Marek disease virus (MDV) is a herpesvirus of chickens that induces T lymphomas within 3 weeks of infection. The short latency and polyclonal nature of MDVinduced tumors have suggested that the virus may encode one or more direct-acting oncogenes. To date, however, no MDVspecific tumor antigens or candidate transforming genes have been demonstrated. In this paper, we report the identification of a MDV gene encoding a protein with homology to the leucine-zipper class of nuclear oncogenes. It also contains a proline-rich domain characteristic of another class of transcription factors. This gene, designated meq, maps to the long repeat of MDV and is one of the few genes that are highly expressed in MDV-induced T-cell tumors. To our knowledge, a herpesvirus gene closely related to the fos/jun family of oncogenes has not been reported previously.Marek disease virus (MDV) is an avian herpesvirus that causes malignant transformation of T cells in chickens. After a brief cytolytic infection of several days' duration, lymphomas develop at many sites. The short latency and polyclonal nature of the tumors suggest that MDV may encode potent oncogene(s) of its own. Vaccination with a nononcogenic strain or the related avirulent herpesvirus of turkeys can prevent development of lymphoma (1, 2). Although MDV is capable of infecting many chicken cell types, the target cells for transformation have been shown to be limited to a subset of activated T cells (3). Presently, little is known about the putative oncogene(s) of MDV or their cellular targets in lymphocytes.The genome structure of MDV is similar to human alphaherpesviruses (e.g., varicella-zoster virus and herpes simplex virus), with long and short unique regions each bounded by inverted repeats (4). Although characterization of the nucleotide sequence of MDV has only recently begun, mapping data indicate that MDV genes are colinear with varicellazoster virus or herpes simplex virus in the long unique region but differ in organization in both repeats and the short unique region (5, 6). In lytically infected cells, transcription of viral genes throughout the entire MDV genome is detected. By contrast, in MDV-induced lymphoblast tumors, the viral gene expression is limited to areas in or near the repeat regions (7-9).In this paper, we report the identification and characterization of a MDV gene located in the BamHI 12 (Bam 12) fragment of the large repeat, which is highly expressed in MDV-induced T-cell tumors. ¶ This gene encodes a protein of 362 amino acids, which has a leucine zipper repeat and an upstream domain rich in basic amino acids, both characteristics of the fos/jun family of transcriptional activators. It also contains a domain rich in proline residues. We have developed antiserum against a synthetic peptide deduced from the DNA sequence and were able to demonstrate the presence of a 40-kDa protein in a MDV-transformed lymphoblastoid cell line.

Retroviruses and herpesviruses are naturally occurring pathogens of humans and animals. Coinfection of the same host with both these viruses is common. We report here that a retrovirus can integrate directly into a herpesvirus genome. Specifically, we demonstrate insertion of a nonacute retrovirus, reticuloendotheliosis virus (REV), into a herpesvirus, Marek disease virus (MDV). Both viruses are capable of inducing T lymphomas in chickens and often coexist in the same animal. REV DNA integration into MDV occurred in a recently attenuated strain of MDV and in a short-term coinfection experiment in vitro. We also provide suggestive evidence that REV has inserted into pathogenic strains of MDV in the past. Sequences homologous to the REV long terminal repeat are found in oncogenic MDV but not in nononcogenic strains. These results raise the possibility that retroviral information may be transmitted by herpesvirus and that herpesvirus expression can be modulated by retroviral elements. In addition, retrovirus may provide a useful tool to characterize herpesviral function by insertional mutagenesis.

No abstract

We previously described the integration of a nonacute retrovirus, reticuloendotheliosis virus (REV), into the genome of a herpesvirus, Marek disease virus (MDV), following both long-term and short-term coinfection in cultured fibroblasts. The long-term coinfection occurred in the course of attenuating the oncogenicity of the JM strain of MDV and was sustained for >100 passages. The short-term coinfection, which spanned only 16 passages, was designed to recreate the insertion phenomenon under controlled conditions. We found that REV integrations into MDV were common and could occur within the first passage following coinfection. Now we have mapped the integration sites. After 5-16 passages in vitro, 17 out of 19 REV junction sites are clustered in two