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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The inhibitory potency of 3'-azido-3'-deoxythymidine 5'-triphosphate (AZTTP) against HIV-1 reverse transcriptase (HIV-1 RT) has been further evaluated. The results indicate that the previously reported low Ki values for AZTTP against HIV-1 RT (2.35 nM) are due neither to the to the direct tight binding of AZTTP to HIV-1 RT nor to the interaction of the enzyme with AZTMP moiety terminated primer-templates, but instead they are an artifact of the use of a homotemplate-primer [poly(rA).oligo(dT)]. With a set of RNAs of defined sequence as templates, we demonstrate that the observed Ki value for AZTTP depends on the length of the poly(rA) region following the primer in the RNA template. The more adenosyl residues in the RNA template that are available for processive incorporation of TMP moieties, the lower is the observed Ki value for AZTTP. Since the potencies of new inhibitors of HIV-1 RT are usually compared with that for AZTTP, these results have important consequences for the process of discovery of new HIV inhibitors that are of potential use in AIDS therapy.
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PMID:The observed inhibitory potency of 3'-azido-3'-deoxythymidine 5'-triphosphate for HIV-1 reverse transcriptase depends on the length of the poly(rA) region of the template. 137 Oct 70

A comparison of the fidelity of reverse transcriptases (RT) from human immunodeficiency virus (HIV-1) and avian myeloblastosis virus (AMV) is made using RNA and DNA primer-template molecules in vitro. Selected template target sites containing either uracil or thymine are used to measure nucleotide insertion fidelities and to compare the efficiency of extending mismatched nucleotides at primer 3'-termini. HIV-1 reverse transcriptase is observed to incorporate as many as three consecutive mismatches and to continue efficient elongation from mismatched primer 3'-termini without discernible pausing. Nucleotide misinsertion and mispair extension efficiencies are similar for both enzymes on RNA and DNA templates having identical surrounding sequence. HIV-1 and AMV reverse transcriptases form G.T and G.U mismatches most efficiently, between 1.6 x 10(-4) and 7 x 10(-4), and both enzymes extend G.U with exceptionally high efficiencies, 2.7 x 10(-2) for HIV-1 RT and 4.5 x 10(-2) for AMV RT. Extension of the G.T mismatch is similar for AMV RT (5.8 x 10(-2) but 20-fold less efficient for HIV-1 RT. C.U and C.T mismatches are formed by both enzymes in a frequency range of 4.4 x 10(-5)-2.4 x 10(-4). HIV-1 RT extends these mismatches with slightly higher efficiencies (5.5 x 10(-3)-5.9 x 10(-3)) than AMV RT (5.6 x 10(-4)-2.1 x 10(-3)). Insertion of dTMP opposite U and T occur at about 1 x 10(-4)-2 x 10(-4) for HIV-1 RT. For AMV RT, formation of T.U mispairs occurs with an 8-fold lower efficiency, whereas insertion of dTMP opposite T is not detected. This particular DNA template sequence generates a pause site for AMV RT but not HIV-1 RT. HIV-1 RT dissociation rate constants are about 8-fold larger from a DNA primer bound to a DNA template (0.5 s-1), as compared with an RNA template (0.06 s-1) at one site, and are at most 2-fold larger at another site. The equilibrium binding constant for HIV-1 RT bound to DNA primed RNA and DNA templates appears to be similar, KD approximately 2.5 nM. Values of kpol from 0.3 to 1.5 nucleotides/s are obtained for HIV-1 RT at the RNA and DNA template sites used to measure insertion and extension fidelity. The relatively high efficiency of mispair extension catalyzed by reverse transcriptases with both RNA and DNA templates suggests that a significant component of retroviral genetic variability may be related to the ability of reverse transcriptases to continue efficient synthesis of DNA containing mismatches on both RNA and DNA templates.
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PMID:Comparison of HIV-1 and avian myeloblastosis virus reverse transcriptase fidelity on RNA and DNA templates. 137 33

Chancroid is linked to the spread of human immunodeficiency virus type 1 (HIV-1) in East Africa. Effective, easily administered therapy is a priority for the control of Haemophilus ducreyi. The efficacy of a single oral dose of fleroxacin, 400 mg, was compared to a 3-day oral course of trimethoprim-sulfamethoxazole (TMP-SMZ), 160/800 mg, twice daily for the treatment of chancroid in 98 HIV-1-seronegative men in Nairobi, Kenya. No differences were noted between the two groups with respect to demographic characteristics, sexual behavior, and clinical characteristics. Culture-proven failure occurred in 1 (3%) of 36 fleroxacin-treated patients and in 11 (30%) of 37 TMP-SMZ-treated patients (P = .005). Fleroxacin, as a single oral dose, is an effective treatment for culture-proven chancroid in patients who are HIV-1 seronegative. TMP-SMZ is no longer predictably effective due to the recent emergence of resistance to both sulfonamides and to trimethoprim.
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PMID:A randomized, double-blind study of the efficacy of fleroxacin versus trimethoprim-sulfamethoxazole in men with culture-proven chancroid. 156 47

Drug allergy is the most common and significant allergic manifestation of HIV3 infection. Initially described in patients treated with SMX-TMP for PCP, allergy is now known to involve a multitude of drugs. The pathogenesis of, and risk factors for, allergy in HIV infection are poorly understood, although there is evidence suggesting that allergy is more common with advancing immunodeficiency. HIV-negative subjects with sulfonamide allergy may have drug-specific antibodies and drug metabolite-induced lymphocyte cytotoxicity, abnormalities that could partly explain the allergic mechanisms and which may have future diagnostic potential; these abnormalities have not been described in HIV-infected subjects. Therapy includes avoidance, suppressive agents such as corticosteroids, and desensitization, although the appropriate role for each is not entirely clear. Serum IgE levels have been shown to rise with progressive disease; those patients with higher levels may have a worse prognosis. The mechanisms of this rise are multifactorial, probably a combination of altered T-lymphocyte regulation of IgE synthesis and of production of specific IgE directed against microbial antigens.
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PMID:Allergic manifestations of human immunodeficiency virus (HIV) infection. 167 34

Human immunodeficiency virus 1 (HIV-1) reverse transcriptase has been found to conduct error-prone synthesis on DNA and RNA templates. We find here that tolerance of an A:G mispair with poly(rA) as template is particularly strong, such that extensive poly(dG) synthesis is conducted. This type of extensive misincorporation is not observed with several reference DNA polymerases. Surprisingly, HIV reverse transcriptase processivity and kcat for dGMP misincorporation and normal dTMP incorporation are about the same. However, the Km value for dGTP in poly(dG) synthesis is approximately 1000-fold higher than the Km for dTTP in poly(dT) synthesis. Comparison of thermodynamic parameters for dGMP misincorporation and normal dNMP incorporation indicates a lower energy of activation for dGMP misincorporation than for normal dNMP incorporation. Entropy of activation (delta S*) for normal dTMP incorporation is positive (approximately 10 cal/kmol), whereas delta S* for dGMP misincorporation is negative (-36 cal/kmol). Since differences in delta S* are usually considered to reflect differences in solvation for the transition state complex, these results are consistent with the interpretation that the active site of HIV reverse transcriptase is flexible enough to misincorporate dGMP without the usual dispersion of water molecules.
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PMID:Thermodynamics of A:G mismatch poly(dG) synthesis by human immunodeficiency virus 1 reverse transcriptase. 170 95

The in vitro fidelity of highly purified recombinant reverse transcriptase from simian immunodeficiency virus of African green monkeys (SIVagm) was determined. By using the phi X174am16 reversion assay an overall error rate of 1/19,000 was determined. This is 2.4-fold higher than the overall accuracy of purified recombinant HIV-1 reverse transcriptase, measured in parallel. The evaluation of error frequencies from nucleotide pool bias studies suggest an even higher accuracy for the SIVagm-derived reverse transcriptase. T:dGMP mismatches were formed most frequently with an error rate of 1/155,000, followed by G:dGMP (1/230,000), A:dGMP (1/315,000), G:dAMP (1/340,000), T:dCMP (1/540,000), T:dTMP (1/790,000), and A:dCMP (1/1,050,000) mispairs. Thus, according to pool bias effects and depending on the mismatch under consideration SIVagm reverse transcriptase appears to be 2 to 20-fold more accurate than the homologous enzyme from the human immunodeficiency virus type 1. This higher accuracy is not due to a co-purifying exonuclaease activity. Like the enzyme from HIV-1, the simian monkey-derived enzyme was found to be devoid of a proofreading 3' to 5' exonuclease.
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PMID:Fidelity of reverse transcriptase of the simian immunodeficiency virus from African green monkey. 170 65

Succinylfluorescein-labeled dideoxyTTP has been used as a substrate for reverse transcriptase from HIV-1. On addition to the 3'-end of a primer molecule, there is a reduction of fluorescence yield of a factor of ca. 4. Release of a fluorescent DNA/DNA primer/template duplex from its complex with reverse transcriptase results in a reduction of fluorescence by a further factor of 2. The fluorescent nucleotide is incorporated somewhat less efficiently than 3'-azidoTMP and TMP, which show similar incorporation kinetics. Fluorescent chain-terminated primers have been used to investigate the interaction of normal and chain-terminated primer/template complexes with reverse transcriptase. The dissociation constant of a 36/18-mer was 0.65 nM, whereas that of the same complex after the addition of the fluorescent chain-terminating nucleotide to the primer was 3 nM at 25 degrees C. The rate of dissociation of the latter complex from the enzyme was 0.04 s-1. This was decreased by a factor of ca. 10 at high concentrations (greater than 200 microM) of the nucleotide triphosphate complementary to the next position of the template. The results obtained suggest that potent inhibition of reverse transcriptase activity in in vitro assays results from formation of a slowly dissociating complex between the enzyme and chain-terminated primer/template complexes. However, arguments are presented that lead to the conclusion that this is not the mode of inhibition in cells invaded by HIV. At the prevailing relative concentrations in this situation, chain termination resulting in incomplete transcription is likely to be the major factor.
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PMID:Interaction of fluorescently labeled dideoxynucleotides with HIV-1 reverse transcriptase. 170 67

Pneumocystis carinii pneumonia complicated the course of two patients with multiple myeloma. The diagnosis was established in both cases by bronchoalveolar lavage, which demonstrated the typical pneumocysts. Clinical and roentgenographic improvement in both patients was observed following a course of trimethoprim-sulfamethoxazole. One patient had lymphocyte subsets performed with a CD4/CD8 ratio of 0.8; both patients were HIV antibody-negative by ELISA. Both patients tolerated prophylactic TMP-SMX given concurrently with the subsequent chemotherapy for myeloma. We suggest that the immune defect seen in multiple myeloma may have placed these patients at risk for opportunistic infections such as P carinii pneumonia; however, as opposed to patients with AIDS, our patients tolerated therapy with TMP-SMZ quite well.
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PMID:Pneumocystis carinii pneumonia complicating multiple myeloma. 199 21

3'-Azido-3'-deoxythymidine triphosphate (erythro) and its threo isomer were synthesized and investigated for their inhibition of HIV reverse transcriptase from virus isolate U 937/HTLV-III. The erythro isomer was a competitive inhibitor of the reaction directed by (rA)n(dT)12-18 and the Ki value was 0.0022 microM. The threo isomer was at least 100-fold less active. The inhibition was specific for dTMP incorporation, and dGMP incorporation using (rC)n(dG)12-18 as template/primer was not affected. The Km value for dTTP varied between 0.7 microM and 1.7 microM. Reverse transcriptase from nine HIV isolates were tested for inhibition by the erythro isomer and only slight differences in sensitivity were observed.
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PMID:Inhibition of the reverse transcriptase from HIV by 3'-azido-3'-deoxythymidine triphosphate and its threo analogue. 244 Mar 80

Reverse transcriptase from the human immunodeficiency virus type I (HIV-1) was expressed in E. coli and purified to near homogeneity. The enzyme was shown to contain reverse transcriptase, DNA polymerase and ribonuclease H activities. The DNA polymerase activity converted singly-primed phi X174 (+) DNA into the double-stranded form. Two third of the replication product is ligatable to covalently closed circular DNA (RFIV-form DNA) indicating that DNA synthesis by HIV reverse transcriptase can proceed until the enzyme matches the 5'-end of a pre-existing primer molecule. The in vitro accuracy of HIV reverse transcriptase was measured with the phi X174am16 reversion assay to be 1/7,400. Reversion rates for the individual mispairs were determined from pool bias studies to be 1/8,000 for the dGMP:T template mismatch, 1/35,000 for the dGMP:A template mismatch, 1/45,000 for the dAMP:G template mismatch, 1/73,000 for the dCMP:T template mispair, 1/140,000 for the dCMP:A template mispair, and 1/180,000 for the dGMP:G template mismatch. The dTMP:T template mispair was below the detection limit of the assay indicating a reversion rate of less than 1/300,000 for this particular mispair.
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PMID:Fidelity of human immunodeficiency virus type I reverse transcriptase in copying natural DNA. 246 38


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