Insertion of two amino acids combined with changes in reverse transcriptase containing tyrosine-215 of HIV-1 resistant to multiple nucleoside analogs

• Published in: AIDS (London) Vol. 13; no. 1; pp. 75 - 80
• Main Authors: DE JONG, J. J, GOUDSMIT, J, LUKASHOV, V. V, HILLEBRAND, M. E, BAAN, E, HUISMANS, R, DANNER, S. A, TEN VEEN, J. H, DE WOLF, F, JURRIAANS, S
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 14-01-1999
• Subjects: Adult; Amino Acids; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Dideoxynucleosides - therapeutic use; Drug Resistance, Microbial; Genotype; HIV Infections - drug therapy; HIV Infections - virology; HIV Reverse Transcriptase - drug effects; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - enzymology; HIV-1 - genetics; Human viral diseases; Humans; Infectious diseases; Male; Medical sciences; Middle Aged; Mutagenesis, Insertional; Nevirapine - therapeutic use; Pharmacology. Drug treatments; Phenotype; Reverse Transcriptase Inhibitors - therapeutic use; Tyrosine - genetics; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; RNA-directed DNA polymerase; Drug susceptibility test; HIV-1 virus; Insertion; Mechanism; Multiple resistance; N terminal-Sequence; Antiviral; Pyrimidine nucleoside; Aminoacid sequence; Human; Immunopathology; Nucleoside analogue; Enzyme; Transferases; Retroviridae; Genotype; AIDS; Immune deficiency; Lentivirus; Infection; Virus; Resistance; Nucleotidyltransferases; Chemotherapy; Treatment; Viral disease; Aminoacid; Dideoxynucleoside; Human immunodeficiency virus; Zidovudine
• ISSN: 0269-9370; 1473-5571
• DOI: 10.1097/00002030-199901140-00010

To identify genotypic drug resistance patterns of HIV-1 in patients who were extensively pretreated with anti-HIV drugs and not responding to their current antiretroviral combination therapy.
Drug susceptibility of the viruses was tested by a phenotypic recombinant virus assay. Genotypic analysis of HIV resistance was performed by sequencing of the amino-terminal part of the corresponding reverse transcriptase (RT) gene (amino acids 1-280) for serum-derived and recombinant viruses.
Among viruses from 92 patients studied, three (3%) viruses contained a T215Y amino-acid change as well as a previously unseen combination of an amino-acid change at codon 67 (N-->E/S) and a two amino-acid insertion between codons 68 and 69 of the RT gene of HIV-1. Phenotypic resistance analysis showed high levels of resistance to zidovudine, lamivudine and stavudine (in all patients) and moderate levels of resistance to didanosine and zalcitabine (in two patients), whereas neither serum-derived nor recombinant viruses contained previously known amino-acid changes conferring resistance to didanosine, zalcitabine, lamivudine and stavudine. However, all recombinant viruses contained an insertion of two amino acids between codons 68 and 69 of RT as well as an amino-acid change at codon 67, as was seen in the serum-derived viruses.
Antiretroviral therapy including zidovudine may yield replicating viruses with a two amino-acid insertion in RT in combination with amino-acid changes at codons 67 and 215, which are highly resistant to lamivudine and stavudine on top of zidovudine and have unpredictable susceptibility to didanosine and zalcitabine despite lack of previously reported corresponding resistance-associated amino-acid changes. It is currently unknown what regimens can induce the emergence of this type of multidrug-resistant viruses. This will only be elucidated when resistance assays are capable of detecting these mutants.