Background: Despite the diffusion of drug-resistant malaria, chloroquine (CQ) is at present the most widely diffused antimalarial in Africa. This drug exerts anti-HIV effects additive to those of NRTI by inhibiting viral particle maturation in the Golgi and also inhibits surface drug transporters such as the P-glycoprotein (P-gp) and the multidrug-resistance associated protein-1 (MRP1). As many countries with endemic malaria have also endemic HIV/AIDS, we further defined the anti-HIV effects of CQ by studying its effects on viral particle glycosylation, and  tested its in vitro effects in combination with protease inhibitors (PI), on HIV replication and on P-gp / MRP1, in view of an increased diffusion of HAART in these countries.

Methods: Anti-HIV effects were assessed using CD4⁺ cell lines infected with laboratory strains and PBMC from different donors infected with primary isolates. HIV replication was assessed by p24 ELISA. HIV glycosylation was measured by metabolic labeling of viral particles with [3H] glucosamine and Western blot. Synergism was tested using isobolograms. P-gp and MRP1 functions were assayed using rhodamine 123 (Rh¹²³) and carboxyfluorescein (CF) efflux assays, respectively, in peripheral blood lymphocytes from at least 3 different donors.

Results: CQ inhibited HIV replication and glycosylation in a dose-dependent manner. In combination with indinavir, ritonavir, or saquinavir, CQ had a synergistic effect (sum of FIC < 0.5) at concentrations found in blood of subjects under antimalarial prophylaxis (0.1 to 1 mM). As shown by regression analysis, CQ decreased the EC₅₀ of indinavir in primary isolates from Africa and restored the response to indinavir and saquinavir in drug-resistant isolates (p< 0.05). Finally, CQ increased the block of Rh¹²³ and CF efflux activity exerted by PI (Kolmogorov Smirnov statistics, p < 0.05).

Conclusions: The inhibitory effects of CQ on HIV glycosylation are associated with a synergistic effect in combination with PI. Synergism is likely to be attributed to the convergent effects of both CQ and PI on viral particle infectivity. This synergism accounts for the decreased threshold of susceptibility to PI in resistant viruses in the presence of CQ. The combined inhibitory effects of the CQ / PI combination on P-gp and MRP1 function could have an impact on intracellular drug concentrations in an in-vivo setting.

Keywords: antimalarial; virus replication; drug interactions