Connection subdomain mutations in HIV-1 subtype-C treatment-experienced patients enhance NRTI and NNRTI drug resistance

• Published in: Virology (New York, N.Y.) Vol. 435; no. 2; pp. 433 - 441
• Main Authors: Delviks-Frankenberry, Krista A, Lengruber, Renan B, Santos, Andre F, Silveira, Jussara M, Soares, Marcelo A, Kearney, Mary F, Maldarelli, Frank, Pathak, Vinay K
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.01.2013
• Subjects: Amino Acid Sequence; Anti-HIV Agents - pharmacology; Brazil; Cell Line; Connection domain; Drug resistance; Drug Resistance, Viral - genetics; Genomes; HIV Infections - drug therapy; HIV Infections - virology; HIV Reverse Transcriptase - chemistry; HIV Reverse Transcriptase - genetics; HIV-1 - drug effects; HIV-1 - genetics; Human immunodeficiency virus 1; Humans; Infectious Disease; Molecular Sequence Data; Mutation; Nitriles; NNRTI; NRTI; nucleosides; Polymerization; Protein Structure, Tertiary - genetics; Pyridazines - pharmacology; Pyrimidines; Reverse Transcriptase Inhibitors - pharmacology; Ribonuclease H; ribonuclease Rh; RNA-directed DNA polymerase; Subtype C; Thymidine; Zidovudine; Zidovudine - pharmacology; Brazil; Connection domain; NNRTI; Drug resistance; NRTI; Subtype C
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2012.09.021

Abstract Mutations in the connection subdomain (CN) and RNase H domain (RH) of HIV-1 reverse transcriptase (RT) from subtype B-infected patients enhance nucleoside and nonnucleoside RT inhibitor (NRTI and NNRTI) resistance by affecting the balance between polymerization and RNase H activity. To determine whether CN mutations in subtype C influence drug sensitivity, single genome sequencing was performed on Brazilian subtype C-infected patients failing RTI therapy. CN mutations identified were similar to subtype B, including A376S, A400T, Q334D, G335D, N348I, and A371V, and increased AZT resistance in the presence of thymidine analog mutations. CN mutations also enhanced NNRTI resistance in the presence of classical NNRTI mutations: etravirine resistance was enhanced 6- to 11-fold in the presence of L100I/K103N/Y181C. These results indicate that selection of CN mutations in treatment-experienced patients also occurs in subtype-C-infected patients and are likely to provide valuable information in predicting clinical RTI resistance.