title: 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.affiliation: URIA-CPM, Faculdade de Farmácia de Lisboa, Lisbon, Portugal.
authors.forename: Pedro
authors.initials: P
authors.lastname: Borrego
authors.forename: Rita
authors.initials: R
authors.lastname: Calado
authors.forename: José M
authors.initials: JM
authors.lastname: Marcelino
authors.forename: Inês
authors.initials: I
authors.lastname: Bártolo
authors.forename: Cheila
authors.initials: C
authors.lastname: Rocha
authors.forename: Patrícia
authors.initials: P
authors.lastname: Cavaco-Silva
authors.forename: Manuela
authors.initials: M
authors.lastname: Doroana
authors.forename: Francisco
authors.initials: F
authors.lastname: Antunes
authors.forename: Fernando
authors.initials: F
authors.lastname: Maltez
authors.forename: Umbelina
authors.initials: U
authors.lastname: Caixas
authors.forename: Helena
authors.initials: H
authors.lastname: Barroso
authors.forename: Nuno
authors.initials: N
authors.lastname: Taveira
mesh_terms: D000577:Amides / Q000494:pharmacology / Q000627:therapeutic use; D019380:Anti-HIV Agents / Q000494:pharmacology / Q000627:therapeutic use; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000494:pharmacology* / Q000627:therapeutic use; D000077560:Enfuvirtide; D005260:Female; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology* / Q000627:therapeutic use; D023581:HIV Fusion Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D015658:HIV Infections / Q000188:drug therapy / Q000821:virology; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D008297:Male; D000077592:Maraviroc; D008826:Microbial Sensitivity Tests; D010446:Peptide Fragments / Q000494:pharmacology* / Q000627:therapeutic use; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology / Q000627:therapeutic use; D014230:Triazoles / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000577:Amides; D019380:Anti-HIV Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D010446:Peptide Fragments; D000644:Quaternary Ammonium Compounds; D014230:Triazoles; C474741:peptide T1249; D000077560:Enfuvirtide; C119369:TAK 779; D000077592:Maraviroc