Pharmacological inhibition of in vitro infectivity of human T lymphotropic virus type I.

Human T lymphotropic virus type I (HTLV-I) is an exogenous RNA tumor virus etiologically linked to adult T cell leukemia and related diseases. In this paper, we describe that two 2',3'-dideoxynucleoside analogues, erythro 3'-azido-2',3'-dideoxythymidine (also called azidothymidine) and 2',3'-dideoxycytidine can inhibit the infectivity of HTLV-I against helper/inducer T cells in vitro. Both 2',3'-dideoxynucleoside analogues inhibited the overgrowth of target T cells, which was a consequence of virally mediated transformation, when they were exposed to the virus and cultured with the compounds.

Long-term inhibition of human T-lymphotropic virus type III/lymphadenopathy-associated virus (human immunodeficiency virus) DNA synthesis and RNA expression in T cells protected by 2',3'-dideoxynucleosides in vitro.

We report that 2',3'-dideoxyadenosine and 2',3'-dideoxycytidine inhibit retroviral DNA synthesis and mRNA expression in T cells exposed to the virus that causes acquired immunodeficiency syndrome, and afford such cells long-term protection in vitro under conditions of substantial viral excess. Both 2',3'-dideoxyadenosine and 2',3'-dideoxycytidine appear to completely block reverse transcription from viral RNA to viral DNA. Viral mRNA expression is also not detected in cells protected by the drugs throughout 30 days of culture following exposure to the virus.

Structure of the long terminal repeat of simian lymphotropic virus type III (African green monkey) and its relatedness to that of HIV.

The simian T-lymphotropic virus type III (STLV-III[AGM]) is a retrovirus in wild African green monkeys which is serologically related to the human T-lymphotropic virus type III (HTLV-III/LAV-1/HIV) and other related human retroviruses. The long terminal repeats (LTR) contained in clones of viral DNA of (STLV-III[AGM]) were subcloned in M13 and their DNA sequence was determined and compared with that of HIV (HTLV-III[BH10]). The STLV-III(AGM) LTR is considerably larger than that of HTLV-III(BH10) (800 bp vs 634 bp) and contains a 498 bp U3 region, a 176 bp R region, and a 126 bp U5 region.

In vitro generation of an HTLV-III variant by neutralizing antibody.

Transmission and culture of "parental" virus (HTLV-III) from H9 cells transfected with the cloned isolate (lambda HXB-2D) in human serum possessing HTLV-III neutralizing antibody selected for a "variant" that was not neutralized by the selecting serum but was neutralized by another antibody-positive serum "Control" virus, selected in serum lacking neutralizing antibody, and the variant showed highly similar tryptic peptide maps of the major envelope glycoprotein, and no changes in restriction enzyme patterns of viral DNA. These findings show that HTLV-III type-specific neutralizing antibodies occur, can influence the propagation of variant viruses that may arise, and presumably result from minor changes in the eliciting antigen. The extent to which such type-specific neutralizing antibodies influence immune surveillance against HTLV-III infection in vivo, a question with relevance to future vaccination attempts, remains to be determined.

Infection of human T lymphotropic virus-I-specific immune T cell clones by human T lymphotropic virus-I.

Human T lymphotropic virus-I (HTLV-I)-specific T cell lines were established and cloned. K5, an OKT8+ clone bearing multiple proviral integration sites, retained its HTLV-I-specific cytotoxicity and a normal dependence on interleukin 2 (IL-2), indicating that there is a finite number of transforming integration sites. R2, an OKT4+ HTLV-I-infected clone, initially mounted a proliferative response to HTLV-I; but then its IL-2-independent proliferation increased and the antigen specificity was lost.

Gibbon ape leukaemia virus RNA in leukaemic T-lymphoid cell lines: expression of a novel RNA transcript.

Fibroblast cell lines infected in vitro with different strains of gibbon ape leukaemia virus or the related woolly monkey virus (SSAV) synthesized two RNA species of approximately 8.4 kb and 2.9 kb.

Alterations in cytotoxic and helper T cell function after infection of T cell clones with human T cell leukemia virus, type I.

HTLV-I is a transforming human retrovirus that is an etiologic agent of adult T cell leukemia/lymphoma. To investigate the effects of this virus on T cell functions, two OKT3+, OKT4+, OKT8- cytotoxic clones (8.7 and 8.

Serological characterization of human T-cell leukemia (lymphotropic) virus, type I (HTLV-I) small envelope protein.

Murine monoclonal antibodies were developed against the protein products produced by murine C127 cells which had been transfected with a recombinant plasmid clone containing the human T-cell leukemia (lymphotropic) virus type I (HTLV-I) proviral DNA coding regions for part of env, px, and the 3' LTR. Four antibodies with different binding patterns were obtained. One of these antibodies, F1.

Activation of a novel KpnI transcript by downstream integration of a human T-lymphotropic virus type I provirus.

A cDNA library was constructed from the HUT102 cell line established from a patient with adult T-cell leukemia/lymphoma and screened for cDNA clones that contain (i) cellular sequences abundantly expressed in HUT102 cells and not in the virus-negative T-cell line HUT78, and (ii) viral long terminal repeat (LTR) sequences either in the 5' end or in the 3' end. One such cDNA clone, KT1, was isolated and its nucleotide sequence was determined. It contains three regions: a KpnI repeat, a unique cellular region (UCR), and the U3 + R sequence of the human T-lymphotropic virus type I LTR.

Configuration and expression of the T cell receptor beta chain gene in human T-lymphotrophic virus I-infected cells.

We studied the configuration and expression of the gene encoding the beta chain of the T cell receptor (TCR beta) in cell lines and primary tumor cells infected by the human T cell leukemia/lymphoma (lymphotrophic) virus type I (HTLV-I). Most of the cell lines and all the primary tumor cells showed rearrangement of the TCR beta gene, and in each case the rearrangement was distinct. The majority of cases examined were clonal with respect to a particular TCR beta gene rearrangement.

Type 1 human T-cell leukemia virus small envelope protein expressed in mouse cells by using a bovine papilloma virus-derived shuttle vector.

In an attempt to express the small (transmembrane) envelope protein p21e of type 1 human T-cell leukemia (lymphotrophic) virus (HTLV-1) exclusive of other viral gene products, we have constructed a recombinant plasmid clone (pMBE-1) in a bovine papillomavirus-derived mammalian expression vector. Mouse C127 cells transfected with the pMBE-1 plasmid expressed the introduced HTLV-1 viral gene(s) as demonstrated by Northern blot and indirect immunofluorescence with natural human antisera. The transfected mouse cells were injected into BALB/c mice, and a monoclonal antibody was recovered which specifically recognizes a 21-kilodalton protein present in HTLV-1 virions, indicating that the pMBE-1 plasmid encodes the small envelope protein.

Nucleotide sequence of transforming human c-sis cDNA clones with homology to platelet-derived growth factor.

Three c-sis cDNA clones were obtained from polyadenylated RNA of a human T-cell lymphotropic virus (HTLV) type I transformed cell line. Two clones, designated pSM-1 and pSM-2, have cDNA inserts of 2498 and 2509 base pairs (bp), respectively, excluding the sizes of the guanylate tails, and the polyadenylate tracts. These clones are shorter than the estimated size of the c-sis mRNA of 4200 bp.

Human T cell leukemia/lymphoma virus I infection and subsequent cloning of normal human B cells. Direct responsiveness of cloned cells to recombinant interleukin 2 by differentiation in the absence of enhanced proliferation.

A human T cell leukemia/lymphoma virus (HTLV)-I-infected B cell clone expressed Tac antigen on its cell surface and responded to recombinant interleukin 2 (IL-2) by increased production of IgM without any increase in proliferation. Anti-Tac antibody completely inhibited the IL-2-induced differentiation of this HTLV-I-infected B cell clone. This study demonstrates that HTLV-I can directly infect normal mature human B cells, and that the Tac antigen, which may be induced by infection with HTLV-I, is the functional receptor for IL-2-induced B cell differentiation.

Age-related changes in proprioception and sensation of joint position.

With a clinical goniometer we measured the ability of 29 normal women to (a) reproduce the perceived position of each knee with that of the other knee, and (b) reproduce from memory the perceived resting position of each knee following its return to rest. Fifteen subjects were under 30 years old and 14 were over 60. The younger group scored higher in all trials.

Effects of room reverberation and noise on speech discrimination by the elderly.

Speech discrimination performance was measured in sound field for 10 young normal-hearing subjects, 10 elderly 'normal-hearing' subjects with a mean pure-tone average of 9.9 dB HTL, and 10 elderly hearing-impaired subjects with a mean pure-tone average of 48.5 dB HTL.

The first human retroviruses: are there others?

Three related, but very different, retroviruses have recently been identified in man. Human T-cell leukaemia virus (HTLV) type I apparently causes adult T-cell leukaemia. HTLV type II has been isolated only rarely and has not been identified with a disease.

Coagulation factors and proteinase inhibitors in the plasma of children with acute lymphoblastic leukoses. Behaviour before and during treatment according to Protocol I of the Cooperative Leukaemia Study COALL-80.

The thrombocyte count, the factor XIII (F XIII) activity, the concentration of fibrinogen (F I), prothrombin (F II), fibronectin (CIG), albumin and the proteinase inhibitors antithrombin III (AT III), alpha 2-macroglobulin (A2M), alpha 1-antitrypsin (A1A) and Cl-esterase inactivator (Cl-INA) were determined in ten children with acute lymphoblastic leukaemia (ALL). Changes due to the disease and to therapy were observed. Before the start of treatment the patients had thrombocytopenia secondary to the disease, and the proteinase inhibitors--especially Cl-INA and A1A--were raised.

Functional properties of antigen-specific T cells infected by human T-cell leukemia-lymphoma virus (HTLV-I).

Tetanus-toxoid specific helper-inducer T-cell clones, which had been infected and transformed by human T-cell leukemia-lymphoma virus (HTLV-I), were obtained from an antigen-specific human T cell line by using a limiting dilution technique in the presence of the virus. These HTLV-I-infected T-cell clones proliferated specifically in response to soluble tetanus toxoid but, unlike normal T cells, they could do so in the absence of accessory cells. The HTLV-I-infected T-cell clones did not present the antigen to autologous antigen-specific T cells that were not infected with HTLV-I.

Transforming potential of human c-sis nucleotide sequences encoding platelet-derived growth factor.

The nucleotide sequence of a transforming human c-sis complementary DNA shows an open reading frame 723 base pairs in length located downstream from an in-phase terminator thymine-guanine-adenine codon. Sequences within this region were identical to those previously determined for the exons of the normal human c-sis gene. Thus, the predicted transforming product, a protein of 27,281 daltons, may be the actual precursor for normal human platelet-derived growth factor chain A.