3rd IAS Conference on HIV Pathogenesis and Treatment
July 24 - 27, 2005, Rio de Janerio, Brazil
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HIV Protease Inhibitors Have Anti-malarial Effects Malaria and HIV-1/AIDS heavily burden overlapping regions; yet little is known about treating both diseases simultaneously. Though displaying poor anti-HIV-1 activity per se, the quinoline antimalarial chloroquine exerts synergistic anti-HIV-1 effects in combination with indinavir, ritonavir and saquinavir [Savarino et al. JAIDS 2004]. Conversely,
the present study is aimed at finding a target for HIV-1
protease inhibitors (PIs) in Plasmodium falciparum
and determining the combined anti-HIV-1 and antiplasmodial effects
of quinoline antimalarials and PIs. Structural
alignments and protein/ligand docking were calculated bioinformatically.
Plasmepsin IV (PMIV) activity was evaluated spectrophotometrically.
P. falciparum viability and HIV-1 replication were measured by standard
techniques. The effects of drug combinations were assessed by analysis
of the sum of the fractional inhibitory concentrations (SFIC). There is a significant structural similarity between the HIV-1 protease and P. falciparum aspartic proteases, namely plasmepsins (P < 0.001), thus allowing PIs to establish hydrogen bonding to the active site of PMIV. Several PIs dose-dependently inhibited PMIV and decreased the viability of both chloroquine-sensitive and resistant parasites in vitro. Synergistic effects occurred in combination with quinoline antimalarials (SFIC < 0.5). Of note, ritonavir and the combination ritonavir/lopinavir (Kaletra) increased the survival of mice infected with P. berghei (Kaplan Meyer; P < 0.01). In cellular models for HIV-1 infection, chloroquine was synergistic with lopinavir in both PI-sensitive and resistant isolates (SFIC < 0.5), in agreement with its capacity to decrease the fusion-competence of viral envelope glycoproteins and to block P-glycoprotein. Mefloquine exerted anti-HIV-1 effects by similar mechanisms, approx. 1.5-fold more potently than chloroquine. Conclusions Combinations
of PIs and quinoline antimalarials might represent a basis for strategies
simultaneously attacking HIV-1/AIDS and malaria. "HIV protease
inhibitors partially restore the response to chloroquine in chloroquine-resistant
malaria parasites," Dr. Andrea Savarino of the Universita Cattolica
del Sacro Cuore in Rome told Reuters Health. However,
Dr. Savarino does not advocate the use of HIV protease inhibitors
as single treatment for malaria, because they are not as effective
as antimalarials. Instead, he said, "The combination of HIV
protease inhibitors and chloroquine might represent a basis for
the investigation of possible treatments for HIV-malaria coinfection." Università Cattolica del Sacro Cuore, Rome, Italy, Istituto Superiore di Sanità, Rome, Italy, Università di Perugia, Perugia, Italy, Università degli Studi di Milano, Milan, Italy, AZ Sint Jan, Bruges, Belgium, King's College, London, United Kingdom. 08/22/05 Reference <---
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