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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. J. Med. Virol. 80:754–761, 2008. © 2008 Wiley‐Liss, Inc.