Loading...
Publication
Baseline susceptibility of primary HIV-2 to entry inhibitors
| Name: | Description: | Size: | Format: | |
|---|---|---|---|---|
| 278.61 KB | Adobe PDF |
Advisor(s)
Abstract(s)
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 cellbased assay. The 50% inhibitory concentration (IC50), 90% inhibitory concentration (IC90) and dose–response curve slopes were determined for each drug.
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 IC50 and IC90 values. MVC, however, inhibited the replication of R5 HIV-2 variants with significantly higher IC90 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.
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 cellbased assay. The 50% inhibitory concentration (IC50), 90% inhibitory concentration (IC90) and dose–response curve slopes were determined for each drug.
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 IC50 and IC90 values. MVC, however, inhibited the replication of R5 HIV-2 variants with significantly higher IC90 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.
Description
This is the author’s version of a work accepted for publication by International Medical Press. Changes resulting from the publishing process, including peer review, editing and formatting, might not be reflected in this document. A definitive version was published in Antiviral Therapy, 17 (3): 565-570, January © 2012 International Medical Press.
Keywords
HIV-2 inhibitors
Pedagogical Context
Citation
Antiviral Therapy 2012; 17:565-570 doi: 10.3851/IMP1996