Isolation and transmission of human retrovirus (human t-cell leukemia virus)

Nine new isolates of human T-cell leukemia-lymphoma virus (HTLV) were obtained from cells of seven patients with malignancies of mature T cells and from two clinically normal relatives of a T-cell leukemia patient. These people were from the United States, Israel, the West Indies, and Japan. The virus was detected in the fresh T cells and was isolated from the established T-cell lines. Each isolate is closely related to the first HTLV isolate, and all the new HTLV isolates were transmitted into normal human T cells obtained from the umbilical cord blood of newborns.     

Serological analysis of a subgroup of human T-lymphotropic retroviruses (HTLV-III) associated with AIDS

The two main subgroups of the family of human T-lymphotropic retroviruses (HTLV) that have previously been characterized are known as HTLV-I and HTLV-II. Both are associated with certain human leukemias and lymphomas. Cell surface antigens (p61 and p65) encoded by HTLV-I are frequently recognized, at low titers, by antibodies in the serum of patients with acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that precede AIDS (pre-AIDS). This suggests an involvement of HTLV in these disorders. Another subgroup of HTLV, designated HTLV-III, has now been isolated from many patients with AIDS and pre-AIDS. In the studies described in this report, virus-associated antigens in T-cell clones permanently producing HTLV-III were subjected to biochemical and immunological analyses. Antigens of HTLV-III, specifically detected by antibodies in serum from AIDS or pre-AIDS patients and revealed by the Western blot technique, are similar in size to those found in other subgroups of HTLV. They include at least three serologically unrelated antigenic groups, one of which is associated with group-specific antigens (p55 and P24) and another with envelope-related (p65) proteins, while the antigens in the third group are of unknown affiliation. The data show that HTLV-III is clearly distinguishable from HTLV-I and HTLV-II but is also significantly related to both viruses. HTLV-III is thus a true member of the HTLV family.     

Antigens on HTLV-infected cells recognized by leukemia and AIDS sera are related to HTLV viral glycoprotein

Cross-reactive antigens of molecular size of 61,000 to 68,000 daltons are found on the surface of human cells infected by human T-cell leukemia-lymphoma virus (HTLV). They are recognized by antibodies from patients with adult T-cell leukemias and lymphomas, from healthy carriers of HTLV, and from patients with the acquired immunodeficiency syndrome (AIDS). The latter finding has been one of the major reasons for suggesting an association of HTLV with AIDS. However, whether these antigens are of cellular or viral origin has not been clear. These antigens have now been shown to be associated with the presence of viral proteins in the cells, and a cross-reactive glycoprotein of molecular size of 46,000 daltons has been found to be a consistent structural part of viruses purified from several HTLV-producer cell lines. The findings thus suggest a viral (HTLV) origin of these antigens.     

Natural antibodies to human retrovirus HTLV in a cluster of Japanese patients with adult T cell leukemia

Human T cell lymphoma leukemia virus (HTLV) is a human retrovirus (RNA tumor virus) that was originally isolated from a few patients with leukemias or lymphomas involving mature T lymphocytes. Here we report that the serum of Japanese patients with adult T cell leukemia, but not the serum of tested normal donors, contains high titers of antibodies to HTLV. These observations, together with data from Japan showing that adult T cell leukemia is endemic in southwest Japan, suggest that HTLV is involved in a subtype of human T cell malignancy, including Japanese adult T cell leukemia.     

Detection, isolation, and continuous production of cytopathic retroviruses (HTLV-III) from patients with AIDS and pre-AIDS

A cell system was developed for the reproducible detection of human T-lymphotropic retroviruses (HTLV family) from patients with the acquired immunodeficiency syndrome (AIDS) or with signs or symptoms that frequently precede AIDS (pre-AIDS). The cells are specific clones from a permissive human neoplastic T-cell line. Some of the clones permanently grow and continuously produce large amounts of virus after infection with cytopathic (HTLV-III) variants of these viruses. One cytopathic effect of HTLV-III in this system is the arrangement of multiple nuclei in a characteristic ring formation in giant cells of the infected T-cell population. These structures can be used as an indicator to detect HTLV-III in clinical specimens. This system opens the way to the routine detection of HTLV-III and related cytopathic variants of HTLV in patients with AIDS or pre-AIDS and in healthy carriers, and it provides large amounts of virus for detailed molecular and immunological analyses.     

Productive infection and cell-free transmission of human T-cell leukemia virus in a nonlymphoid cell line

Human T-cell leukemia virus (HTLV), American PL isolate, was transmitted by cocultivation and by cell-free filtrates to a nonlymphoid human osteogenic sarcoma (HOS) cell line, designated HOS/PL, but not to nine other lines bearing receptors for HTLV. HOS and HOS/PL cells are not dependent on interleukin-2 and do not express interleukin-2 receptors that are recognized by anti-Tac monoclonal antibody. HTLV released by the Japanese MT2 cell line was also transmitted to HOS cells. The infected HOS cells release substantial titers of progeny HTLV which is antigenically indistinguishable from parental virus and is able to transform T cells.     

Human T-cell leukemia virus (HTLV-I) antibodies in Africa

Antibodies specific for human T-cell leukemia-lymphoma virus type I (HTLV-I) were demonstrated in serum samples from various groups of people in South Africa, Uganda, Ghana, Nigeria, Tunisia, and Egypt. The samples had been collected for other purposes and were presumably selected without bias toward clinical conditions associated with HTLV infections. Regional differences in antibody positivity were observed, indicating widely distributed loci of occurrence of HTLV on the African continent in people of both black and white ancestry. Two patients with high titers of antibody to HTLV-I had some signs of adult T-cell leukemia-lymphoma. In several groups a high frequency of false positive serum reactions was indicated when specific confirmation steps were included in the assay. Further characterization of these sera revealed highly elevated immunoglobulin levels, possibly due to polyclonal activation of immunoglobulin synthesis in these subjects. The possibility that related cross-reactive human retroviruses coexist in the same groups was not eliminated.     

Expression of the 3' terminal region of human T-cell leukemia viruses

Human T-cell leukemia viruses (HTLV) are closely associated with some human T-cell leukemias and lymphomas. A unique 3' region of the HTLV genome is believed to be involved in HTLV-induced cellular transformation, although the function of this region has yet to be determined. A subgenomic messenger RNA transcribed from this region of HTLV has now been characterized. These results provide direct evidence for the expression of a novel gene in HTLV.     

Structure of 3' terminal region of type II human T lymphotropic virus: evidence for new coding region

The sequence of the 3' terminus of the human T lymphotropic virus type II (HTLV-II) was determined and compared to the corresponding sequence of HTLV-I. The 1557-nucleotide-long sequence can be divided into a 5' region that is not conserved between the two viruses, and a 3', 1011-nucleotide-long region that is highly conserved and that corresponds precisely with a long open reading frame for both HTLV-I and -II. The proteins that could be encoded by these open reading frames have a molecular weight of about 38,000 and are closely related in primary amino acid sequence. The genomic structure in the 3' region of HTLV was found to be similar to that of bovine leukemia virus.     

Human T cell leukemia viruses use a receptor determined by human chromosome 17

Human T cell leukemia viruses (HTLV-I and HTLV-II) can infect many cell types in vitro. HTLV-I and HTLV-II use the same cell surface receptor, as shown by interference with syncytium formation and with infection by vesicular stomatitis virus (VSV) pseudotypes bearing the HTLV envelope glycoproteins. Human-mouse somatic cell hybrids were used to determine which human chromosome was required to confer susceptibility to VSV(HTLV) infection. The only human chromosome common to all susceptible cell hybrids was chromosome 17, and the receptor gene was localized to 17cen-qter. Antibodies to surface antigens known to be determined by genes on 17q did not block the HTLV receptor.     

Proviral DNA of a retrovirus, human T-cell leukemia virus, in two patients with AIDS

The acquired immune deficiency syndrome (AIDS) is characterized by T-lymphocyte dysfunction and is frequently accompanied by opportunistic infections and Kaposi's sarcoma. Human T-cell leukemia virus (HTLV) is associated with T-cell malignancies and can transform T lymphocytes in vitro. In an attempt to find evidence of HTLV infection in patients with AIDS, DNA from samples of peripheral blood lymphocytes from 33 AIDS patients was analyzed by Southern blot-hybridization with a radiolabeled cloned HTLV DNA probe. Analysis of DNA from both the fresh (uncultured) lymphocytes and from T cells cultured with T-cell growth factor revealed the presence of integrated HTLV proviral sequences in lymphocytes from two of the patients, both of whom had antibody to HTLV. The proviral sequences could not be detected in blood samples obtained from these individuals at a later date, consistent with the possibility that the population of infected cells had become depleted.     

High rate of HTLV-II infection in seropositive i.v. drug abusers in New Orleans

Confirmed infection with HTLV-II (human T cell leukemia virus type II) has been described only in rare cases. The major limitation to serological diagnosis of HTLV-II has been the difficulty of distinguishing HTLV-II from HTLV-I (human T cell leukemia virus type I) infection, because of substantial cross-reactivity between the viruses. A sensitive modification of the polymerase chain reaction method was used to provide unambiguous molecular evidence that a significant proportion of intravenous drug abusers are infected with HTLV, and the majority of these individuals are infected with HTLV-II rather than HTLV-I. Of 23 individuals confirmed by polymerase chain reaction analysis to be infected with HTLV, 21 were identified to be infected with HTLV-II, and 2 were infected with HTLV-I. Molecular identification of an HTLV-II--infected population provides an opportunity to investigate the pathogenicity of HTLV-II in humans.     

Antigens encoded by the 3'-terminal region of human T-cell leukemia virus: evidence for a functional gene

Antibodies in sera from patients with adult T-cell leukemia-lymphoma or from healthy carriers of type I human T-cell leukemia virus (HTLV) recognize an antigen of approximately 42 kilodaltons (p42) in cell lines infected with HTLV-I. Radiolabel sequence analysis of cyanogen bromide fragments of p42 led to the conclusion that this antigen is encoded in part by LOR, a conserved portion of the "X" region that is flanked by the envelope gene and the 3' long terminal repeat of HTLV-I. It is possible that this novel product mediates the unique transformation properties of the HTLV family.     

Sequence of the envelope glycoprotein gene of type II human T lymphotropic virus

The sequence of the envelope glycoprotein gene of type II human T lymphotropic virus (HTLV) is presented. The predicted amino acid sequence is similar to that of the corresponding protein of HTLV type I, in that the proteins share the same amino acids at 336 of 488 residues, and 68 of the 152 differences are of a conservative nature. The overall structural similarity of these proteins provides an explanation for the antigenic cross-reactivity observed among diverse members of the HTLV retrovirus family by procedures that assay for the viral envelope glycoprotein, for example, membrane immunofluorescence.     

Alteration of T-cell functions by infection with HTLV-I or HTLV-II

Two functionally different types of human T-cell clones, one with helper function and two with specific activity, were infected with different isolates of HTLV-I and HLTV-II. Both types of human T cells showed alterations in specific function after infection with either of the HTLV subgroups. Before HTLV infection, the T-cell clone with helper function proliferates and provides help to B cells only in the presence of both a specific soluble antigen (keyhole limpet hemocyanin) and histocompatible antigen-presenting cells. After HTLV infection, these cells respond with increased proliferation and indiscriminant stimulation of polyclonal immunoglobulin production by B cells, regardless of the histocompatibility of the antigen-presenting cells or the presence of the soluble antigen. Infection of the normal cytotoxic T-cell clones led to a dimunition or loss of the cytotoxic function. The results of these studies suggest some possible mechanisms for induction of immune deficiency and of polyclonal B-cell activation by viruses of the HTLV family.