HIV-2 integrase gene polymorphism and phenotypic susceptibility of HIV-2 clinical isolates to the integrase inhibitors raltegravir and elvitegravir in vitro

• Published in: Journal of antimicrobial chemotherapy Vol. 62; no. 5; pp. 914 - 920
• Main Authors: Roquebert, B., Damond, F., Collin, G., Matheron, S., Peytavin, G., Bénard, A., Campa, P., Chêne, G., Brun-Vézinet, F., Descamps, D.
• Format: Journal Article
• Language: English
• Published: Oxford Oxford University Press 01.11.2008; Oxford Publishing Limited (England)
• Subjects: Amino Acid Sequence; Amino Acid Substitution - genetics; Antibiotics. Antiinfectious agents. Antiparasitic agents; Biological and medical sciences; Catalytic Domain; Codon, Nonsense; Cohort Studies; Conserved Sequence; Drug resistance; Drug Resistance, Viral; France; Genotype & phenotype; HIV; HIV Infections - virology; HIV Integrase - genetics; HIV-1 - drug effects; HIV-2 - drug effects; HIV-2 - isolation & purification; HIV/AIDS; Human immunodeficiency virus; Human immunodeficiency virus 1; Human immunodeficiency virus 2; human immunodeficiency virus type 2; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Inhibitor drugs; Inhibitory Concentration 50; Integrase Inhibitors - pharmacology; Medical sciences; Microbial Sensitivity Tests; Molecular Sequence Data; Mutation, Missense; mutations; Pharmacology. Drug treatments; Polymorphism; Polymorphism, Genetic; Pyrrolidinones - pharmacology; Quinolones - pharmacology; Raltegravir Potassium; resistance; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; France; HIV/AIDS; human immunodeficiency virus type 2; mutations; resistance; Antiretroviral agent; Genetic variability; Integrase inhibitor; Antiviral; Genetics; Clinical isolate; Human; Immunopathology; Retroviridae; Elvitegravir; Genotype; AIDS; Immune deficiency; Lentivirus; In vitro; HIV-2 virus; Infection; Virus; Resistance; Phenotype; Sensitivity; Viral disease; Human immunodeficiency virus; Mutation; Raltegravir
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkn335

Objectives We investigated the in vitro phenotypic susceptibility of HIV-2 isolates from integrase inhibitor (INI)-naive patients to INIs and its relation to HIV-2 integrase gene polymorphism. Methods We determined the phenotypic susceptibility to raltegravir and elvitegravir of co-cultured isolates obtained from the HIV-2 ROD reference strain and from 14 clinical isolates. IC50 values were compared with those for HIV-1 reference strains. HIV-2 integrase gene polymorphism was assessed in isolates from 52 INI-naive patients enrolled in the French HIV-2 cohort. Results Median raltegravir and elvitegravir IC50 values for the 14 clinical HIV-2 isolates were 2.4 and 0.7 nM, respectively, and were similar to those observed for HIV-2 ROD and HIV-1 reference strains. Overall, 38% of HIV-2 integrase amino acids were polymorphic. The catalytic triad DDE and the HHCC and RKK motifs were fully conserved, at the same genomic positions as described in HIV-1. In subtype B isolates, the total length of the integrase gene varied, owing to the presence of stop codons at positions 288, 294, 297 and 302. Fourteen of the positions associated with substitutions conferring INI resistance in HIV-1 were polymorphic in HIV-2. Conclusions Despite 40% heterogeneity between the HIV-1 and HIV-2 integrase genes, the phenotypic susceptibility of clinical HIV-2 isolates to INIs was similar to that of HIV-1. This new class of antiretroviral drugs thus represents a novel therapeutic possibility for HIV-2-infected patients who otherwise have few treatment options.