Homology of human T-cell leukaemia virus envelope gene with class I HLA gene

Human T-cell leukaemia virus (HTLV), first isolated in the United States from a patient with cutaneous T-cell lymphoma, is a unique horizontally transmitted retrovirus which is highly associated with certain adult T-cell malignancies. Also, HTLV can be transmitted in vitro to cord blood T-lymphocytes. In the accompanying paper it was shown that all T cells producing HTLV, whether cultured from infected persons or infected in vitro, bind a monoclonal antibody (4D12) which recognizes an epitope shared by certain cross-reactive class I major histocompatibility antigens. This antigen may account for the extra HLA-A and -B specificities detected in HTLV-infected cells using alloantisera. Because of the unusual findings of apparently inappropriate HLA antigens in HTLV infected cells, we had previously looked for rearrangement of class I-related genes in HTLV infected cells but failed to find any. Here, using molecular clones of HTLV and human major histocompatibility antigen DNA, we have shown homology between the envelope gene region of HTLV and the region of an HLA-B locus gene which codes for the extracellular portion of a class I histocompatibility antigen.     

Molecular characterization of genome of a novel human T-cell leukaemia virus

A novel human retrovirus (HTLV-II) was previously found associated with a T-cell variant of hairy-cell leukaemia. Molecular cloning demonstrates that the complete provirus genome is 8.8 kilobase pairs in size and is transmissible to uninfected cells. Two types of infectious deleted provirus were also characterized. The sequences of HTLV-II are distinct from those of HTLV-I.     

Transduction and rearrangement of the myc gene by feline leukaemia virus in naturally occurring T-cell leukaemias

Evidence of myc gene transduction by feline leukaemia virus in several spontaneous lymphoid tumours of cats suggests that recombinant viruses carrying oncogenes may be much more involved in oncogenesis in natural conditions than previously recognized.     

Aetiology of AIDS--antibodies to human T-cell leukaemia virus (type III) in haemophiliacs

Human T-cell leukaemia virus type III (HTLV-III) is suspected of having a key role in the pathogenesis of acquired immune deficiency syndrome (AIDS). Epidemiological data suggest that AIDS is transmitted by an infectious agent through intimate contact with body secretions, blood or blood products. To maintain haemostasis, many haemophiliac patients depend on commercially prepared clotting concentrates made from large multi-donor plasma pools and are thus at increased risk of developing the disease. We report here that, using indirect membrane immunofluorescence and radioimmunoprecipitation with SDS-polyacrylamide gel electrophoresis, we have detected antibodies to HTLV-III in 30 of 47 (64%) asymptomatic haemophiliacs and in all of three haemophiliacs who either had or soon developed AIDS. Of 34 samples drawn before 1984, 18 (53%) were antibody-positive, whereas of 16 samples drawn during 1984, 15 (94%) were positive (P less than or equal to 0.002). These data suggest that exposure to HTLV-III antigens is widespread among asymptomatic haemophiliacs.     

Unique cell lines harbouring both Epstein-Barr virus and adult T-cell leukaemia virus, established from leukaemia patients

Members of three distinct classes of animal virus have been associated with naturally occurring neoplasias in man: Epstein--Barr virus (EBV), a DNA virus belonging to herpesvirus group, papillomavirus, and a novel human RNA (retro) virus, human T-cell leukemia virus or adult T-cell leukaemia (ATL) virus. We have established seven continuous cell lines from ATL patients and 0.1-7% of these cells consistently express ATL-specific antigens (ATLA). EBV-associated nuclear antigen (EBNA) is also found in more than 90% of these cells. We have cloned cells from two of these lines and show here that both ATLA and EBNA were present in the same B-cell clone carrying surface immunoglobulin (sIg).     

Developmental regulation of T-cell receptor gene expression

In contrast to B cells or their antibody products, T lymphocytes have a dual specificity, for both the eliciting foreign antigen and for polymorphic determinants on cell surface glycoproteins encoded in the major histocompatibility complex (MHC restriction). The recent identification of T-cell receptor glycoproteins as well as the genes encoding T-cell receptor subunits will help to elucidate whether MHC proteins and foreign antigens are recognized by two T-cell receptors or by a single receptor. An important feature of MHC restriction is that it appears to be largely acquired by a differentiating T-cell population under the influence of MHC antigens expressed in the thymus, suggesting that precursor T cells are selected on the basis of their reactivity with MHC determinants expressed in the host thymus. To understand this process of 'thymus education', knowledge of the developmental regulation of T-cell receptor gene expression is necessary. Here we report that whereas messenger RNAs encoding the beta-and gamma-subunits are relatively abundant in immature thymocytes, alpha mRNA levels are very low. Interestingly, whereas alpha mRNA levels increase during further development and beta mRNA levels stay roughly constant, gamma mRNA falls to very low levels in mature T cells, suggesting a role for the gamma gene in T-cell differentiation.     

Inversion of chromosome 14 marks human T-cell chronic lymphocytic leukaemia

Rare cases of chronic lymphocytic leukaemia (CLL) in man stem from the malignant proliferation of T cells. The disease is usually more aggressive clinically than B-cell-derived CLL. Various haematological tumours are associated with specific chromosome aberrations (for example, refs 1, 2). Only limited numbers of T-cell CLL patients have so far been studied cytogenetically and, whereas chromosome 12 seems particularly to be involved in B-cell CLL, several markers have been found in T-cell tumours. Recently, by stimulating malignant clones with different mitogens, novel chromosome abnormalities have been detected in T-cell CLL. Using the same approach for additional cases of T-cell CLL, we now report that the most consistent chromosome change is an inversion of the long arm of chromosome 14, inv(14)(q11 q32), in four of five patients. Another remarkable chromosome aberration is trisomy for the long arm of chromosome 8, found in three of five patients.     

Breakpoints in the human T-cell antigen receptor alpha-chain locus in two T-cell leukaemia patients with chromosomal translocations

Specific chromosomal translocations have been observed in several human and animal tumours and are believed to be important in tumorigenesis. In many of these translocations the breakpoints lie near cellular homologues of transforming genes, suggesting that tumour development is partly due to the activation of these genes. The best-characterized example of such a translocation occurs in mouse plasmacytoma and human B-cell lymphoma, where c-myc, the cellular homologue of the viral oncogene myc, is brought into close proximity with either the light- or heavy-chain genes of the immunoglobulin loci, resulting in a change in the regulation of the myc gene. T-cell malignancies also have characteristic chromosomal abnormalities, many of which seem to involve the 14q11-14q13 region. This region has recently been found to contain the alpha-chain genes of the human T-cell antigen receptor. Here we determine more precisely the chromosome breakpoints in two patients whose leukaemic T cells contain reciprocal translocations between 11p13 and 14q13. Segregation analysis of somatic cell hybrids demonstrates that in both patients the breakpoints occur between the variable (V) and constant (C) region genes of the T-cell receptor alpha-chain locus, resulting in the translocation of the C-region gene from chromosome 14 to chromosome 11. As the 11p13 locus has been implicated in the development of Wilms' tumour, it is possible that either the Wilms' tumour gene or a yet unidentified gene in this region is involved in tumorigenesis and is altered as a result of its translocation into the T-cell receptor alpha-chain locus.     

Amplification of a gene coding for human T-cell differentiation antigen

Using previously isolated mouse L-cell transferents for the human T-cell differentiation antigen Leu-2, we now report the first example of spontaneous gene amplification for membrane antigens. The Leu-2 (or T8) antigen is normally expressed on T lymphocytes that have cytotoxic or suppressor functions. Cells of a Leu-2 transfected clone were stained with fluorescein-tagged monoclonal anti-Leu-2, and the brightest 0.1-0.3% of cells were viably separated using a fluorescence activated cell sorter (FACS). After growth of these selected cells, sorting and regrowth was repeated six times, resulting in a population of cells that, compared with the starting population, stains 40 times brighter for Leu-2 and whose DNA transforms 20 times more efficiently for Leu-2. In addition, these cells have 10- to 50-fold amplified human DNA sequences and numerous double minute chromosome fragments, a common indicator of gene amplication in mouse cells.     

Identification of a photoreceptor-specific mRNA encoded by the gene responsible for retinal degeneration slow (rds)

Mutant mice homozygous for 'retinal degeneration slow' (rds/rds) are characterized phenotypically by abnormal development of photoreceptor outer segments in the retina, followed by gradual degeneration of photoreceptors. This process of degeneration is complete by one year, with preservation of all other retinal cells. The biochemical defect that leads to the mutant phenotype is not known. Our strategy for cloning the rds gene was based upon three previously reported observations. First, the rds locus maps to chromosome 17. Second, experimental rds/rds----+/+ and rds/+----+/+ tetra-parental mice manifest patchy photoreceptor changes in the retina, suggesting that the wild-type rds locus is expressed within cells of the photoreceptor lineage. Finally, the process of degeneration is specific to photoreceptors. On the basis of these observations, we predicted that the rds mRNA is encoded by a gene on chromosome 17 and is normally expressed exclusively within photoreceptors in the retina. We here present evidence that this is the case.