virus enhancers in U3 with the corresponding region of the Mo-MuLV genome.
We compared the pathological diagnoses obtained by anal Papanicolaou (Pap) smear with those obtained by anal biopsy or by surgical excision for 153 men who have sex with men (MSM). Analysis of these paired specimens showed that anal Pap smears were an inaccurate predictor of high-grade anal dysplasia, regardless of human immunodeficiency virus (HIV) serostatus. The presence of any abnormal anal cytological finding indicates a potential for high-grade dysplasia on histological examination of MSM.
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