Sequence analysis of original HIV-1.
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Biomedical subjects
Publications and source records attributed to W Blattner.
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Serologic assays for human T cell lymphotropic virus types I and II (HTLV I/II) infection were done in 676 intravenous drug users (IVDUs) in San Francisco between 1985 and 1987: 150 in 1985, 44 in 1986, and 482 in 1987. All sera were tested by Western blot, ELISA, and p24 RIA. A total of 111 participants were seropositive in a minimum of two assays. Duration of intravenous heroin use was strongly associated with the risk of HTLV I/II seropositivity: greater than or equal to 21 years odds ratio, 6.1 (95% confidence interval [CI], 2.2-17.5), compared with less than 10 years of heroin use. Additional independent risk factors included black or Hispanic race, female sex, and the use of drugs in a shooting gallery. Coinfection of HTLV I/II and human immunodeficiency virus was less frequent than expected by chance (P less than .02). Longitudinal specimens were available in 154 participants. The age- and race-adjusted seroconversion rate was 3.4% (95% CI, 1.3-8.9) per person per year. Of the 349 homosexual men tested, none were HTLV I/II-seropositive.
In Jamaican children infective dermatitis is a chronic eczema associated with refractory nonvirulent Staphylococcus aureus or beta-haemolytic streptococcus infection of the skin and nasal vestibule. 14 children between the ages of 2 and 17 years with typical infective dermatitis, attending the dermatology clinic at the University Hospital of the West Indies in Jamaica, were tested for antibody to human T-lymphotropic virus type 1 (HTLV-1). All were seropositive, whereas 11 children of similar age with atopic eczema were all negative. In 2 of 2 cases of infective dermatitis, the biological mother was HTLV-1 seropositive. None of the 14 patients showed signs of adult T-cell leukaemia/lymphoma, though experience with previous cases of infective dermatitis indicates the possibility of such progression.
The prevalence of antibodies to human immunodeficiency virus (HIV) was determined in the relatives, friends, and sex partners of AIDS patients in Haiti and in other unrelated Haitian population groups. Among contacts of AIDS patients, HIV seroprevalence was highest among sex partners of the opposite sex (55%) and lowest among female relatives and friends (9%) of female AIDS patients. Male relatives and friends of male AIDS patients had a seroprevalence rate of 19% and also had a history of multiple heterosexual partners and frequent contact with prostitutes. The HIV seroprevalence rate among unrelated groups of Haitian adults ranged from 2% in rural healthy adults to 22% among tuberculosis patients to a high of 49% among Haitian prostitutes. This seroprevalence pattern suggests that HIV infection is widespread in Haiti and that heterosexual activity plays a major role in transmission.
We determined the rates of seroconversion to human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus Type I (HTLV-I) in a cohort of patients receiving transfusions of blood components screened for antibody to HIV-1. Preoperative and postoperative serum samples were collected from 4163 adults undergoing cardiac surgery who received 36,282 transfusions of blood components. The postoperative samples from all patients were tested for serologic evidence of HIV-1 infection, and those that were positive were compared with the corresponding preoperative samples. One case of HIV-1 transmission by transfusion of screened blood components was identified; two preexisting HIV-1 infections were found. Samples from 2749 patients were tested similarly for serologic evidence of HTLV-I infection; these patients received 20,963 units of blood components. Five new cases and two preexisting cases of HTLV-I infection were detected. The observed risk of HIV-1 transmission by transfusion was 0.003 percent per unit; the risk of HTLV-I transmission was 0.024 percent per unit. We conclude that there is a very small risk of HTLV-I infection from transfused blood products that have been screened for antibodies to HIV-1, but that it is nearly 10-fold higher than the risk of HIV-1 infection.
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Adult T cell leukaemia/lymphoma was first recognised as a clinical entity in southwest Japan. Subsequently the Caribbean has been found to be another area where the disease is endemic, and sporadic cases have been identified in different parts of the world. The human T cell leukaemia/lymphoma virus (HTLV-I) is causally related to adult T cell leukaemia/lymphoma. A subgroup of HTLV, designated HTLV-III, has recently been isolated from many patients with the acquired immunodeficiency syndrome (AIDS) and preAIDS, and there is now evidence that this variant is the primary cause of AIDS. This is the first report from Trinidad to describe 12 cases of adult T cell leukaemia/lymphoma and 14 of AIDS. All were in patients of African descent. No cases were seen in subjects of East Indian descent, who, like those of African descent, comprise as much as 40% of the population. West Indians of African descent may have increased susceptibility to infection with both HTLV-I and HTLV-III.
Cytogenetic studies were conducted on fresh and cultured cells from 11 patients with human T-cell leukemia virus-associated adult T-cell leukemia-lymphoma. Clones with abnormal karyotypes were detected in 9 of the 11 patients. Chromosome numbers were near-diploid in cells from all but 1 patient who also had a tetraploid clone. The chromosome abnormalities in these cells were extensive; numerous complex structural changes were seen in every chromosome pair. Structural abnormalities occurred most frequently in chromosome 6. The 6 patients with chromosome 6 deletions had breakpoints at bands q11, q13, q16q23, q21q23, q22q24, and q23q24. The characteristic clinical features of these 6 patients were aggressive course, short survival, poor response to chemotherapy, high white blood cell counts, hypercalcemia, and bone lesions, whereas cytogenetically abnormal patients without chromosome 6q deletions tended to have a more indolent course. The precise role of the 6q deletion cannot be established with certainty from these data. However, this abnormality appears to occur with a greater than expected frequency in this large cell aggressive lymphoma, in association with hypercalcemia and lytic bone lesions.
Human T-cell leukemia/lymphoma virus I can transform mature T-lymphocytes in vitro and is associated with the human T-cell cancer, adult T-cell leukemia/lymphoma. Adult T-cell leukemia/lymphoma is a distinct clinicopathological entity associated with leukemia, lymphadenopathy, hepatosplenomegaly, skin lesions, hypercalcemia, and lytic bone lesions. Although morphologically diverse it pursues an aggressive clinical course. Human T-cell leukemia/lymphoma virus III is associated with acquired immunodeficiency syndrome, which in its early stages shows follicular lymphoid hyperplasia; however, lymphoid atrophy is progressive and ultimately results in virtually total lymphoid depletion of lymph nodes. Patients with human T-cell leukemia/lymphoma virus III infections appear to have an increased risk of high-grade B-cell lymphomas and perhaps Hodgkin's disease.
Ten out of 26 leukaemic patients who had emigrated from the Caribbean region to the United Kingdom had adult T-cell leukaemia with associated serum antibodies to HTLV I. Antibodies to HTLV were also detected in sera from a small proportion of non-leukaemic Caribbean immigrants but not in any sera from other (non-ATL) T-cell leukaemias or a variety of control groups. The long period between immigration to the UK and diagnosis of leukaemia (up to 30 years) suggests that an extensive latent period in disease development may exist. Cell lines were isolated from two patients with HTLV antibody-positive ATL and were shown to be virus-positive by electron microscopy and immunofluorescence using antibodies to the p19 and p24 viral proteins. HTLV1 provirus integration and active transcription were demonstrated by Southern blotting of DNA and in situ hybridization respectively using molecularly cloned HTLV1 probes. Virus from one of these cell lines could be transmitted to normal T cells by co-cultivation.
Human T-cell leukemia/lymphoma virus is a unique family of T-cell tropic, human, type-C retroviruses. The discovery of this class of retroviruses provides the first proven link between retroviruses and cancer in humans. This virus is endemic in certain parts of the world, including the southeastern United States, and is associated with the development of adult T-cell leukemia/lymphoma, a fulminant lymphoproliferative disorder frequently accompanied by opportunistic infections and hypercalcemia. Over the last few years, major advances have been made in understanding the clinical, epidemiologic, molecular biologic, and immunologic features of this unique class of human RNA tumor viruses.
We studied the clinical features of 11 patients with adult T-cell lymphoma associated with the human T-cell lymphoma virus. The patients were predominantly young, black, and born in the southeastern United States. They had an aggressive course, with the rapid onset of disseminated skin lesions or symptoms related to hypercalcemia and other metabolic disturbances, or both. Common findings included rapid enlargement of peripheral, hilar, and retroperitoneal lymph nodes, with sparing of the mediastinum; invasion of the central nervous system, lungs, or gastrointestinal tract; and opportunistic infections. A paraneoplastic syndrome characterized by increased bone turnover, abnormal bone scintigraphy, and hypercalcemia was present in all patients. Intensive combination chemotherapy produced prompt complete clinical remissions, which were generally of short duration. Similar features have been described in patients in Japan and the West Indies who had adult T-cell lymphoma, which is also associated with the human T-cell lymphoma virus. This syndrome should be suspected in patients presenting with the acute onset of widespread T-cell lymphoma in association with metabolic bone disease and hypercalcemia. The presence of the syndrome can be confirmed by appropriate serologic and virologic studies.
To determine whether the human T-cell lymphoma-leukemia virus (HTLV) is associated with particular cancers, patient sera were surveyed for HTLV-specific antibodies. An association was seen with aggressive cancers of mature T-cells, specifically Japanese adult T-cell leukemia (ATL) and T-cell lymphosarcoma cell leukemia (TLCL), a similar cancer of Caribbean blacks. Ninety to 100% of these patients possessed HTLV-specific antibody. Forty-seven and 20% of relatives of ATL and TLCL patients, respectively, and 12 and 4% of healthy donors from ATL and TLCL endemic areas were also antibody positive. Visceral organ involvement, hypercalcemia, and skin manifestation, features of ATL and TLCL, were often seen in other antibody-positive patients. Childhood cancers, most cutaneous T-cell and all non-T-cell leukemias and lymphomas, myeloid leukemias, Hodgkin's disease, and solid tumors were not associated with HTLV. Healthy United States donors and European patients with non-malignant diseases were antibody negative. HTLV is thus associated with a subtype of adult T-cell leukemia-lymphoma, clustered in viral endemic areas, with apparent racial and geographic predilection.
Tumour suppressor genes, whose usual function seems to be controlling normal cell proliferation, have been implicated in many inherited and sporadic forms of malignancies Much evidence supports the concept of tumour formation by loss-of-function mutations in suppressor genes, as predicted by the two-hit model of Knudson and DeMars. The suppressor gene, p53, is affected in such a manner by numerous mutations, which occur in a variety of human tumours. These mutations usually represent the loss of one allele and the substitution of a single base in the other. We have now analysed the p53 gene in a family affected by Li-Fraumeni syndrome, a rare autosomal dominant syndrome characterized by the occurrence of diverse mesenchymal and epithelial neoplasms at multiple sites. In some instances the neoplasms seem to be related to exposure to carcinogens, including ionizing radiation. The Li-Fraumeni family that we studied had noncancerous skin fibroblasts (NSF) with an unusual radiation-resistant phenotype. DNA derived from the NSF cells of four family members, spanning two generations, had the same point mutation in codon 245 (GGC----GAC) of the p53 gene. This mutation leads to substitution of aspartic acid for glycine in one of the regions identified as a frequent target of point mutations in p53. The NSF cell lines with the mutation also retained the normal p53 allele. This inherited p53 mutation may predispose the members of this family to increased susceptibility to cancer.