Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Entry of human immunodeficiency type 1 virus (HIV-1) into target cells requires both CD(4)and one of the chemokine receptors. Viruses predominantly use one, or occasionally both, of the major co-receptors CCR5 and CXCR4, although other receptors, including CCR2B and CCR3, function as minor co-receptors. A 32-nucleotide deletion (D32) within the b-chemokine receptor 5 gene (CCR5) has been described in subjects who remain uninfected despite extensive exposition to HIV-1. The heterozygous genotype delays disease progression. This allele is common among Caucasians, but has not been found in people of African or Asian ancestry. A more common transition involving a valine to isoleucine switch in transmembrane domain I of CCR2B (64I), with unknown functional consequences, was found to delay disease progression but not to reduce infection risk. As the Brazilian population consists of a mixture of several ethnic groups, we decided to examine the genotype frequency of these polymorphisms in this country. There were 11.5% CCR5 heterozygotes among the HIV-1 infected population and 12.5% among uninfected individuals, similar to data from North America and Western Europe. The prevalence of CCR2-64I homozygotes and heterozygotes was 0.06 and 15.2%, respectively, also similar to what is known for North America and Western Europe.
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PMID:Frequency of polymorphisms of genes coding for HIV-1 co-receptors CCR5 and CCR2 in a Brazilian population. 1453 83

Isopropyl substituted 4-thioazolyl valine side chains are highly optimized P(2)-P(3) ligands for C2 symmetry-based HIV protease inhibitors, as exemplified by the drug ritonavir. Replacement of the side chain with the conformationally constrained hexahydrofurofuranyloxy P(2) ligand in combination with a dimethylphenoxyacetate on the other end of the ritonavir core diamine yielded highly potent HIV protease inhibitors. The in vitro antiviral activity in MT4 cells increased by 10- and 20-fold, respectively, in the absence and presence of 50% human serum compared to ritonavir. The structure-activity relationships of inhibitor series with this combination of ligands were investigated. Preliminary pharmacokinetic studies in rats indicated rapid elimination of the inhibitors from the blood, and the plasma levels were not significantly enhanced by coadministration with ritonavir. However, the novel structural features and the high intrinsic antiviral potency of this series provides potential for the future exploration of prodrug strategies.
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PMID:Synthesis and SAR studies of potent HIV protease inhibitors containing novel dimethylphenoxyl acetates as P2 ligands. 1455 51

Both D- and L-2'-fluoro-4'-thio-2',3'-unsaturated nucleosides were synthesized and their anti-HIV activity against the drug sensitive virus and lamivudine-resistant mutant (M184V) were evaluated. In vitro antiviral evaluation indicated that the L-isomers are more potent than the D-isomers, but unfortunately all were cross-resistant with 3TC. Molecular modeling studies revealed that the unnatural sugar moiety of the L-nucleosides as well as 4'-sulfur atom of the D-isomer has a steric conflict with the bulky side chain of valine 184, resulting in cross-resistance.
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PMID:2'-Fluoro-4'-thio-2',3'-unsaturated nucleosides: anti-HIV activity, resistance profile, and molecular modeling studies. 1456 38

Virus-specific cytotoxic T lymphocytes (CTL) exert intense selection pressure on replicating simian immunodeficiency virus (SIV) and human immunodeficiency virus type 1 (HIV-1) in infected individuals. The immunodominant Mamu-A(*)01-restricted Gag p11C, C-M epitope is highly conserved among all sequenced isolates of SIV and therefore likely is structurally constrained. The strategies used by virus isolates to mutate away from an immunodominant epitope-specific CTL response are not well defined. Here we demonstrate that the emergence of a position 2 p11C, C-M epitope substitution (T47I) in a simian-human immunodeficiency virus (SHIV) strain 89.6P-infected Mamu-A(*)01(+) monkey is temporally correlated with the emergence of a flanking isoleucine-to-valine substitution at position 71 (I71V) of the capsid protein. An analysis of the SIV and HIV-2 sequences from the Los Alamos HIV Sequence Database revealed a significant association between any position 2 p11C, C-M epitope mutation and the I71V mutation. The T47I mutation alone is associated with significant decreases in viral protein expression, infectivity, and replication, and these deficiencies are restored to wild-type levels with the introduction of the flanking I71V mutation. Together, these data suggest that a compensatory mutation is selected for in SHIV strain 89.6P to facilitate the escape of that virus from CTL recognition of the dominant p11C, C-M epitope.
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PMID:Simian-human immunodeficiency virus escape from cytotoxic T-lymphocyte recognition at a structurally constrained epitope. 1461 Jan 80

We selected for study a set of B44-supertype molecules collectively represented in >40% of the individuals in all major ethnicities (B*1801, B*4001, B*4002, B*4402, B*4403, and B*4501). The peptide-binding specificity of each molecule was characterized using single amino acid substitution analogues and nonredundant peptide libraries. In all cases, only peptide ligands with glutamic acid in position 2 were preferred. At the C terminus, each allele was associated with a unique but broad pattern of preferences, but all molecules tolerated hydrophobic/aliphatic (leucine, isoleucine, valine, methionine), aromatic (tyrosine, phenylalanine, tryptophan), and small (alanine, glycine, threonine) residues. Secondary anchor motifs were also defined for all molecules. Together, these features were used to define a B44 supermotif and a novel algorithm for calculating degeneracy scores that can be used to predict B44-supertype degenerate binders. Approximately 90% of the peptides with a B44 supermotif degeneracy score of >10 bound at least three of the six B44-supertype molecules studied with high affinity. Finally, a number of peptides derived from hepatitis B and C viruses, HIV, and Plasmodium falciparum have been identified that have degenerate B44 supertype-binding capacity. Taken together, these findings have important implications for epitope-based approaches to vaccination, immunotherapy, and the monitoring of immune responses.
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PMID:Simultaneous prediction of binding capacity for multiple molecules of the HLA B44 supertype. 1463 8

3'-Azido-2', 3'-dideoxyuridine (AZDU, AzddU, CS-87) has been shown to have potent anti-HIV activity in vitro. However, the compound exhibits a relatively short half-life and incomplete oral bioavailability in humans. In an effort to improve the pharmacokinetic properties of AZDU, prodrug 3'-azido-2',3'-dideoxyuridine-5'-O-valinate hydrochloride (AZDU-VAL) was synthesized by the esterification of 5'-OH function in AZDU. The objective of this study was to investigate the biotransformation and pharmacokinetics of AZDU-VAL along with its antiviral parent compound AZDU following intravenous and oral administration to rats. Adult male Sprague-Dawley rats were administered AZDU or AZDU-VAL by intravenous injection or oral gavage. Concentrations of AZDU-VAL and AZDU were determined by HPLC. Pharmacokinetic parameters were generated by area-moment analysis. The bioavailability of AZDU after oral administration was approximately 53%. The terminal phase half-life of the nucleoside analogue ranged between 0.6 h after intravenous administration and 1 h following oral administration. In vivo the prodrug was rapidly and efficiently biotransformed to yield AZDU following intravenous and oral administration. The apparent availability of AZDU was virtually complete following oral administration of prodrug AZDU-VAL averaging 101%. The bioavailability of AZDU following intravenous administration of AZDU-VAL averaged 106%. In summary, the disposition of AZDU was dose dependent over the dose range of 25-100 mg/kg. Renal clearance and steady state volume of distribution were lower at the higher dose level. Prodrug AZDU-VAL demonstrated improved oral bioavailability as evidenced by complete absorption and efficient bioconversion to AZDU. The results suggest that AZDU-VAL may be a promising prodrug for the delivery of AZDU.
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PMID:Pharmacokinetic evaluation of 3'-azido-2', 3'-dideoxyuridine-5'-O-valinate-hydrochloride as a prodrug of the anti-HIV nucleoside 3'-azido-2', 3'-dideoxyuridine. 1469 89

Methionine at position 184 of human immunodeficiency virus type-1 (HIV-1) reverse transcriptase (RT) was changed to valine, isoleucine, threonine, or alanine in an HIV-1-based vector. The vectors were analyzed for replication capacity and for resistance to the nucleoside analog 2',3'-dideoxy-3'thiacytidine (3TC) using a single-cycle assay. Viruses containing the valine or isoleucine mutations were highly resistant to 3TC and replicated almost as well as the wild-type virus. The virus containing the threonine mutation was resistant to 3TC, but replicated about 30% as well as the wild-type. The alanine mutation conferred partial resistance to 3TC, but replicated poorly. The amounts of viral DNA synthesized decreased in 3TC-treated cells when the cells were infected with wild-type virus and the M184A mutant. The effect of these mutations on the generation of the ends of the linear viral DNA was determined using the sequence of the 2-LTR circle junctions. The M184T mutation increased the proportion of 2-LTR circle junctions containing a tRNA insertion, suggesting that the mutation affected the RNase H activity of RT.
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PMID:Mutations at position 184 of human immunodeficiency virus type-1 reverse transcriptase affect virus titer and viral DNA synthesis. 1506 12

Human organic anion transporter 4 (hOAT4) belongs to a superfamily of organic ion transporters that play critical roles in the body disposition of clinically important drugs, including anti-HIV therapeutics, antitumor drugs, antibiotics, antihypertensives, and anti-inflammatories. In this study, we investigated the role of conserved glycine residues in hOAT4 function. We mutagenized each of the six glycine residues (at positions 11, 241, 383, 388, 400, and 466) to serine, and their functional properties were analyzed in COS-7 cells by measuring the uptake of [(3)H]estrone sulfate. Our results showed that mutants G11S, G383S, G388S, and G466S exhibited transport activities comparable with those of wild-type hOAT4. In contrast, mutants G241S and G400S almost completely lost transport function. We then further characterized Gly-241 and Gly-400 by mutagenizing these residues to amino acids with varying sizes of side chains, including alanine, valine, and leucine. We demonstrated that increasingly larger side chains at positions 241 and 400 increasingly impaired hOAT4 function. Cell-surface biotinylation using an impermeant biotinylating reagent showed that mutations of Gly-241 and Gly-400 interfered with the trafficking of the transporter onto cell surface. Immunofluorescence analysis of mutant-transfected cells confirmed these results. Substitutions of amino acids with large side chains at positions 241 and 400 resulted in decreased V(max) and increased K(m.) These results suggest that Gly-241 and Gly-400 are important both in targeting the transporter to the plasma membrane and in substrate binding. This is the first identification and characterization of critical amino acid residues in hOAT4 and may provide important insights into the structure-function relationships of the organic ion transporter family.
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PMID:The role of glycine residues in the function of human organic anion transporter 4. 1510 42

Ala-114, together with Asp-113, Tyr-115 and Gln-151, form the pocket that accommodates the 3'-OH of the incoming dNTP in the HIV-1 RT (reverse transcriptase). Four mutant RTs having serine, glycine, threonine or valine instead of Ala-114 were obtained by site-directed mutagenesis. While mutants A114S and A114G retained significant DNA polymerase activity, A114T and A114V showed very low catalytic efficiency in nucleotide incorporation assays, due to their high apparent K(m) values for dNTP. Discrimination between AZTTP (3'-azido-3'-deoxythymidine triphosphate) and dTTP was not significantly affected by mutations A114S and A114G in assays carried out with heteropolymeric template/primers. However, both mutants showed decreased susceptibility to AZTTP when poly(rA)/(dT)16 was used as substrate. Steady-state kinetic analysis of the incorporation of ddNTPs compared with dNTPs showed that substituting glycine for Ala-114 produced a 5-6-fold increase in the RT's ability to discriminate against ddNTPs (including the physiologically relevant metabolites of zalcitabine and didanosine), a result that was confirmed in primer-extension assays. In contrast, A114S and A114V showed wild-type ddNTP/dNTP discrimination efficiencies. Discrimination against ribonucleotides was not affected by mutations at position 114. Misinsertion and mispair extension fidelity assays as well as determinations of G-->A mutation frequencies using a lacZ complementation assay showed that, unlike Tyr-115 or Gln-151 mutants, the fidelity of HIV-1 RT was not largely affected by substitutions of Ala-114. The role of the side-chain of Ala-114 in ddNTP/dNTP discrimination appears to be determined by its participation in van der Waals interactions with the ribose moiety of the incoming nucleotide.
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PMID:Nucleotide specificity of HIV-1 reverse transcriptases with amino acid substitutions affecting Ala-114. 1554 34

Valaciclovir (Valtrex, Zelitrex), the L-valine ester of aciclovir, increases aciclovir bioavailability by 3- to 5-fold over that achievable with oral aciclovir. It addresses many unmet needs of currently available anti-herpesvirus therapies. Valaciclovir extends the efficacy of aciclovir in the treatment of herpes zoster and genital HSV infections, using less frequent dose regimens but retaining the highly acceptable safety profile established for aciclovir. The potential for valaciclovir in CMV prophylaxis has now been proven, and further refining to identify the optimal dose regimen is ongoing. After oral administration, valaciclovir is rapidly absorbed and extensively converted to aciclovir and L-valine, the essential amino acid. The mode of action and spectrum of antiviral activity of valaciclovir are thus identical to aciclovir. The bioavailability of aciclovir after valaciclovir, characterised from studies in healthy adult volunteers, is similar in a wide range of patient populations, including the elderly, those with advanced HIV disease, patients with impaired liver or renal function, or undergoing bone marrow transplantation. No clinically significant drug interactions with valaciclovir have so far been identified. Dosage reductions in clinical use of valaciclovir are only necessary when renal function is severely impaired. In controlled clinical trials in herpes zoster, valaciclovir (1000 mg three times daily) is superior to aciclovir in speeding the resolution of zoster-associated pain and post-herpetic neuralgia. It is as effective as aciclovir in hastening rash healing. In patients with ophthalmic zoster, no differences were evident between valaciclovir and aciclovir treatment on zoster-associated pain or the occurrence of ocular complications. The safety profiles of valaciclovir, aciclovir and placebo were not different in this study programme. In a series of controlled, randomised trials of valaciclovir, aciclovir and placebo for the acute treatment of genital HSV infections in approximately 3000 patients, twice daily valaciclovir was proven as effective as the standard 5 times daily aciclovir regimen in resolving the clinical signs and symptoms of lesional disease. Early patient-initiated valaciclovir therapy (500 mg twice daily) of recurrent genital herpes episodes was shown significantly to increase the chance of prevention of vesicular or ulcerative lesions, a valuable clinical advantage not prospectively proven for aciclovir. When used for periods of up to one year, valaciclovir (500 mg once daily) effectively suppresses genital herpes recurrences. Long-term studies of valaciclovir for HSV suppression, evaluating doses of up to 1000 mg daily in approximately 3000 patients, about 25% of whom were HIV seropositive (CD+ > 100 cells/microl), revealed a highly acceptable clinical tolerability profile for valaciclovir that did not differ from aciclovir or placebo. There were no cases resembling thrombotic microangiopathy in these long-term studies. The aciclovir safety heritage and pharmacokinetic rationale for the development of valaciclovir have been realised through the clinical research programmes in the zoster and HSV indications. Further studies in these and related areas, including CMV prophylaxis, are in progress and aim to expand further the clinical potential of valaciclovir in the future.
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PMID:Valaciclovir: development, clinical utility and potential. 1598 1


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