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)

Antibody to hepatitis C as measured by the ELISA method is common in alcoholics. The presence of antibody to C 100-3 has been associated with more advanced disease. However, few studies have investigated the clinical significance of hepatitis C infection as defined by the presence of circulating viral RNA in alcoholics. We have prospectively examined 48 consecutive alcoholic patients for the presence of antibody to hepatitis C by an ELISA for antibody to the C100-3 antigen and by the reverse transcriptase polymerase chain reaction (PCR) using nested primers for the 5' nontranslated region of the viral RNA. Patients with liver disease were scored for disease severity by the combined clinical and laboratory index (CCLI). Overall, 12 of 48 patients (25%) were ELISA positive and eight of 48 (16%) were PCR positive. Among the 34 patients with liver disease, 10 (29%) were ELISA positive and six (18%) were PCR positive. All PCR-positive patients were also ELISA positive. There was no significant difference in the disease severity score (CCLI) or the duration of clinical disease in PCR-positive versus PCR-negative patients with liver disease. However, PCR-positive patients were significantly younger (43 +/- 6 vs. 55 +/- 10 yr, p = 0.001), indicating an earlier onset of severe disease in PCR-positive patients. There were no false-negative ELISA tests in either those with or those without liver disease. Among the 34 patients with liver disease, four of 10 patients with positive antibody were negative by PCR. Neither individual immunoglobulin levels (IgG, IgM, IgA) nor total globulins were significantly different between the ELISA-positive/PCR-negative patients and ELISA-positive/PCR-positive patients. When the entire group of 34 patients with liver disease was considered, we could not detect a significant correlation between ELISA absorbance and total globulins, and only a weak correlation between absorbance and immunoglobulin G (p = 0.49). These data show that the majority of alcoholic patients with liver disease and positive antibody to hepatitis C also have demonstrable viremia by PCR, and may require further evaluation and treatment. Elevated immunoglobulins in these patients do not correlate strongly with ELISA absorbance for anti-HCV. The presence of clinically advanced disease at a significantly younger age in the PCR-positive group is consistent with the concept of synergy between active viral infection and alcohol abuse in the development of liver disease in alcoholic patients.
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PMID:Hepatitis C infection by polymerase chain reaction in alcoholics: false-positive ELISA results and the influence of infection on a clinical prognostic score. 831 32

L-697,661 is a non-nucleoside analogue with potent, selective inhibitory activity against the reverse transcriptase of human immunodeficiency virus type 1 (HIV-1). The present study evaluated the potential role of this compound in the treatment of HIV-1-infected patients in a double-blinded, placebo- and zidovudine-controlled trial using plasma viremia as a marker of antiviral activity and real-time phenotypic evaluation of viral isolates for the emergence of resistance. Participants received 12 weeks of either placebo, 25 mg twice a day, 100 mg three times a day, or 500 mg twice a day of L-697,661, or zidovudine, 100 mg five times a day. Mean logarithmic reciprocal titers of plasma virus in patients taking either L-697,661 or zidovudine decreased by week 4 of therapy; for L-697,661 recipients these changes were dose-dependent and, at the highest dose tested, were comparable in magnitude to those seen with zidovudine. Viral suppression induced by L-697,661 persisted through 8 weeks of treatment but decreased by week 12. This rebound paralleled emergence of viral isolates showing resistance to L-697,661. We conclude that although L-697,661 has potent antiretroviral activity in vivo, its utility may be compromised by rapid emergence of L-697,661-resistant virus. Plasma viremia is a highly sensitive technique affording considerable utility in the early testing of such agents.
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PMID:Plasma viremia as a sensitive indicator of the antiretroviral activity of L-697,661. 851 7

In vitro experiments have suggested that interleukin (IL)-6 may contribute to human immunodeficiency virus (HIV) burden and to immunological abnormalities in HIV-infected patients. We had the opportunity to directly address this question in vivo through the virological and immunological monitoring of HIV-infected patients treated with an anti-IL-6 monoclonal antibody (mAb) for a lymphoma (ANRS 018 trial). Sixteen courses of anti-IL-6 mAb administration, performed in 11 patients, were studied. All patients were at a late stage of HIV infection. The HIV load and the immunological status were determined at the initiation of each course and at its end, 21 days later. The mAb induced no significant change of HIV load, as evaluated by p24 antigenemia, plasma viremia, and quantification of circulating HIV RNA by reverse transcriptase-polymerase chain reaction and branched DNA techniques. The anti-IL-6 mAb also did not affect CD4+, CD8+, and CD19+ circulating cell counts, nor the serum concentrations of sIL-2R and of sCD8. In contrast, the mAb completely abrogated acute-phase reaction, as demonstrated by the normalization of C-reactive protein and fibrinogen circulating levels (p = 0.013 and p = 0.008, respectively). It increased serum albumin concentration. The latter effect was restricted to patients with a spontaneously low albuminemia (p = 0.01). It decreased B-lymphocyte hyperactivity, as reflected by decreased IgG and IgA serum levels (p = 0.008 and p < 0.001, respectively), and by a decreased production of IgG in vitro (p = 0.017). In contrast, the IgM hyperproduction was not affected by the mAb. Therefore, increased IL-6 production in HIV-infected patients at a late stage of the infection may not stimulate HIV replication in vivo, but it may represent a key mechanism contributing to the metabolic and immunological dysbalance of the disease.
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PMID:In vivo role of IL-6 on the viral load and on immunological abnormalities of HIV-infected patients. 852 34

A high prevalence of antibodies to the hepatitis C virus (anti-HCV) has been demonstrated among patients with alcoholic liver disease, whereas the prevalence of HCV viremia in these patients remains uncertain. The aims of this study were to determine the prevalence of anti-HCV in alcoholic patients both with and without clinically apparent liver disease and to determine the presence of HCV RNA in those patients who tested positive for anti-HCV by RIBA II (Chiron Corporation, Emeryville, CA). One hundred male patients consecutively admitted to an alcoholic rehabilitation program were included. Group 1 was comprised of 40 patients with clinically apparent liver disease. Group 2 was comprised of 60 patients without clinically apparent liver disease. Anti-HCV was performed by a second-generation ELISA assay and confirmed by RIBA II. HCV RNA was performed by Quantiplex assay (Chiron Corporation) and a nested reverse transcriptase-polymerase chain reaction. No significant differences were found between the two groups with regards to age, quantity and duration of alcohol intake, or accepted risk factors for HCV. The overall prevalence of anti-HCV in our patients was 23%, with 43% of these in group 1 and 10% in group 2. HCV RNA tested positive in 94% of the anti-HCV-positive patients in group 1 and in 67% of the anti-HCV-positive patients in group 2. These data suggest that HCV infection is an important cofactor in the pathogenesis of liver disease among alcoholic patients.
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PMID:Hepatitis C virus in alcoholic patients with and without clinically apparent liver disease. 856 Dec 87

SIVsm chronically infected cultures were obtained after infection of CEMX174 cells with either SIVsmH3 or SIVsmE660. These phenotypically CD4 cells, formed syncytia but only when cocultivated with CD4+ cells. Single cell clones were derived from these cultures and examined for the production of virus-specific proteins. The majority of the clones expressed SIV p27 antigen and low levels of virus reverse transcriptase activity. Western blot analysis, performed with either monoclonal or polyclonal sera, showed that a chronically infected clone (B7) produced particles which contained envelope (gp135 and gp43), gag precursors and gag proteins (p27, p16 and p8). However, these particles (SIVsmB7) lacked detectable levels of vpx and of integrase, and contained several fusion proteins which expressed viral protease antigens. This defective virus failed to infect established CD4+ cell lines, as well as primary cultures of macrophages and of peripheral blood lymphocytes, obtained both from humans and from rhesus macaques. Lack of infection correlated with lack of viral DNA detection by PCR amplification of genomic DNA extracted from these cell cultures. In addition, SIVsmB7 virus lacked infectivity in vivo. Rhesus macaques inoculated with high concentrations of SIVsmB7 showed no viremia and their PBMC were PCR negative. Thus, B7 cells produced stable, non-infectious virus mutants, which contained env and gag proteins, but lacked detectable amounts of vpx and of enzymes required for virus replication. Due to the high constitutive expression of this virus-like particle, we are now testing this preparation as a vaccine.
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PMID:Properties of virus-like particles produced by SIV-chronically infected human cell clones. 857 47

We attempted to determine whether HIV-1 developed resistance to (--)-2',3'-dideoxy-3'-thiacytidine ((--)-3TC or 3TC, lamivudine) in patients with advanced human immunodeficiency virus type 1 (HIV-1) infection during therapy with 3TC. Genotypic analysis of HIV-1 strains isolated from 6 patients receiving 3TC revealed that as early as 2 months of therapy, HIV-1 developed a Met to Val amino acid substitution at codon 184 (Met184-->Val) in the reverse transcriptase-coding region of the pol gene. A detailed study of a series of HIV-1 strains isolated from a patient demonstrated that Met at codon 184 was first substituted with Ile by 2 weeks of 3TC therapy, followed by the substitution with Val by 8 weeks. All HIV-1 strains with the Met184-->Val substitution were profoundly less susceptible to 3TC (1800- to 5500-fold decreased sensitivity) as compared to pretherapy virus strains. These strains were also moderately less sensitive to 2',3'-dideoxycytidine (4.5- to 9-fold), but more sensitive to 3'-azido-2',3'-dideoxythymidine (2- to 14-fold). A decrease in viremia levels and an increase in CD4 counts were observed early in therapy; however, these changes were only transient. Our data suggest that reversal of such beneficial changes is associated with the Met184-->Val substitution of the pol gene of HIV-1. The data also suggest that 3TC, as a single agent, may induce virologic and immunologic improvement in patients with advanced HIV-1 infection, but only transiently.
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PMID:Genotypic and phenotypic characterization of HIV-1 isolated from patients receiving (--)-2',3'-dideoxy-3'-thiacytidine. 858 67

Treatment of chronic hepatitis B virus (HBV) infections with the reverse transcriptase inhibitor lamivudine leads to a rapid decline in plasma viremia and provides estimates for crucial kinetic constants of HBV replication. We find that in persistently infected patients, HBV particles are cleared from the plasma with a half-life of approximately 1.0 day, which implies a 50% daily turnover of the free virus population. Total viral release into the periphery is approximately 10(11) virus particles per day. Although we have no direct measurement of the infected cell mass, we can estimate the turnover rate of these cells in two ways: (i) by comparing the rate of viral production before and after therapy or (ii) from the decline of hepatitis B antigen during treatment. These two independent methods give equivalent results: we find a wide distribution of half-lives for virus-producing cells, ranging from 10 to 100 days in different patients, which may reflect differences in rates of lysis of infected cells by immune responses. Our analysis provides a quantitative understanding of HBV replication dynamics in vivo and has implications for the optimal timing of drug treatment and immunotherapy in chronic HBV infection. This study also represents a comparison for recent findings on the dynamics of human immunodeficiency virus (HIV) infection. The total daily production of plasma virus is, on average, higher in chronic HBV carriers than in HIV-infected patients, but the half-life of virus-producing cells is much shorter in HIV. Most strikingly, there is no indication of drug resistance in HBV-infected patients treated for up to 24 weeks.
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PMID:Viral dynamics in hepatitis B virus infection. 863 78

One hundred thirty-two recipients of blood components that retrospectively tested positive for antibody to human immunodeficiency virus type 1 (anti-HIV-1) were identified. Fourteen (11%) remained seronegative throughout follow-up. Donor and recipient characteristics that could have influenced transmission were examined. Attributes did not differ for infected and uninfected recipients. Peripheral blood mononuclear cells (PBMC) from uninfected recipients were HIV-1-negative by DNA amplification and culture but were susceptible to in vitro infection. Transmitting and nontransmitting donors at donation differed only for HIV-1 RNA positivity. By immunocapture reverse transcriptase-polymerase chain reaction, 6 of 11 transmitters and 0 of 11 nontransmitters tested RNA-positive (P = .02). A more sensitive quantitative RNA assay detected RNA in all donation sera, but median levels were higher in transmitting than nontransmitting sera (P = .01). Median CD4 cell counts were lower for transmitting than nontransmitting donors at enrollment (P = .02). Level of viremia is an important determinant of HIV infection by blood transfusion.
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PMID:Factors influencing human immunodeficiency virus type 1 transmission by blood transfusion. Transfusion Safety Study Group. 865 10

Rationally designed synthetic inhibitors of retroviral proteases inhibit the processing of viral polypeptides in cultures of human T lymphocytes infected with human immunodeficiency virus type 1 (HIV-1) and therefore suppress the infectivity of HIV-1 in vitro. We have previously reported the antiviral activity in vitro of HIV-1 protease inhibitors against the C-type retrovirus Rauscher murine leukemia virus (RMuLV) and the lentivirus simian immunodeficiency virus (SIV). The same compounds which blocked the infectivity of HIV-1 also inhibited the infectivity of RMuLV and SIV in vitro. This report extends these findings by testing the antiviral activity of HIV-1 protease inhibitors in vivo in the RMuLV model. RMuLV-infected mice were treated twice a day (bid) with either an active (SKF 108922) or inactive (SKF 109273) compound for fourteen days by the intraperitoneal (i.p.) route. Compared with excipient control, SKF 108922, formulated with hydroxypropyl-beta-cyclodextrin (HPB), reduced virus-induced splenomegaly, viremia, and serum reverse transcriptase (RT) levels, while SKF 109273 was inactive. The HPB vehicle by itself enhanced replication of RMuLV. The effects of changing the formulation and the route of administration were examined. SKF 108922, formulated in HPB, had similar antiviral activity when administered by the i.p. or subcutaneous (SC) routes. However, SKF 108922 administered as a colloidal suspension in cholesterol sulfate (CS) had no detectable antiviral effect. Measurements of the circulating levels of the protease inhibitor in plasma explained this result. Plasma concentrations of SKF 108922 exceeded 1000 nM within 10 min after SC administration of the compound solubilized in HPB, but SKF 108922 was not detected in plasma after SC administration of the same dose formulated with CS. Information on optimal conditions for administering these agents should prove useful in guiding their clinical application Therefore, RMuLV should provide a good model for the preclinical evaluation and development of this class of agents for the treatment of HIV.
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PMID:Effects of SKF 108922, an HIV-1 protease inhibitor, on retrovirus replication in mice. 873 97

The (-) enantiomer of 3'-thiacytidine (lamivudine) has been found to be a potent inhibitor of hepatitis B virus (HBV) and human immunodeficiency virus (HIV) replication. Mutation of methionine to valine or isoleucine at the YMDD (tyrosine, methionine, aspartate, aspartate) motif of the HIV reverse transcriptase has been shown to be responsible for lamivudine resistance in HIV. The hepadnaviruses also have the YMDD motif in their DNA polymerase. Therefore, it is possible that hepadnaviruses could develop lamivudine resistance by a similar mutation at this motif. We analyzed the HBV from a liver transplantation patient who developed recurrent HBV viremia during lamivudine treatment. The polymerase gene was amplified by polymerase chain reaction (PCR), and the region coding for the YMDD motif was sequenced. The pretreatment HBV sequence coded for YMDD, while the lamivudine-resistant mutant HBV coded for YIDD (tyrosine, isoleucine, aspartate, aspartate). With the documented changes in the YMDD motif of lamivudine-resistant HIV, it is likely that the methionine-to-isoleucine mutation in the YMDD motif of the HBV polymerase contributes significantly to the lamivudine-resistance of HBV isolated from this patient.
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PMID:Mutation in HBV RNA-dependent DNA polymerase confers resistance to lamivudine in vivo. 878 48


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