Structural effects of amino acid variations between B and CRF02-AG HIV-1 integrases.
HIV-1 integrase is one of the three essential enzyme required for viral replication and has a great potential as a novel target for anti-HIV drugs. The sequence variability of the entire integrase (IN) was examined in HIV-1 subtype B and CRF02-AG antiretroviral naïve infected patients for the presence of naturally occurring polymorphisms IN gene sequences and protein structures from both subtypes were compared. The phylogenetic analysis showed a total concordance between the 3 pol gene sequences for patients identified as subtype B whereas 3% of patients identified as CRF02-AG showed a mixture of subtypes. The analysis of IN aa sequences showed that 13 positions (K/R14, V/I31, L/I101, T/V112, T/A124, T/A125, G/N134, I/V135, K/T136, V/I201, T/S206, L/I234, and S/G283) differed between subtypes B and CRF02-AG. As observed in the 3D model of the preintegration complex, these differences may impact the functional property of IN. The fact that most variations were grouped suggests that some of them are linked together through compensatory mechanisms. This comparison allowed us to identify several variations of amino acids in HIV-1 IN subtype CRF02-AG that could have a putative impact on anti-integrase sensitivity. In particular, the region formed by Thr125, Thr124, Val31 contains at least one residue, T125, which variation has been involved in eliciting resistance to the naphtyridine carboxamide L870,810 IN inhibitor. In conclusion, virological response to anti-integrase should be studied carefully, according to the subtype, in clinical trials.
Malet
Isabelle
I
UPMC Université Paris 06, Paris, France. isabelle.malet@psl.aphp.fr
Soulie
Cathia
C
Tchertanov
Luba
L
Derache
Anne
A
Amellal
Bahia
B
Traore
Ousmane
O
Simon
Anne
A
Katlama
Christine
C
Mouscadet
Jean-François
JF
Calvez
Vincent
V
Marcelin
Anne-Geneviève
AG
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics*; D024882:Drug Resistance, Viral; D015658:HIV Infections / Q000821:virology*; D019427:HIV Integrase / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary; D012367:RNA, Viral / Q000235:genetics; D016415:Sequence Alignment; D017422:Sequence Analysis, DNA; D014481:United States
D012367:RNA, Viral; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1