Human T-lymphotropic virus type 1 (HTLV-1) is a suspected causative agent of adult T-cell leukemia. One of the viral genes encodes a protein (tat) that not only results in transactivation of viral gene expression but may also regulate the expression of certain cellular genes that are important for cell growth. Transgenic mice that expressed the authentic tat protein under the control of the HTLV-1 long terminal repeat were generated, and cell types that are permissive for the viral promoter and the effects of the tat gene on these cells were studied. Three of eight founder mice with high levels of expression of the transgene in muscle were bred and then analyzed. All developed soft tissue tumors at multiple sites between 13 to 17 weeks of age. This phenotype was transmitted to nine of nine offspring that inherited the tat gene and were available for analysis. The remaining five founders expressed the transgene in the thymus, as well as in muscle. This second group of mice all exhibited extensive thymic depletion and growth retardation; in all of these mice, death occurred between 3 to 6 weeks of age before tumors became macroscopically visible. The tat gene under the control of the HTLV-1 regulatory region showed tissue-specific expression and the tat protein efficiently induced mesenchymal tumors. The data establish tat as an oncogenic protein and HTLV-1 as a transforming virus.

When the human immunodeficiency virus transactivating gene under the control of the viral regulatory region is introduced into the germline of mice, skin lesions are induced that resemble Kaposi's sarcoma seen in AIDS. Our findings indicate that HIV could play a direct part in causing cancer.

Human T-lymphotropic virus type 1 (HTLV-1) has been associated with the neurologic disorder tropical spastic paraparesis and possibly with multiple sclerosis. The tat gene of HTLV-1 under control of its own long terminal repeat is capable of inducing tumors in transgenic mice. The morphologic and biologic properties of these tumors indicate their close resemblance to human neurofibromatosis (von Recklinghausen's disease), the most common single gene disorder to affect the nervous system. The high spontaneous incidence of this disease, together with the diverse clinical and pathologic features associated with it, suggests that environmental factors may account for some of the observed cases. Multiple tumors developed simultaneously in the transgenic tat mice at approximately 3 months of age, and the phenotype was successfully passed through three generations. The tumors arise from the nerve sheaths of peripheral nerves and are composed of perineural cells and fibroblasts. Tumor cells from these mice adapt easily to propagation in culture and continue to express the tat protein in significant amounts. When transplanted into nude mice, these cultured cells efficiently induce tumors. Evidence of HTLV-1 infection in patients with neural and other soft tissue tumors is needed in order to establish a link between infection by this human retrovirus and von Recklinghausen's disease and other nonlymphoid tumors.

The nucleotide sequence of the integrated proviral genome of avian myelocytomatosis virus (MC29) coding for gag-myc protein has been determined. By comparison of this nucleotide sequence with the helper virus as well as the c-myc region, it was possible to localize the junction points between helper viral and v-myc sequences. These studies demonstrate that (i) the large terminal repeat sequence of MC29 is very similar to that of Rous sarcoma virus, (ii) the viral genome has suffered extensive deletions in the gag, pol, and env genes, (iii) the gag region can code for p19, plO, and part of p27, (iv) the recombination between viral and cellular sequences occurred in the coding region of p27 such that the open reading frame extends for an additional stretch of 1,266 base pairs, resulting in a gag-myc hybrid protein, (v) the open reading frame terminated within the v-myc region 300 bases upstream of v-myc-helper viral junction, and (vi) the v-myc helperviral junction at the 3' end occurred in the middle of env gene, rendering it defective.Myelocytomatosis virus (MC29) is a replication-defective avian retrovirus that induces a broad spectrum of malignant diseases, including myelocytomas, renal and liver tumors, and, less typically, carcinomas, sarcomas, and erythroblastosis (1, 2). The same virus induces morphological transformation of fibroblasts, epithelial cells, and macrophages in culture (3)(4)(5). This virus arose by recombination of the nondefective helper virus (MC29-associated virus) and cellular sequences present within the normal chicken genome. These latter sequences termed "myc" appear to code for the transforming properties of the virus (6-8). The 5.7-kilobase (kb) RNA of MC29 has been shown to contain 1.6 kb of myc sequences that are flanked by partial Agag gene at the 5' end and Aenv gene at the 3' end (6). Nonproducer quail cell lines transformed by MC29 contain a 110,000-dalton protein with viral antigenic determinants (9). This protein appears to be a hybrid protein, the amino-terminal region of which is composed of helper virus gag gene products. The development of molecular cloning and DNA sequence analysis techniques has made the detailed analysis of the virus genome structure possible. In an attempt to better understand the structural organization and possible molecular mechanisms involved in transformation by MC29, we have undertaken primary DNA sequence analysis of the molecularly cloned integrated viral genome. Putative regulatory signals for transcription and translation of v-myc sequences have been identified. Sequence analysis has also demonstrated the occurrence of a long open reading frame within v-myc region that could code for the MC29 transforming protein.MATERIALS AND METHODS Molecular Cloning. The integrated proviral genome of MC29 was initially cloned in Agt WES-AB (10). In the present studies, two subclones of this DNA fragment were utilized for sequence analysis. A 1.4-kilobase-pair (kbp) Xho I fragment that contained the 5' large terminal repeat (LTR) and gag sequences...