Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0021051 (immunodeficiency)
 71,517 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidine derivatives are potent and specific inhibitors of human immunodeficiency virus type 1 (HIV-1). The development of in vitro resistance to two derivatives, 5-ethyl-1-(ethoxymethyl)-(6-phenylthio)-uracil (E-EPU), was evaluated by serial passage of HIV-1 in increasing concentrations of inhibitor. HIV-1 variants exhibiting > 500-fold resistance to E-EPSeU and E-EPU were isolated after sequential passage in 1, 5, and 10 microM inhibitor. The resistant variants exhibited coresistance to related acyclic 6-substituted pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- pyrimidines and the HIV-1-specific inhibitors (+)-(5S)-4,5,6,7-tetrahydro-5- methyl-6-(3-methyl-2-butenyl)imidazo[4,5,1-jk]benzodiazepin-2(1H)- thione (TIBO R82150) and nevirapine, but remained susceptible to 3'-azido-3'-deoxythymidine, 2',3'-dideoxycytidine, 2',3'-dideoxyinosine, and phosphonoformic acid. DNA sequence analysis of reverse transcriptase (RT) derived from E-EPSeU-resistant virus identified a Tyr (TAT)-to-Cys (TGT) mutation at either codon 188 (Cys-188; 9 of 15 clones) or codon 181 (Cys-181; 5 of 15 clones). The same amino acid changes were found in RT from E-EPU-resistant virus, but the Cys-181 mutation was more common (9 of 10 clones) than the Cys-188 mutation (1 of 10 clones). Site-specific mutagenesis and production of mutant recombinant viruses demonstrated that both the Cys-181 and Cys-188 mutations cause resistance to E-EPSeU and E-EPU. Of the two mutations, the Cys-188 substitution produced greater E-EPSeU and E-EPU resistance. The predominance of the Cys-188 mutation in E-EPSeU-resistant variants has not been noted for other classes of HIV-1 specific RT inhibitors. HIV-1 resistance is likely to limit the therapeutic efficacy of acyclic 6-substituted pyrimidines if they are used as monotherapy.
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PMID:Resistance of human immunodeficiency virus type 1 to acyclic 6-phenylselenenyl- and 6-phenylthiopyrimidines. 784 May 79

Sequence analysis of integrated proviruses of human immunodeficiency virus type 1 (HIV-1) which utilize tRNA(His) to initiate reverse transcription [virus derived from pHXB2(His-AC-TGT)] revealed five additional nucleotide substitutions in the U5 and primer binding site (PBS) regions (ATGAC for CCTGT at nucleotides 152, 160, 174, 181, and 200, respectively) (Z. Zhang et al., Virology 226:306-317, 1996). We constructed a mutant proviral genome [pHXB2(His-AC-GAC)] which contained the ATGAC substitutions to test if they represented a necessary adaptation by the virus for use of tRNA(His) to initiate reverse transcription. Viruses from pHXB2(His-AC-TGT) and pHXB2(His-AC-GAC) were infectious. Sequence analysis of the U5 and PBS regions of integrated provirus from a cell culture infected with virus derived from pHXB2(His-AC-TGT) revealed a G-to-A change in CCTGT at nucleotide 181 after limited in vitro culture, suggesting that this nucleotide change represented an adaptation by the virus to efficiently utilize tRNA(His) to initiate reverse transcription. To further address this possibility, we used a specific mutation in reverse transcriptase (RT), a methionine-to-valine change in the highly conserved YMDD amino acid motif of HIV-1 RT (M184V), which has been shown in previous studies to influence the fidelity and activity of the enzyme. The M184V RT mutation was cloned into pHXB2(His-AC-GAC) and pHXB2(His-AC-TGT). Virus derived from pHXB2(His-AC-GAC) with M184V RT had slightly delayed replication compared to the virus from pHXB2(His-AC-GAC) with wild-type RT; in contrast, virus from pHXB2(His-AC-TGT) with M184V RT was severely compromised in replication. Using an endogenous reverse transcription-PCR assay to analyze the reverse transcription of viruses obtained after transfection, we found that viruses derived from pHXB2(His-AC-GAC) with the wildtype RT were slightly faster in the initiation of reverse transcription than viruses with M184V RT. The initiation of reverse transcription was delayed in viruses derived from pHXB2(His-AC-TGT) with wild-type RT and M184V RT compared to viruses derived from pHXB2(His-AC-GAC). Finally, sequence analysis of U5 and PBS regions of proviruses from pHXB2(His-AC-GAC) with wild-type RT revealed considerably more nucleotide substitutions than in viruses derived from pHXB2(His-AC-GAC) containing the M184V mutation in RT after extended in vitro culture. Our studies point to a role for these additional nucleotide substitutions in U5 as an adaptation by the virus to utilize an alternative tRNA to initiate reverse transcription.
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PMID:Nucleotide substitutions within U5 are critical for efficient reverse transcription of human immunodeficiency virus type 1 with a primer binding site complementary to tRNA(His). 926 48

Nevirapine (single dose), commonly used to prevent the mother-to-child transmission of human immunodeficiency virus (HIV) in developing countries, frequently induces viral resistance. Even mutations which occur only in a minor population of the HIV quasispecies (<20%) are associated with subsequent treatment failure but cannot be detected by population-based sequencing. We developed sensitive allele-specific real-time PCR (ASPCR) assays for two key resistance mutations of nevirapine. The assays were specifically designed to analyze HIV-1 subtype A and D isolates accounting for the majority of HIV infections in Uganda. Assays were evaluated using DNA standards and clinical samples of Ugandan women having preventively taken single-dose nevirapine. Lower detection limits of drug-resistant HIV type 1 (HIV-1) variants carrying reverse transcriptase mutations were 0.019% (K103N [AAC]), 0.013% (K103N [AAT]), and 0.29% (Y181C [TGT]), respectively. Accuracy and precision were high, with coefficients of variation (the standard ratio divided by the mean) of 0.02 to 0.15 for intra-assay variability and those of 0.07 to 0.15 (K103N) and 0.28 to 0.52 (Y181C) for inter-assay variability. ASPCR assays enabled the additional identification of 12 (20%) minor drug-resistant HIV variants in the 20 clinical Ugandan samples (3 mutation analyses per patient; 60 analyses in total) which were not detectable by population-based sequencing. The individual patient cutoff derived from the clinical baseline sample was more appropriate than the standard-based cutoff from cloned DNA. The latter is a suitable alternative since the presence/absence of drug-resistant HIV-1 strains was concordantly identified in 92% (55/60) of the analyses. These assays are useful to monitor the emergence and persistence of drug-resistant HIV-1 variants in subjects infected with HIV-1 subtypes A and D.
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PMID:Detection and quantification of minor human immunodeficiency virus type 1 variants harboring K103N and Y181C resistance mutations in subtype A and D isolates by allele-specific real-time PCR. 1943 56