Natural polymorphism of the HIV-1 integrase gene and mutations associated with integrase inhibitor resistance.
BACKGROUND
Two inhibitors of the HIV-1 integrase enzyme (INIs) are in late stage clinical development. To date, approximately 42 mutations within the HIV-1 integrase (IN) gene have been associated with INI drug resistance. Naturally occurring IN gene polymorphisms may have important implications for INI development. In this study, we evaluated clinical HIV-1 strains from INI-naive patients to determine the prevalence of IN gene polymorphisms, and the frequency of naturally occurring amino acid (aa) substitutions at positions associated with INI resistance and at sites crucial for LEDGF/p75 binding and HIV-1 integration.


METHODS
The IN gene from 67 INI-naive, HIV-1 clade B-infected patients were sequenced using standard population-based DNA sequencing methods. In addition, 176 unique full-length HIV-1 clade B IN gene sequences from INI-naive patients obtained from the HIV Los Alamos database were analysed.


RESULTS
Analysis of 243 IN genes from HIV-1 clade B, INI-naive clinical strains revealed that 64% of the aa positions were polymorphic. Of the 42 aa substitutions currently associated with INI resistance, 21 occurred as natural polymorphisms: V72I, L74I, T97A, T112I, A128T, E138K, Q148H, V151I, S153Y/A, M154I, N155H, K156N, E157Q, G163R, V165I, V201I, I203M, T206S, S230N and R263K. IN aa positions crucial to LEDGF/P75 binding and HIV-1 integration were well conserved.


CONCLUSIONS
Major INI mutations within the catalytic domain and extended active sites associated with high level resistance to the compounds in late stage development, especially strand transfer inhibitors (STIs), were infrequent in our study, which may help explain the excellent virological responses demonstrated in clinical trials.
Lataillade
Max
M
Yale University School of Medicine, New Haven, CT, USA. Max.Lataillade@yale.edu
Chiarella
Jennifer
J
Kozal
Michael J
MJ
D000595:Amino Acid Sequence; D016384:Consensus Sequence; D024882:Drug Resistance, Viral / Q000235:genetics*; D015658:HIV Infections / Q000821:virology; D019427:HIV Integrase / Q000737:chemistry / Q000187:drug effects / Q000235:genetics*; D019428:HIV Integrase Inhibitors / Q000494:pharmacology*; D015497:HIV-1 / Q000145:classification / Q000187:drug effects* / Q000201:enzymology / Q000235:genetics; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D011110:Polymorphism, Genetic; D012367:RNA, Viral / Q000097:blood / Q000235:genetics; D017422:Sequence Analysis, DNA
D019428:HIV Integrase Inhibitors; D012367:RNA, Viral; D019427:HIV Integrase