Baseline Susceptibility of Primary HIV-2 to Entry Inhibitors

• Autor(a) principal: Borrego, P
• Data de Publicação: 2012
• Outros Autores: Calado, R, Marcelino, JM, Bártolo, I, Rocha, C, Cavaco-Silva, P, Doroana, M, Antunes, F, Maltez, F, Caixas, U, Barroso, H, Taveira, N
• Tipo de documento: Artigo
• Idioma: eng
• Título da fonte: Repositório Científico de Acesso Aberto de Portugal (Repositórios Cientìficos)
• Texto Completo: http://hdl.handle.net/10400.17/2417
• topic: HSJ MED; HCC INF; Amides/pharmacology; Amides/therapeutic use; Anti-HIV Agents/pharmacology; Anti-HIV Agents/therapeutic use; CCR5 Receptor Antagonists; Cyclohexanes/pharmacology; Cyclohexanes/therapeutic use; HIV Envelope Protein gp41/pharmacology; HIV Envelope Protein gp41/therapeutic use; HIV Fusion Inhibitors/pharmacology; HIV Fusion Inhibitors/therapeutic use; HIV Infections/drug therapy; HIV Infections/virology; HIV-1/drug effects; HIV-2/drug effects; Inhibitory Concentration 50; Microbial Sensitivity Tests; Peptide Fragments/pharmacology; Peptide Fragments/therapeutic use; Quaternary Ammonium Compounds/pharmacology; Quaternary Ammonium Compounds/therapeutic use; Triazoles/pharmacology; Triazoles/therapeutic use

BACKGROUND: The baseline susceptibility of primary HIV-2 to maraviroc (MVC) and other entry inhibitors is currently unknown. METHODS: The susceptibility of 19 HIV-2 isolates obtained from asymptomatic and AIDS patients and seven HIV-1 clinical isolates to the fusion inhibitors enfuvirtide (ENF) and T-1249, and to the coreceptor antagonists AMD3100, TAK-779 and MVC, was measured using a TZM-bl cell-based assay. The 50% inhibitory concentration (IC(50)), 90% inhibitory concentration (IC(90)) and dose-response curve slopes were determined for each drug. RESULTS: ENF and T-1249 were significantly less active on HIV-2 than on HIV-1 (211- and 2-fold, respectively). AMD3100 and TAK-779 inhibited HIV-2 and HIV-1 CXCR4 tropic (X4) and CCR5 tropic (R5) variants with similar IC(50) and IC(90) values. MVC, however, inhibited the replication of R5 HIV-2 variants with significantly higher IC(90) values (42.7 versus 9.7 nM; P<0.0001) and lower slope values (0.7 versus 1.3; P<0.0001) than HIV-1. HIV-2 R5 variants derived from AIDS patients were significantly less sensitive to MVC than variants from asymptomatic patients, this being inversely correlated with the absolute number of CD4(+) T-cells. CONCLUSIONS: T-1249 is a potent inhibitor of HIV-2 replication indicating that new fusion inhibitors might be useful to treat HIV-2 infection. Coreceptor antagonists TAK-779 and AMD3100 are also potent inhibitors of HIV-2 replication. The reduced sensitivity of R5 variants to MVC, especially in severely immunodeficient patients, indicates that the treatment of HIV-2-infected patients with MVC might require higher dosages than those used in HIV-1 patients, and should be adjusted to the disease stage.