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. CONCLUSION: 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.
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-infectedpatients 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. CONCLUSION: 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.
Authors: Masanori Kobayashi; Tomokazu Yoshinaga; Takahiro Seki; Chiaki Wakasa-Morimoto; Kevin W Brown; Robert Ferris; Scott A Foster; Richard J Hazen; Shigeru Miki; Akemi Suyama-Kagitani; Shinobu Kawauchi-Miki; Teruhiko Taishi; Takashi Kawasuji; Brian A Johns; Mark R Underwood; Edward P Garvey; Akihiko Sato; Tamio Fujiwara Journal: Antimicrob Agents Chemother Date: 2010-11-29 Impact factor: 5.191
Authors: Alonso Heredia; Said Hassounah; Sandra Medina-Moreno; Juan C Zapata; Nhut M Le; Yingshan Han; James S Foulke; Charles Davis; Joseph Bryant; Robert R Redfield; Mark A Wainberg Journal: J Antimicrob Chemother Date: 2017-09-01 Impact factor: 5.790
Authors: Manuel Tsiang; Gregg S Jones; Anita Niedziela-Majka; Elaine Kan; Eric B Lansdon; Wayne Huang; Magdeleine Hung; Dharmaraj Samuel; Nikolai Novikov; Yili Xu; Michael Mitchell; Hongyan Guo; Kerim Babaoglu; Xiaohong Liu; Romas Geleziunas; Roman Sakowicz Journal: J Biol Chem Date: 2012-04-25 Impact factor: 5.157
Authors: Saleta Sierra; Nadine Lübke; Hauke Walter; Eugen Schülter; Stefan Reuter; Gerd Fätkenheuer; Markus Bickel; Hugo da Silva; Rolf Kaiser; Stefan Esser Journal: Med Microbiol Immunol Date: 2011-04-08 Impact factor: 3.402