HIV treatments reduce malaria liver stage burden in a non-human primate model of malaria infection at clinically relevant concentrations in vivo.

Charlotte V Hobbs,Kennan Marsh,Patrick E Duffy,Stephen L Hoffman,Solomon Conteh,Lynn Lambert,Scott R Penzak,Sumana Chakravarty,Jingyang Chen,Liam Donnelly,William Borkowsky,Jillian Neal,Jessica Hinderer,Sara Healy,Sachy Orr-Gonzalez,Bruce Russell

doi:10.1371/journal.pone.0100138

Abstract

We have previously shown that the HIV protease inhibitor lopinavir-ritonavir (LPV-RTV) and the antibiotic trimethoprim sulfamethoxazole (TMP-SMX) inhibit Plasmodium liver stages in rodent malarias and in vitro in P. falciparum. Since clinically relevant levels are better achieved in the non-human-primate model, and since Plasmodium knowlesi is an accepted animal model for the study of liver stages of malaria as a surrogate for P. falciparum infection, we investigated the antimalarial activity of these drugs on Plasmodium knowlesi liver stages in rhesus macaques. We demonstrate that TMP-SMX and TMP-SMX+LPV-RTV (in combination), but not LPV-RTV alone, inhibit liver stage parasite development. Because drugs that inhibit the clinically silent liver stages target parasites when they are present in lower numbers, these results may have implications for eradication efforts.

Highlights

This paper describes for the first time the use of cryopreserved P. knowlesi sporozoites, used as a surrogate for P. falciparum in vivo since liver stage duration is comparable in time [9], and which allows for reproducible and controlled sporozoites inoculum in this host
We have demonstrated that TMP-SMX and LPV-RTV+TMPSMX-combination-treated animals had no detectable parasites by smear and prolonged time to PCR detection of parasites in blood, suggesting a reduction of liver stage parasite burden in the P. knowlesi rhesus macaque model
We show TMP-SMX has a P. knowlesi-liver stage killing effect, as reflected in the increase in time to detection of parasites in blood

Summary

Introduction

As more patients are managed for HIV exposure and infection, understanding HIV drug impact on malaria infection is important. We and others have previously shown that HIV PIs have a more potent effect against liver stage and asexual stage Plasmodium in rodent malaria models and in P. falciparum in vitro compared with NNRTIs [2,3,4,5,6]. Many clinical studies have shown the antibiotic, trimethoprim-sulfamethoxazole (TMP-SMX), commonly used in HIV-exposed infants and HIV-infected patients in malaria endemic areas [1] can reduce clinical malaria burden [7], and we have previously shown that TMP-SMX blocks development of liver stage Plasmodium in rodent malaria models [4] and in P. falciparum in vitro [4]. If medications used in HIV management can have a beneficial effect in reducing malaria burden through killing of liver stage parasites, these treatments may be tailored or timed to maximize those benefits

Methods

Results

Conclusion