E17A mutation in HIV-1 Vpr confers resistance to didanosine in association with thymidine analog mutations

• Published in: Antiviral research 2012-01, Vol.93 (1), p.167-174
• Main Authors: Fourati, Slim, Malet, Isabelle, Guenzel, Carolin A., Soulie, Cathia, Maidou-Peindara, Priscilla, Morand-Joubert, Laurence, Wirden, Marc, Sayon, Sophie, Peytavin, Gilles, Simon, Anne, Katlama, Christine, Benichou, Serge, Calvez, Vincent, Marcelin, Anne-Geneviève
• Format: Article
• Language: English
• Subjects: Adult; Aged; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; Didanosine; Didanosine - pharmacology; Didanosine - therapeutic use; Drug resistance; Drug Resistance, Viral - genetics; Female; Genes, vpr; HEK293 Cells; HeLa Cells; HIV Infections - drug therapy; HIV Infections - virology; HIV-1; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus 1; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Male; Medical sciences; Microbial Sensitivity Tests; Middle Aged; Molecular Sequence Data; Mutation; Pharmacology. Drug treatments; Polymorphism, Genetic; Protein Transport; Thymidine - analogs & derivatives; Thymidine - genetics; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Virus Replication - genetics; Vpr; vpr Gene Products, Human Immunodeficiency Virus - genetics
• ISSN: 0166-3542; 1872-9096
• DOI: 10.1016/j.antiviral.2011.11.008

► Vpr E17A frequent in antiretroviral experienced patients failing HAART. ► Vpr E17A associated with TAMs and the use of didanosine in patients treatment histories. ► Decrease in didanosine susceptibility of HIV-1 harboring Vpr E17A with TAMs in phenotypic assays. HIV-1 accessory Vpr protein is involved in the reverse transcription process and has been shown to modulate the virus mutation rate. This process may play a role in the kinetics of appearance of drug resistance mutations under antiretroviral treatment. Vpr sequences were analyzed from plasma viruses derived from 97 HIV-1-infected individuals failing antiretroviral treatment and 63 antiretroviral-naïve patients. Vpr genetic variability was analyzed for association with specific drug treatment and drug resistance mutations. Biological and virological experiments were employed to characterize a mutation in Vpr found to be associated with virological failure. E17A mutation located in the first α-helix of Vpr was more prevalent in HAART-treated individuals compared to untreated individuals. E17A was associated with thymidine analog mutations (TAMs) in reverse transcriptase M41L, L210W and T215Y and with the use of didanosine in the patients’ treatment histories. E17A had no impact on the biochemical and functional properties of Vpr, and did not affect kinetics of replication of wild-type or TAMs-containing viruses. However, its association with TAMs and the use of didanosine was consistent with phenotypic susceptibility assays showing a significant 3-fold decrease in didanosine susceptibility of viruses harboring Vpr E17A combined with TAMs compared to viruses harboring TAMs alone. These findings highlight a novel role of Vpr in HIV-1 drug resistance. Vpr E17A confers resistance to didanosine when associated with TAMs. Whether Vpr E17A facilitates excision of didanosine is still to be determined.