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Subtype diversity associated with the development of HIV‐1 resistance to integrase inhibitors
Author(s) -
Brenner Bluma G.,
Lowe Matthew,
Moisi Daniela,
Hardy Isabelle,
Gag Simon,
Charest Hugues,
Baril Jean Guy,
Wainberg Mark A.,
Roger Michel
Publication year - 2011
Publication title -
journal of medical virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.782
H-Index - 121
eISSN - 1096-9071
pISSN - 0146-6615
DOI - 10.1002/jmv.22047
Subject(s) - integrase , raltegravir , virology , integrase inhibitor , biology , phylogenetic tree , genetics , genotype , reverse transcriptase , genetic diversity , lentivirus , virus , gene , human immunodeficiency virus (hiv) , polymerase chain reaction , viral disease , viral load , antiretroviral therapy , medicine , population , environmental health
Abstract 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.