Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.7.49 (reverse transcriptase)
31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Deletions were constructed within a functional human immunodeficiency virus type 1 (HIV-1) proviral clone in order to assess the role of the envelope protein in virus particle formation. A graded exonuclease deletion technique was used to produce 12 clones with deletions of 175-308 nucleotides in the first conserved domain of envelope. This included 9 clones with frameshift deletions and 3 clones with in-frame deletions. Isogenic pairs of env deletion clones were produced with or without an additional deletion in the vif and vpr genes. Upon transfection, all clones produced virus particles, as determined by p24 antigen, reverse transcriptase, and sucrose gradient assays with conditioned media. Virus particles produced from clones with deletions in env or vif and vpr, or both regions, banded on sucrose gradients with a mobility similar to that of virus produced by the parental clone. The p24 gag capsid protein in the particles was resistant to trypsin, but the particles were disrupted by treatment with Triton X-100, suggesting the presence of a surrounding lipid bilayer. Furthermore, electron microscopic studies revealed both mature and immature virus particles derived from COS cells transfected with the env deletion clones. Cocultivation experiments with lymphoid cells and cells transfected with each of the env deletion clones demonstrated that the virus particles were noninfectious.
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PMID:Formation of noninfectious HIV-1 virus particles lacking a full-length envelope protein. 182 17

In the present report, we have studied the in vitro transition of normal blood monocytes to macrophages by changes in cell morphology, and the expression of surface antigens with a panel of monoclonal antibodies. The maturation process was accompanied by notable changes in cell-surface markers in a time-dependent manner. The percentage of cells expressing CD11c, ICAM-1, HLA-DR, and Fc receptor class III increased while the CD4 and CD35 expression was markedly decreased. After demonstrating that in vitro monocytes mature to macrophages in a recognizable manner, we studied the susceptibility to HIV-1 infection at time points representing different stages of cell maturation. The results show that monocyte/macrophages are susceptible to HIV-1 infection at all stages of differentiation. However, the kinetics of virus replication depends on the degree of maturation at the time of infection. Two major patterns of replication were observed: Infection of monocytes resulted in efficient virus production measurable by reverse transcriptase activity in culture supernatant, whereas infection of fully differentiated macrophages yielded low but sustained virus release only demonstrable by p24 antigen assay. We were not able to detect differences in the capacity of the virus to infect and replicate in monocyte/macrophages with respect to cellular origin of the virus isolate and whether the viruses were laboratory-adapted strains or low-passaged patient isolates.
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PMID:In vitro maturation of mononuclear phagocytes and susceptibility to HIV-1 infection. 185 87

The expression of the gag-pol polyprotein of human immunodeficiency virus type 1 (HIV-1) occurs via ribosomal frameshifting between the gag and pol genes. Because low levels of the gag-pol precursor are naturally produced in HIV-1-infected cells, a limited amount of information is available on the biology of this molecule. To further study this polyprotein, two mutant HIV-1 proviral genomes were created to position the gag and pol genes in the same translational reading frame. The mutations inserted a single thymidine nucleotide at the site of ribosomal frameshifting (nucleotide 1635), which results in the addition of a phenylalanine residue (frameshift 1 [FS1]), or a single adenine nucleotide, which results in the addition of a leucine residue (frameshift 2 [FS2]). Transfection of the mutant proviral genomes into COS-1 cells resulted in the expression of the p160gag-pol polyprotein precursor as well as the proteolytically processed gag and pol gene products. Metabolic labeling of the transfected cells with [3H]myristic acid revealed that the p160gag-pol and p17gag proteins expressed from the mutant genomes were myristylated. While the supernatants from COS-1 cells transfected with wild-type or mutant proviral genomes contained similar amounts of p24 antigen, the levels of reverse transcriptase were, on the average, 10 times greater in the supernatants from cells transfected with the FS1 and FS2 proviral genomes. The cells transfected with the wild-type proviral genome released infectious viral particles, while the mutant proviral genomes released p24 and reverse transcriptase in the absence of detectable particle formation. The mutant proviral genomes were completely noninfectious as determined by coculture of the transfected COS-1 cells with SupT1 cells. These results demonstrate that the gag-pol polyprotein of HIV-1 contains the appropriate signals for proteolytic processing and association with intracytoplasmic membranes in the absence of virion formation.
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PMID:Overexpression of the gag-pol precursor from human immunodeficiency virus type 1 proviral genomes results in efficient proteolytic processing in the absence of virion production. 187 Feb 15

Monocytes treated with interferon-alpha (IFN-alpha) at virus challenge show no evidence of human immunodeficiency virus (HIV) infection: no p24 antigen or reverse transcriptase (RT) activity, no viral mRNA and no proviral DNA. Levels of p24 antigen and RT activity in monocytes infected with HIV 1-3 weeks before IFN-alpha treatment gradually decrease to baseline. HIV-induced cytopathic changes are markedly reduced, as are levels of HIV mRNA: the frequency of productively infected cells is less than or equal to 1%. But, levels of proviral DNA in the IFN-alpha-treated and control HIV-infected cells are indistinguishable, and remain so through 3 weeks. Large quantities of proviral DNA in IFN-alpha-treated cells with little active transcription suggest true microbiological latency. The major potential source for IFN-alpha in HIV-infected patients is the macrophage. With any of 15 virus isolates, tumor necrosis factor-alpha, interleukin-1 beta, interleukin-6, IFN-omega or IFN-beta are not detected nor the mRNA expressed in HIV-infected or uninfected monocytes. Both uninfected and HIV-infected monocytes produce high levels of these cytokines after treatment with synthetic double-stranded RNA (poly-I:C). Uninfected monocytes also produce high levels of IFN-alpha after treatment with Poly-I:C, Newcastle disease virus or herpes simplex virus. In marked contrast, HIV-infected monocytes express no IFN-alpha activity or mRNA before or after treatment with any of these agents. The markedly diminished capacity of HIV-infected monocyte to produce IFN-alpha reflects a specific transcriptional block and may be an adaptive mechanism of virus to alter basic microbicidal functions of this cell.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of cytokine and viral gene expression in monocytes infected with the human immunodeficiency virus. 188 15

Infection due to the human immunodeficiency virus (HIV) has been complicated by the development of acute nonlymphocytic leukemia in five patients whose cases have previously been reported; other manifestations, including preleukemia, myelofibrosis, and myeloid hyperplasia, have also been reported in patients infected with HIV. We report the sixth case of an HIV-infected patient who developed acute myelomonocytic leukemia; HIV infection was documented by tests for serum antibodies (enzyme-linked immunosorbent assay and western blotting), by a markedly elevated p24 antigen level in plasma, and by cultures of CSF and peripheral blood that were positive for HIV. Furthermore, myelomonoblasts that were cultured without the addition of growth factors displayed evidence of HIV replication through the presence of p24 antigen and reverse transcriptase activity, both of which lasted for 4 weeks in the supernatant fluid of the cell cultures. This case report provides the first data indicating that HIV may infect myelomonoblasts in vivo and represents the sixth reported case of an association between HIV infection and pure acute nonlymphocytic leukemia.
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PMID:Relationship between acute myelomonoblastic leukemia and infection due to human immunodeficiency virus. 190 61

Interferon alpha was one of the first drugs tested for the treatment of patients with AIDS-related Kaposi's sarcoma based on its known antiviral properties and its abilities to modulate immune function and inhibit neoplastic cell proliferation. In vitro studies demonstrated defective production of interferon by blood cells of HIV-infected individuals and suppression of HIV replication by interferons alpha and beta. Interferons have also been shown to inhibit angiogenesis induced by tumour cells or by allogeneic lymphocytes in mice. The efficacy of recombinant interferon alpha for the treatment of AIDS-related Kaposi's sarcoma has been well documented with antitumour responses seen in approximately 30% of all patients treated in single agent efficacy trials with doses of at least 20 MU/m2. In several uncontrolled studies, response of Kaposi's sarcoma to treatment with interferon alpha was associated with longer survival and few opportunistic infections. Tumour response appears to be correlated with an absence of opportunistic infection and with CD4 cell numbers. Several studies using high interferon alpha doses have demonstrated decreases in serum HIV P24 core antigens which appear to be confined to patients whose tumours also regressed. The use of interferon alpha in HIV-infected patients with or without Kaposi's sarcoma have demonstrated in vivo anti-HIV activity. Studies have recently evaluated the tolerance and therapeutic potential of interferon alpha in combination with the reverse transcriptase inhibitor, zidovudine (azidothymidine AZT). Synergistic suppression of HIV replication in vitro has been demonstrated with the combination of interferon alpha and zidovudine. The description of HIV isolates with reduced sensitivity to zidovudine following prolonged treatment, and the finding that interferon alpha, but not zidovudine, prevents HIV expression in chronically infected cell lines, suggests that this combination might be useful in long-term treatment of patients with HIV infection.
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PMID:Interferon alpha in the treatment of AIDS-related Kaposi's sarcoma. 193 14

We have performed a prospective 33-month follow-up of the evolution of HIV infection in a cohort of 76 HIV-positive intravenous drug users (IVDUs). We report on immunological and serological variables that proved to be highly predictive of development to AIDS. In a stepwise multivariate analysis of the actuarial progression rate we found the number of CD4+ lymphocytes to be the most powerful predictor of progression to AIDS. We found no independent predictive effects associated with any other variable with predictive power: loss of antibody to p24 antigen, anergy, HIV p24 antigenaemia, loss of antibody to p53 (reverse transcriptase), decreased number of CD8+ T cells, loss of antibody to p31, loss of antibody to p17, beta 2-microglobulin level, loss of antibodies to gp41 and p64, or immunoglobulin A level. We have found that our data differ from those obtained in studies in homosexual men in the different prognostic value of those predictive markers. Our findings should help to identify high risk of progression to clinical AIDS among IVDUs, thereby assisting in the selection of patients for prophylaxis and therapy.
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PMID:Immunological and serological markers predictive of progression to AIDS in a cohort of HIV-infected drug users. 197 43

Infectivity of free and cell-associated human immunodeficiency virus type 1 (HIV-1) treated in vitro at pH 7.4 to 4.9 for 2 hours was assessed on susceptible CEM-ss cells. Viral activity was monitored by cytopathology and production of reverse transcriptase and p24 antigen. The infectivity of cell-free virus was gradually inactivated and at pH 5.4 was completely lost, with or without subsequent adjustment of pH to neutral. Virus-producing cells also gradually lost their ability to infect as the pH decreased; however, restoration of neutral pH resulted in regained infectivity. Since the pH values used in the study are similar to those found at various entry sites of the human body, the data may be relevant to the mode of transmittal of HIV.
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PMID:Acid sensitivity of cell-free and cell-associated HIV-1: clinical implications. 207 21

Heat-treated factor VIII has been implicated in the transmission of HIV to hemophiliacs. Previously, evidence has been limited to documenting cases of seroconversion following administration of heat-treated factor VIII. Here, we present evidence of active HIV infection, i.e., infected and not merely sensitized following factor VIII injections. Six Canadians with hemophilia had seroconverted during a longitudinal study of their HIV immune status. Two of the three patients tested by this method demonstrated HIV gag-specific sequences upon amplification by polymerase chain reaction. In addition, HIV-1 virus was isolated from peripheral blood lymphocytes of one of these two persons as shown by reverse transcriptase activity of culture supernatants as well as neutralizable p24 antigen. This, we believe, is the first evidence of active HIV infection following administration of 60 degrees C, 30 h heat-treated factor VIII.
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PMID:Laboratory evidence of active HIV-1 infection in Canadians with hemophilia associated with administration of heat-treated factor VIII. 210 24

Viral isolates were recovered by cocultivation on macrophage colony-stimulatingfactor (MCSF)-treated monocyte target cells from peripheral blood mononuclear cells (PBMCs) in 25 out of 27 patients seropositive or at risk for HIV infection. Frequency of virus recovery was independent of the patient's age, sex, numbers of CD4+ T cells, clinical stage or zidovudine (azidothymidine) therapy. Sixteen out of 19 HIV isolates were serially passaged in MCSF- treated monocytes. Five out of five virus isolates were also passaged in phytohemagglutinin/interleukin-2 (PHA/IL-2)-treated lymphoblasts. In lymphoblasts, no qualitative or quantitative differences were observed between these isolates and human T-cell leukemia virus IIIB (HTLV-IIIB) for (1) release of p24 antigen reverse transcriptase, and infectious virus, (2) induction of typical cytopathic effects (cell syncytia in 3-10% of cells) and cell lysis, (3) frequency of infected cells (5-20% of PBMC) as detected by in situ hybridization for HIV RNA, (4) down-modulation of T cell plasma membrane CD4, and (5) site of progeny virion assembly and budding (plasma membrane only with no intracytoplasmic accumulation of virus). Progeny virus recovered from infected lymphoblasts was fully infectious for other lymphoblasts, but failed to infect MCSF-treated monocytes. Detailed analysis of target cell tropism among HIV isolates showed that HIV isolated in monocytes infected both monocytes and lymphoblasts; progeny virus isolated in lymphoblasts infected only T cells. HIV interacts differently with monocytes and T cells. Understanding this interaction may more clearly define both the pathogenesis of HIV disease and strategies for therapeutic intervention.
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PMID:Macrophage-HIV interaction: viral isolation and target cell tropism. 211 97


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