Connection subdomain mutations in HIV-1 subtype-C treatment-experienced patients enhance NRTI and NNRTI drug resistance.
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.
Viral Mutation Section, HIV Drug Resistance Program, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA. frankenk@mail.nih.gov
Krista A
KA
Delviks-Frankenberry
Renan B
RB
Lengruber
Andre F
AF
Santos
Jussara M
JM
Silveira
Marcelo A
MA
Soares
Mary F
MF
Kearney
Frank
F
Maldarelli
Vinay K
VK
Pathak
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001938:Brazil; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D054303:HIV Reverse Transcriptase / Q000737:chemistry* / Q000235:genetics*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D009570:Nitriles; D017434:Protein Structure, Tertiary / Q000235:genetics; D011724:Pyridazines / Q000494:pharmacology; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors / Q000494:pharmacology*; D015215:Zidovudine / Q000494:pharmacology
D019380:Anti-HIV Agents; D009570:Nitriles; D011724:Pyridazines; D011743:Pyrimidines; D018894:Reverse Transcriptase Inhibitors; C451734:etravirine; D015215:Zidovudine; C514824:reverse transcriptase, Human immunodeficiency virus 1; D054303:HIV Reverse Transcriptase