Baseline susceptibility of primary HIV-2 to entry inhibitors.

Abstract

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.

• Authors: Pedro Borrego, Rita Calado, José M Marcelino, Inês Bártolo, Cheila Rocha, Patrícia Cavaco-Silva, Manuela Doroana, Francisco Antunes, Fernando Maltez, Umbelina Caixas, Helena Barroso, Nuno Taveira
• Journal: Antiviral therapy (Antivir Ther) Vol. 17 Issue 3 Pg. 565-70 ( 2012) ISSN: 2040-2058 [Electronic] England
• PMID: 22293827 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Amides
• Anti-HIV Agents
• CCR5 Receptor Antagonists
• Cyclohexanes
• HIV Envelope Protein gp41
• HIV Fusion Inhibitors
• Peptide Fragments
• Quaternary Ammonium Compounds
• Triazoles
• peptide T1249
• Enfuvirtide
• TAK 779
• Maraviroc

Topics

• Amides (pharmacology, therapeutic use)
• Anti-HIV Agents (pharmacology, therapeutic use)
• CCR5 Receptor Antagonists
• Cyclohexanes (pharmacology, therapeutic use)
• Enfuvirtide
• Female
• HIV Envelope Protein gp41 (pharmacology, therapeutic use)
• HIV Fusion Inhibitors (pharmacology, therapeutic use)
• HIV Infections (drug therapy, virology)
• HIV-1 (drug effects)
• HIV-2 (drug effects)
• Humans
• Inhibitory Concentration 50
• Male
• Maraviroc
• Microbial Sensitivity Tests
• Peptide Fragments (pharmacology, therapeutic use)
• Quaternary Ammonium Compounds (pharmacology, therapeutic use)
• Triazoles (pharmacology, therapeutic use)