Journal Article

Effect on HIV-1 viral replication capacity of DTG-resistance mutations in NRTI/NNRTI resistant viruses

Pham, Hanh T., Wainberg, Mark A., Mesplède, Thibault

2016

Overview

Background Recommended regimens for HIV-positive individuals include the co-administration of dolutegravir (DTG) with two reverse transcriptase inhibitors (RTIs). Although rare, emerging resistance against DTG is often associated with the R263K substitution in integrase. In-vitro-selected R263K was associated with impaired viral replication capacity, DNA integration, and integrase strand-transfer activity, especially when accompanied by the secondary mutation H51Y. Given the reduced fitness of RTI-resistant viruses, we investigated potential impacts on viral replication of combining R263K and H51Y/R263K with major RTI-resistance substitutions including K65R, L74V, K103N, E138K, and M184I/V. Results We combined the R263K or H51Y/R263K with RTI-resistance mutations into the proviral plasmid pNL4.3 and measured the resulting viral infectiousness, replication capacity, and ability to integrate viral DNA into host cells. Infectiousness was determined by luciferase assay in TZM-bl cells. Replicative capacity was monitored over 7 days and viral DNA integration was studied by real-time Alu -qPCR in PM1 cells. We found that viral infectiousness, replication capacities and integration levels were greatly reduced in triple mutants, i.e. H51Y/R263K plus a RT mutation, and moderately reduced in double mutants, i.e. R263K plus a RT mutation, compared to wild-type and single RT-mutant viruses. Conclusions Our findings help to explain the absence of RTI mutations in individuals who experienced DTG-treatment failure.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V
• Subject: Amino Acid Substitution / Antibodies / Antiviral agents / Biomedical and Life Sciences / Biomedicine / Cancer Research / Care and treatment / Cell Line / Complications and side effects / Drug Resistance, Viral - genetics / Genetic aspects / Genotype / Health aspects / Heterocyclic Compounds, 3-Ring - pharmacology / HIV infection / HIV Integrase - genetics / HIV Integrase Inhibitors - pharmacology / HIV Reverse Transcriptase - genetics / HIV-1 - drug effects / HIV-1 - genetics / HIV-1 - physiology / Humans / Infectious Diseases / Mutation / Mutation, Missense / Protein Structure / Proviruses - genetics / Reverse Transcriptase Inhibitors - pharmacology / Vaccine / Virology / Virus Integration - genetics / Virus Replication - drug effects