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Unusual codon 69 insertions: influence on human immunodeficiency virus type 1 reverse transcriptase drug
Elisabetta Bulgheroni1, Francesco Croce, Paola Citterio
1Istituto di Malattie Infettive e Tropicali, Università degli Studi, Ospedale Luigi Sacco, Via GB Grassi 74, 20157 Milan, Italy.
Summary
Multiple amino acid insertions in HIV-1 reverse transcriptase confer resistance to nucleoside reverse transcriptase inhibitors (NRTIs). These mutations, particularly at codon 69, impact drug susceptibility, highlighting the need for ongoing genotypic surveillance.
Area of Science:
- Virology
- Molecular Biology
- Pharmacology
Background:
- Multiple amino acid substitutions in HIV-1 reverse transcriptase (RT) can lead to simultaneous resistance against most nucleoside RT inhibitors (NRTIs).
- Codon 69 insertions, including various 2-amino acid patterns, represent one pathway to NRTI resistance.
Purpose of the Study:
- To investigate the impact of specific insertions in HIV-1 RT on drug susceptibility.
- To analyze genotypic and phenotypic profiles of HIV-1 isolates from patients treated with antiretroviral drugs.
Main Methods:
- Genotypic analysis of the RT region through amplification, cloning, and sequencing.
- Phenotypic analysis of drug susceptibility using patient-derived peripheral blood mononuclear cells (PBMCs).
Main Results:
- Patients exhibited diverse mutational patterns but consistent multi-drug resistance to NRTIs, including Zidovudine (ZDV) and 3TC.
- All samples showed a T69S substitution with distinct dual amino acid insertions (SG, TG, VG), leading to resistance against 3TC, ZDV, and ABC.
- A novel 2-amino acid insertion (TG) was identified.
Conclusions:
- Mutation inserts in HIV-1 RT significantly impair NRTI efficacy, especially for ZDV and 3TC.
- The T69S insertion combined with specific amino acid patterns contributes to moderate resistance.
- Further investigation of novel RT genotypic insertions is crucial for understanding and managing drug resistance.