TY  - JOUR
A1  - Schneider, Anna
A1  - Corona, Angela
A1  - Spöring, Imke
A1  - Jordan, Mareike
A1  - Buchholz, Bernd
A1  - Maccioni, Elias
A1  - Di Santo, Roberto
A1  - Bodem, Jochen
A1  - Tramontano, Enzo
A1  - Wöhrl, Birgitta M.
T1  - Biochemical characterization of a multi-drug resistant HIV-1 subtype AG reverse transcriptase: antagonism of AZT discrimination and excision pathways and sensitivity to RNase H inhibitors
JF  - Nucleic Acids Research
N2  - We analyzed a multi-drug resistant (MR) HIV-1 reverse transcriptase (RT), subcloned from a patient-derived subtype CRF02_AG, harboring 45 amino acid exchanges, amongst them four thymidine analog mutations (TAMs) relevant for high-level AZT (azidothymidine) resistance by AZTMP excision (M41L, D67N, T215Y, K219E) as well as four substitutions of the AZTTP discrimination pathway (A62V, V75I, F116Y and Q151M). In addition, K65R, known to antagonize AZTMP excision in HIV-1 subtype B was present. Although MR-RT harbored the most significant amino acid exchanges T215Y and Q151M of each pathway, it exclusively used AZTTP discrimination, indicating that the two mechanisms are mutually exclusive and that the Q151M pathway is obviously preferred since it confers resistance to most nucleoside inhibitors. A derivative was created, additionally harboring the TAM K70R and the reversions M151Q as well as R65K since K65R antagonizes excision. MR-R65K-K70R-M151Q was competent of AZTMP excision, whereas other combinations thereof with only one or two exchanges still promoted discrimination. To tackle the multi-drug resistance problem, we tested if the MR-RTs could still be inhibited by RNase H inhibitors. All MR-RTs exhibited similar sensitivity toward RNase H inhibitors belonging to different inhibitor classes, indicating the importance of developing RNase H inhibitors further as anti-HIV drugs.
KW  - ribonuclease H
KW  - HIV-1 subtype AG
KW  - azidothymidine
KW  - reverse transcriptase
KW  - multi-drug resistance
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166423
VL  - 44
IS  - 5
ER  - 
TY  - JOUR
A1  - Flügel, Rolf M.
A1  - Rethwilm, Axel
A1  - Maurer, Bernd
A1  - Darai, Gholamreza
T1  - Nucleotide sequence analysis of the env gene and its flanking regions of the human spumaretrovirus reveals two novel genes
N2  - Recombinant clonesthat represent the 3' part ofthe genome of the human spumaretrovirus (foamy virus) were established from viral DNA and from DNA complementary to viral RNA. The recombinant clones were characterized by blot hybridizations and nucleotide sequence analysis. The deduced protein sequence of the clones at their 5' ends was found to be homologous to the 3' domain of retroviral reverse transcriptases. Downstream of a small intergerne pol-env region a long open reading frame of 985 amino acid residues was identified that according to its genomic location, size, glycosylation signals, and hydrophobicity protile closely resembles the lentiviral env genes. The spumaretroviral env gene is followed by two open reading frames, termed bel-l and bel-2 which are located between env and the long terminal repeat region. The long terminal repeat of 1259 nucleotides is preceded by a polypurine tract and contains the canonical signal sequences characteristic for transcriptional regulation of retroviruses. The provisional classitication of the spumaretrovirus subfamily is discussed.
KW  - Virologie
KW  - foamy retrovirus
KW  - DNA sequence
KW  - reverse transcriptase
KW  - transmembrane protein
Y1  - 1987
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-61509
ER  -