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

Important note: Information in this article was accurate in 1999. The state of the art may have changed since the publication date.

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

AIDS. 1999 Jan 14;13(1):75-80. Unique Identifier : AIDSLINE MED/99223954
de Jong JJ; Goudsmit J; Lukashov VV; Hillebrand ME; Baan E; Huismans R; Danner SA; ten Veen JH; de Wolf F; Jurriaans S; Department of Human Retrovirology, Academic Medical Centre,; University of Amsterdam, The Netherlands.

Abstract: OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Keywords: JOURNAL ARTICLE Adult Amino Acids Anti-HIV Agents/*THERAPEUTIC USE Case Report Dideoxynucleosides/*THERAPEUTIC USE Drug Resistance, Microbial Genotype Human HIV Infections/DRUG THERAPY/*VIROLOGY HIV-1/DRUG EFFECTS/*ENZYMOLOGY/GENETICS HIV-1 Reverse Transcriptase/DRUG EFFECTS/*GENETICS Male Middle Age Mutagenesis, Insertional Nevirapine/*THERAPEUTIC USE Phenotype Reverse Transcriptase Inhibitors/*THERAPEUTIC USE Tyrosine/*GENETICS
990930
A9991339

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