Deep analysis of HIV-1 natural variability across HIV-1 variants at residues associated with integrase inhibitor (INI) resistance in INI-naive individuals.

OBJECTIVES: We evaluated variant-associated variability at positions related to resistance to the integrase (IN) inhibitors (INIs) raltegravir, elvitegravir and dolutegravir using HIV-1 IN sequences from naive individuals retrieved from GenBank. METHODS: We evaluated the frequency of major, secondary and rare amino acid changes associated with INI resistance (INI-R) in 6706 sequences from 3791 INI-naive individuals carrying a large panel of different HIV-1 variants retrieved from GenBank, including four groups: M (6663), O (24), N (15) and P (4). HIV-1 group M sequences included 4599 sequences from the nine group M subtypes and 2064 recombinants ascribed to 54 circulating recombinant forms (CRFs). RESULTS: Primary INI-R mutations were rare in INI-naive participants and only present at a low rate in subtypes B, C and D and recombinants CRF01_AE and CRF14_BG, ranging from one to five per variant. Three secondary INI-R changes appeared with variable frequency in INI-naive individuals carrying specific HIV-1 variants: L74M in CRF43_02G (33.3%); T97A in group P (50%), J (33.3%), CRF18_cpx (20%) and F2 (11.5%); and G163RK in CRF44_BF (100%), CRF46_BF (66.7%), CRF17_BF (28.6%), F1 (21.7%), CRF12_BF (16.7%) and CRF29_BF (12.5%). Rare mutations were absent. CONCLUSIONS: Natural variability in INI-R positions across HIV-1 variants should be studied as they may facilitate or delay the emergence of INI-R viruses.