Baseline susceptibility of primary HIV-2 to entry inhibitors

• Published in: Antiviral therapy Vol. 17; no. 3; pp. 565 - 570
• Main Authors: BORREGO, Pedro, CALADO, Rita, BARROSO, Helena, FAVEIRA, Nuno, M MARCELINO, José, BARTOLO, Inês, ROCHA, Cheila, CAVACO-SILVA, Patrícia, DOROANA, Manuela, ANTUNES, Francisco, MALTEZ, Fernando, CAIXAS, Umbelina
• Format: Journal Article
• Language: English
• Published: London International Medical Press 01.01.2012
• Subjects: Amides - pharmacology; Amides - therapeutic use; Anti-HIV Agents - pharmacology; Anti-HIV Agents - therapeutic use; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Biological and medical sciences; CCR5 Receptor Antagonists; Cyclohexanes - pharmacology; Cyclohexanes - therapeutic use; Female; 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; Human viral diseases; Humans; Immunodeficiencies; Immunodeficiencies. Immunoglobulinopathies; Immunopathology; Infectious diseases; Inhibitory Concentration 50; Male; Medical sciences; Microbial Sensitivity Tests; Peptide Fragments - pharmacology; Peptide Fragments - therapeutic use; Pharmacology. Drug treatments; Quaternary Ammonium Compounds - pharmacology; Quaternary Ammonium Compounds - therapeutic use; Triazoles - pharmacology; Triazoles - therapeutic use; Viral diseases; Viral diseases of the lymphoid tissue and the blood. Aids; Infection; Virus; Immunopathology; Sensitivity; Entry inhibitor; Viral disease; Retroviridae; AIDS; Human immunodeficiency virus; Immune deficiency; Lentivirus; HIV-2 virus
• ISSN: 1359-6535; 2040-2058
• DOI: 10.3851/IMP1996

The baseline susceptibility of primary HIV-2 to maraviroc (MVC) and other entry inhibitors is currently unknown. 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. 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. 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.