4th International Workshop on HIV Drug Resistance & Treatment Strategies Sitges, Spain, 12–16 June 2000

ACTIVITY OF HYDROXYUREA ON MULTIDRUG-RESISTANT HIV-1 VARIANTS

Antivir Ther. 2000 Jun 12-16; 5 (Suppl. 3):10 (Abstract 13

S Paulous, E Race and F Clavel
INSERM U82, Hôpital Bichat-Claude Bernard, Paris, France

OBJECTIVES: Hydroxyurea (HU), an inhibitor of ribonucleotide reductase, has been proposed as an additive to HIV therapy by nucleoside analogues, particularly didanosine, since it can reduce the competing intracellular pool of deoxynucleoside triphosphates (dNTPs). HU is not thought to exert antiviral activity by itself, but has been found to enhance the activity of didanosine on wild-type HIV-1 and on a limited number of didanosine-resistant variants. Although HU is often prescribed as part of salvage therapy, its activity on viruses with multidrug resistance is not known. We have investigated the activity of HU on a variety of nucleoside-analogueresistant HIV-1 variants, using a recombinant virus assay.

RESULTS: We first examined the effect of increasing HU concentrations on the IC₅₀ of didanosine. In nucleoside analogue-sensitive viruses and viruses resistant to a single nucleoside analogue, we observed that HU significantly reduced the IC₅₀ of didanosine, with a maximum decrease of 10-fold obtained at 100 μM HU. In multidrug-resistant HIV-1 variants, the enhancing effect of HU was less pronounced, with a maximal reduction in the IC₅₀ of didanosine of three fold at 100 μM HU. However, we noticed that on these viruses, HU appeared to exert a significant antiviral activity by itself. We therefore investigated the antiviral activity of HU alone on a wider panel of HIV-1 variants. On nucleoside analogue-sensitive viruses, HU exerted no perceptible antiviral effect, with an IC₅₀ above 500 μM. With viruses solely resistant to zidovudine or to lamivudine, the IC₅₀ of HU was marginally reduced, with IC⁵⁰ values of 150–200 μM. Finally, with viruses displaying resistance to multiple nucleoside analogues (n=16), HU was significantly more active, with a median IC₅₀ of 64.5 μM, ranging from 20 to 250 μM. HU sensitivity appeared particularly pronounced in viruses carrying double amino acid insertions next to amino acid 69 of RT. We hypothesize that a reduction in the intracellular pool of dNTPs selectively alters DNA polymerization by poorly processive mutant RTs. This hypothesis is currently being tested in vitro by measuring the selective effect of a reduction in the dNTP concentration on the efficiency of endogenous reverse transcription by viruses found to be sensitive to HU.

CONCLUSIONS: HU significantly and selectively reduces infectivity of some multidrug-resistant HIV-1 variants. This finding could constitute the basis for a rational and targeted use of this compound in antiretroviral salvage therapy.

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2000-06-12
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