Abstract
Background: Novel strategies to increase the efficacy of antiretroviral (ARV) drugs will be of crucial importance. We hypothesize that membranes of HIV-1-infected cells and enveloped HIV-1 particles may be preferentially targeted by the phytopeptide, cycloviolacin O2 (CyO2) to significantly enhance ARV efficacy. Methods: Physiologically safe concentrations of CyO2 were determined via red blood cell (RBC) hemolysis. SYTOX-green dye-uptake and radiolabeled saquinavir (3H-SQV) uptake assays were used to measure pore-formation and drug uptake, respectively. ELISA, reporter assays and ultracentrifugation were conducted to analyze the antiviral efficacy of HIV-1 protease and fusion inhibitors alone and co-exposed to CyO2. Results: CyO2 concentrations below 0.5 μM did not show substantial hemolytic activity, yet these concentrations enabled rapid pore-formation in HIV-infected T-cells and monocytes and increased drug uptake. ELISA for HIV-1 p24 indicated that CyO2 enhances the antiviral efficacy of both SQV and nelfinavir. CyO2 (< 0.5 μM) alone decreases HIV-1 p24 production, but it did not affect the transcription regulatory function of the HIV-1 long terminal repeat (LTR). Ultracentrifugation studies clearly showed that CyO2 exposure disrupted viral integrity and decreased the p24 content of viral particles. Furthermore, direct HIV-1 inactivation by CyO2 enhanced the efficacy of enfuvirtide. Conclusions: The membrane-active properties of CyO2 may help suppress viral load and augment antiretroviral drug efficacy.
Highlights
To address the fact that clinical research with naturally occurring phytopeptides has been hindered by their hemolytic activity [31,33], the effect of cycloviolacin O2 (CyO2) on human red blood cells (RBC) incubated with human serum or fetal bovine serum (FBS) was measured
The percentage of hemolytic activity on RBCs was generally lower in samples incubated with human serum (HS) compared to FBS (Figure 2B,D)
Our findings suggest that CyO2 is effective in increasing antiretroviral drugs (ARVs) entry into productively-infected cells and in the disruption of infectious viral particles, a formidable challenge with the treatment and cure of HIV-infected patients is the elimination of latent reservoirs, which persist despite combination ARV therapy (cART) [65]
Summary
Since the discovery of human immunodeficiency virus type-1 (HIV-1) as the etiologic agent of acquired immune deficiency syndrome (AIDS), more than 39 million people have died of this epidemic, and alarming annual rates of new infections are estimated at two million people worldwide [1,2].Medicines 2019, 6, 33; doi:10.3390/medicines6010033 www.mdpi.com/journal/medicinesDespite the availability of numerous antiretroviral drugs (ARVs), only one-third (~36%) of the population living with HIV-1/AIDS have access to expensive medications; cheaper alternatives, such as natural compounds or phytochemicals, may benefit resource-poor countries [3,4,5].HIV-1 primarily infects and replicates in T-helper cells (Th) and monocytes/macrophages.A number of ARVs are currently available that target different stages of the viral replication cycle. Strategies to enhance the efficacy of FIs and PIs are clearly needed. In this respect, since the infectious HIV-1 virions assemble at the plasma membrane ‘lipid-rafts’ followed by virus exit from cells carrying a lipid envelope that is enriched with phospholipids [15,16] the lipid membrane of infected cells and the lipid envelope of the released virion are novel targets. We hypothesize that membranes of HIV-1-infected cells and enveloped HIV-1 particles may be preferentially targeted by the phytopeptide, cycloviolacin O2 (CyO2) to significantly enhance ARV efficacy. Results: CyO2 concentrations below 0.5 μM did not show substantial hemolytic activity, yet these concentrations enabled rapid pore-formation in HIV-infected T-cells and monocytes and increased drug uptake.
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