The CD4 (T4) antigen is an essential component of the receptor for the AIDS retrovirus

Acquired immune deficiency syndrome (AIDS) is characterized by opportunistic infections and by 'opportunistic neoplasms' (for example, Kaposi's sarcoma). Persistent generalized lymphadenopathy (PGL) is epidemiologically associated with AIDS, especially in male homosexuals. A subset of T lymphocytes positive for the CD4 antigen (also termed T4 antigen), is depleted in AIDS and PGL patients. A retrovirus found in T-cell cultures from these patients is strongly implicated in the aetiology of AIDS because of the high frequency of isolation and the prevalence of specific antibodies in the patients. Here we have detected cell-surface receptors for the AIDS retrovirus (human T-cell leukaemia virus-III (HTLV-III) and lymphadenopathy-associated virus-1 (LAV-1) isolates) by testing the susceptibility of cells to infection with pseudotypes of vesicular stomatitis virus bearing retroviral envelope antigens, and by the formation of multinucleated syncytia on mixing virus-producing cells with receptor-bearing cells. Receptors were present only on cells expressing CD4 antigen; among 155 monoclonal antibodies tested, each of the 14 anti-CD4 antibodies inhibited formation of syncytia and blocked pseudotypes. Productive infection of CD4+ cells with HTLV-III or LAV-1 markedly reduced cell-surface expression of CD4. In contrast, receptors for HTLV-I and HTLV-II were not restricted to CD4+ cells, were not blocked by anti-CD4 antibodies; cells productively infected with HTLV-I and HTLV-II expressed surface CD4. Hence, we conclude that the CD4 antigen is an essential and specific component of the receptor for the causative agent of AIDS.     

Viral transduction of c-myc gene in naturally occurring feline leukaemias

Feline leukaemia virus (FeLV) is epidemiologically associated with induction of the majority of lymphoid tumours of the domestic cat. However, about one-third of these tumours are devoid of exogenous virus or show evidence of virus integration only after tumour outgrowth. To help define the genetic mechanisms of feline lymphomagenesis we have explored here the possibility that cellular oncogenes (c-onc genes) are rearranged in tumour cell DNA. Of 16 FeLV-positive T-cell tumours among 31 naturally occurring lymphomas, 2 showed evidence of recombinant FeLV proviruses containing myc oncogene sequences. One of the two produced a transmissible myc-containing FeLV. In both cases c-myc and its surrounding DNA appeared unaltered. We believe that the association of myc with FeLV may result in its activation and play a part in the development of a significant fraction of cat T-cell lymphomas. Our findings contrast with studies of experimental induction of chicken lymphoma, in which myc activation occurs by retrovirus promoter insertion near c-myc (refs 3-5), rather than by incorporation into virus.     

Identification of a form of the avian erythroblastosis virus erb-B gene product at the cell surface

Avian erythroblastosis virus (AEV) induces both erythroblastosis and fibrosarcoma in chickens. The viral oncogene responsible for these diseases, erb, is divided into two regions, erb-A and erb-B, although recent evidence suggests that it is primarily the erb-B gene product that is responsible for the transforming activity. The erb-B gene product has been reported previously to be a membrane glycoprotein of 68,000 molecular weight (MW), gp68erb -B. However, we show here that gp68erb -B is an intracellular precursor which is modified further to a 74,000 MW protein, gp74erb -B. By the criteria of resistance to digestion with endoglycosidase H, subcellular fractionation and inhibition of biosynthesis by the ionophore monensin, gp74erb -B appears to be located at the cell surface. Recently, a comparison of the erb-B sequence with that of the epidermal growth factor (EGF) receptor has shown that these two genes are highly homologous, and that erb-B appears to represent a truncated form of this growth factor. In light of these data the identification of gp74erb -B at the plasma membrane suggests that this may be the functionally important form of the erb-B gene product.     

Beta 2-microglobulin from serum associates with MHC class I antigens on the surface of cultured cells

Beta 2-microglobulin (beta 2-m) is a highly conserved polypeptide (12,000 molecular weight; 12K) noncovalently associated with the heavy chain (45-48K) of the major histocompatibility complex (MHC) class I antigens. Its synthesis is required for expression of the HLA-A/B and H-2K/D heavy chains at the cell surface; beta 2-m is also associated with the human cell-surface antigens T6 and M241 isolated from thymocytes. However, on the T leukaemic cell line MOLT-4 some of the T6 antigens contain a different 12K subunit, termed beta t (refs 3, 7, 8). Purified human beta 2-m can exchange partially both with human beta 2-m associated with HLA-antigens, and with mouse beta 2-m associated with murine alloantigens. As MOLT-4 cells were grown in the presence of fetal calf serum (FCS) and as serum is known to contain some free beta 2-m, we examined whether beta t was bovine beta 2-m which had replaced endogenous beta 2-m on the surface of the cell. Here we show both that beta 2-m from FCS or human serum (HuS) used in cell culture can exchange with beta 2-m on the cell surface, and that beta t is in fact bovine beta 2-m.     

Bone marrow cells give rise to distinct cell clones within the thymus

The thymus is the major, if not the sole site of maturation of T lymphocytes from their haematopoietic precursors. During embryonic life (at a few well-defined intervals, at least in birds) the thymus receives thymus-homing haematopoietic precursors that give rise to antigen-specific functional T lymphocytes. Although the number and thymic location of distinct T-cell lineages destined to form the peripheral T-cell pool are not yet well defined, at least two independent pathways have been proposed. First, thymic subcapsular lymphoblasts divide and differentiate to give rise to small deep cortical thymic lymphocytes, medullary lymphocytes and thymus emigrants (I.W., unpublished data) and second, the medulla contains an independent self-renewing population that contains the precursors of the peripheral T-cell pool. Following irradiation the thymus may be repopulated by injected haematopoietic cells presumably related to the thymus-homing haematopoietic cells of the embryo. Here we have reconstituted irradiated mice with limiting numbers of bone marrow cells from Thy-1 congeneic donors and have found distinct clones of cells within the thymus. The pattern of reconstitution by the precursor cells indicates that two independent thymus lineages exist: cortex plus medulla, and medulla alone.     

Continuous in vitro generation of multipotential stem cell clones from src-infected cultures

A molecular recombinant of Rous sarcoma virus and murine amphotropic leukaemia virus, src(MoMuLV), where the avian src oncogene has been placed under the influence of a murine virus promoter sequence, has been reported. Infection of long-term marrow cultures with this virus led to a dramatic change in the relative numbers of stem cells, granulocyte-macrophage progenitor cells and mature cells found in normal haematopoietic cell development. However, although the balance between self-renewal, differentiation and development was disturbed, injection of the cultured cells into irradiated syngeneic recipients did not lead to the development of leukaemia. Thus, although the control had been 'loosened', the host regulatory mechanisms were sufficient to impose a restraint on unlimited growth of the cells. We now show that the stem cells from the src-infected cultures show a remarkably increased capacity for self-renewal in vitro in situations which are inimical to the maintenance of self-renewal in normal uninfected stem cells and that self-renewal/differentiation can be modified by the culture conditions.     

DNA sequence and expression of the B95-8 Epstein-Barr virus genome

The complete (172,282 base pairs) nucleotide sequence of the B95-8 strain of Epstein-Barr virus has been established using the dideoxynucleotide/M13 sequencing procedure. Many RNA polymerase II promoters have been mapped and the mRNAs from these promoters have been assigned to the latent or early/late productive virus cycles. Likely protein-coding regions have been identified and three of these have been shown to encode a ribonucleotide reductase, a DNA polymerase and two surface glycoproteins.     

Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts

Clinical organ transplantation between genetically disparate individuals currently requires the use of chemotherapeutic agents to suppress the rejection reaction. The deleterious side effects of these reagents and their inability to prevent rejection completely has led to a continuing search for methods to induce specific transplantation tolerance in adult recipients. Numerous experimental animal models utilizing irradiation and bone marrow transplantation coincident with organ transplantation have been proposed. Bone marrow transplantation, however, has its own major complications, including graft-versus-host reactions and immunoincompetence, probably resulting from a failure of appropriate immune cell interactions in the reconstituted host. We have now attempted to overcome these difficulties by reconstituting the irradiated host with T-cell depleted bone marrow containing both host (syngeneic) and donor (allogeneic or xenogeneic) components. This technique leads to long-term survival of the reconstituted animals and specific prolongation of subsequent skin grafts of donor type. Animals reconstituted in this fashion are fully reactive to third-party allografts and xenografts and do not appear to manifest signs of graft-versus-host disease.