Subtype diversity associated with the development of HIV-1 resistance to integrase inhibitors

• Published in: Journal of medical virology 2011-05, Vol.83 (5), p.751-759
• Main Authors: Brenner, Bluma G., Lowe, Matthew, Moisi, Daniela, Hardy, Isabelle, Gagnon, Simon, Charest, Hugues, Baril, Jean Guy, Wainberg, Mark A., Roger, Michel
• Format: Article
• Language: English
• Subjects: Amino Acid Substitution - genetics; Biological and medical sciences; Cluster Analysis; drug resistance; Drug Resistance, Viral; Evolution, Molecular; Fundamental and applied biological sciences. Psychology; Genetic Variation; genotyping and phylogenetics; HIV Infections - virology; HIV Integrase - genetics; HIV Integrase Inhibitors - pharmacology; HIV subtypes; HIV-1; HIV-1 - classification; HIV-1 - drug effects; HIV-1 - genetics; HIV-1 - isolation & purification; Human immunodeficiency virus 1; Human viral diseases; Humans; Infectious diseases; integrase; Male; Medical sciences; Microbiology; Miscellaneous; Molecular Sequence Data; Phylogeny; pol Gene Products, Human Immunodeficiency Virus - genetics; Recombination, Genetic; Sequence Analysis, DNA; Viral diseases; Virology
• ISSN: 0146-6615; 1096-9071
• DOI: 10.1002/jmv.22047

We used genotypic and phylogenetic analysis to determine integrase diversity among subtypes, and studied natural polymorphisms and mutations implicated in resistance to integrase inhibitors (INI) in treatment‐naïve persons (n = 220) and ‐experienced individuals (n = 24). Phylogenetics revealed 7 and 10% inter‐subtype diversity in the integrase and reverse transcriptase (RT)/protease regions, respectively. Integrase sequencing identified a novel A/B recombinant in which all viruses in a male‐sex‐male (MSM) transmission cluster (n = 12) appeared to possess subtype B in integrase and subtype A in the remainder of the pol region. Natural variations and signature polymorphisms were observed at codon positions 140, 148, 151, 157, and 160 among HIV subtypes. These variations predicted higher genetic barriers to G140S and G140C in subtypes C, CRF02_AG, and A/CRF01_AE, as well as higher genetic barriers toward acquisition of V151I in subtypes CRF02_AG and A/CRF01_AE. The E157Q and E160Q mutational motif was observed in 35% of INI‐naïve patients harboring subtype C infections, indicating intra‐subtype variations. Thirteen patients failed raltegravir (RAL)‐containing regimens within 8 ± 1 months, in association with the major Q148K/R/H and G140A/S (n = 8/24) or N155H (n = 5/24) mutational pathways. Of note, the remaining patients on RAL regimens for 14 ± 3 months harbored no or only minor integrase mutations/polymorphisms (T66I, T97A, H114P, S119P, A124S, G163R, I203M, R263K). These results demonstrate the importance of understanding subtype variability in the development of resistance to INIs. J. Med. Virol. 83:751–759, 2011. © 2011 Wiley‐Liss, Inc.