Inhibition of Plasmodium Hepatic Infection by Antiretroviral Compounds

Abstract

Recent WHO guidelines on control of human immunodeficiency virus (HIV) call for the widespread use of antiretroviral (AR) therapy (ART) for people living with HIV. Given the considerable overlap between infections by HIV and Plasmodium, the causative agent of malaria, it is important to understand the impact of AR compounds and ART regimens on infections by malaria parasites. We undertook a systematic approach to identify AR drugs and ART drug combinations with inhibitory activity against the obligatory hepatic stage of Plasmodium infection. Our in vitro screen of a wide array of AR drugs identified the non-nucleoside reverse transcriptase inhibitors efavirenz and etravirine (ETV), and the protease inhibitor nelfinavir, as compounds that significantly impair the development of the rodent malaria parasite P. berghei in an hepatoma cell line. Furthermore, we show that WHO-recommended ART drug combinations currently employed in the field strongly inhibit Plasmodium liver infection in mice, an effect that may be significantly enhanced by the inclusion of ETV in the treatment. Our observations are the first report of ETV as an anti-Plasmodial drug, paving the way for further evaluation and potential use of ETV-containing ARTs in regions of geographical overlap between HIV and Plasmodium infections.

The Impact of Antiretroviral Therapy on Malaria Parasite Transmission

“…A recent investigation of the impact of ARVs on the liver stage of Plasmodium infection has shown that, consistent with what is observed for erythrocytic stages, the PIs LPV and RTV are potent inhibitors of the parasite's development in hepatic cells (Hobbs et al, 2009). A reduction in the in vivo Plasmodium yoelii liver burden by NNRTIs (Hobbs et al, 2012) and of the in vivo Plasmodium berghei liver burden by etravirine (ETV) (Machado et al, 2017) have also been reported.…”

“…Thus, infection with HIV might increase the severity of Plasmodium infection, while the HIV viral load has been shown to increase during a Plasmodium infection (Nyabadza et al, 2015;Kwenti, 2018). Numerous studies report the effect of HIV ARVs on the different stages of the Plasmodium life cycle (Parikh et al, 2005;Andrews et al, 2006;Lek-Uthai et al, 2008;Hobbs et al, 2009Hobbs et al, , 2012Hobbs et al, , 2013Peatey et al, 2010;Li et al, 2011;Nsanzabana and Rosenthal, 2011;Machado et al, 2017). However, little is known about how ARTs may impair the transmission and mosquito stages of Plasmodium parasites.…”

“…The impact of current first-line ART for adults and adolescents on mosquito infection, which includes EFV, was similar to that of the suggested alternatives employing ETV and RPV. A previous study by Machado et al (2017) FIGURE 3 | In vivo activity of ART on blood and transmission stages of P. berghei. (A) Schematics of drug administration and sample collection schedules.…”

“…Numerous reports describe the effect of ART on the blood and liver stages of Plasmodium parasites (Butcher, 1997;Skinner-Adams et al, 2004;Parikh et al, 2005;Hobbs et al, 2009Hobbs et al, , 2012Peatey et al, 2010Peatey et al, , 2012Nsanzabana and Rosenthal, 2011;Machado et al, 2017). PIs have been systematically described as the most effective ARVs in inhibiting Plasmodium erythrocytic stages (Skinner-Adams et al, 2004;Parikh et al, 2005;Andrews et al, 2006;Lek-Uthai et al, 2008;Peatey et al, 2010;Nsanzabana and Rosenthal, 2011;Hobbs et al, 2013).…”

Novel Harmicines with Improved Potency against Plasmodium

“…The in vitro activity of harmicines against the hepatic stages of Plasmodium infection was evaluated by employing rodent P. berghei parasites and a human hepatoma cell line (Huh7), as previously described [ 25 , 26 ]. Each compound was assessed at 1 and 10 μM ( Figure 2 ), with harmine and DMSO serving as positive and negative controls, respectively.…”