Background:  Our aim was to determine in vitro phenotypic susceptibility to integrase inhibitors (INI) of HIV-2 clinical isolates collected from INI-naïve patients and polymorphism of the HIV-2 integrase (IN) gene.

Methods:  Phenotypic susceptibility to raltegravir (RAL) and elvitegravir (EVG) was determined using the ANRS method in co-cultivated isolates obtained from the ROD HIV-2 reference strain and from 15 of the 50 clinical isolates with available supernatants. IC₅₀ values of HIV-1 reference strain were also determined using the same method adapted for HIV-1 and compared to those obtained in HIV-2. Polymorphism of IN gene was assessed on 50 INI-naïve HIV-2 patients included in the French HIV-2 cohort. Q151M mutation was present in 2 isolates from NRTI-experienced patients. IN gene sequencing was performed on available plasma specimens stored at –80°C. HIV-2 IN sequences were compared with HIV-2 clade A and B consensus sequences.

Results:  Patients were infected with HIV-2 subtypes A (n = 29), B (n = 20), and H (n = 1). Median IC₅₀ values to RAL and EVG of the 15 HIV-2 isolates were 2.65 nM and 0.7 nM, respectively, and were similar to those observed for ROD and HIV-1 reference strains. The presence of the Q151M mutation in the RT gene in 2 isolates had no effect on susceptibility to both RAL and EVG. Overall, 36% of amino acids of HIV-2 IN were polymorphic. The polymorphism of the subtype A and B IN sequences were 28% and 30%, respectively. The catalytic triad DDE and the HHCC and RKK motifs were 100% conserved in HIV-2 at the same genomic positions as described in HIV-1. For all subtype B isolates the total length of the IN gene varied due to the presence of stop codons occurring at different positions on the IN sequence:  288, 294, 297, and 302. This finding was not observed for HIV-2 subtype A isolates. Among the substitutions associated with INI resistance in HIV-1:  14 positions were polymorphic in HIV-2. The presence of an isoleucine at positions 72, 165, or 201 and an alanine at position 97 associated with INI resistance in HIV-1, had no effect on HIV-2 phenotypic susceptibility to INI.

Conclusions:  Despite 40% of heterogeneity between HIV-1 and HIV-2 IN genes, phenotypic susceptibility to INI was similar to that observed for HIV-1. The Q151M MDR mutation did not alter phenotypic susceptibility of HIV-2 to INI. This new class of antiretroviraI drug represent a novel therapeutic option for HIV-2-infected patients in whom antiretroviral arsenal is limited.