ABSTRACT
Previously, we demonstrated that ferulate ethyl and tocopherol reduced HIV replication. In this study, we investigate whether the conjugation of both compounds (O-tocopheryl succinyl O-ethyl ferulate) can increase HIV inhibition. We show here for the first time that O-tocopheryl succinyl O-ethyl ferulate inhibits 80% of HIV replication (HIV-1 acute infection and HIV transmission), inhibits cell lipoperoxidation and prevents cellular glutathione consumption. Compared to ferulate ethyl and tocopheryl succinyl, O-tocopheryl succinyl O-ethyl ferulate inhibits more HIV replication. This may be due in part to the great increase in the lipophilicity of this compound.
Subject(s)
Coumaric Acids/pharmacology , HIV-1/physiology , Lipid Peroxidation/drug effects , Macrophages/physiology , Macrophages/virology , Virus Replication/drug effects , Vitamin A/analogs & derivatives , Caffeic Acids/pharmacology , Cell Line , Cells, Cultured , Glutathione/metabolism , HIV Core Protein p24/analysis , HIV-1/drug effects , Humans , Macrophages/drug effects , Monocytes/cytology , Vitamin A/pharmacology , Vitamin E/pharmacologyABSTRACT
The frequent neoplastic disorders present in HIV-infected patients and the implication of oxidative stress in AIDS-Kaposi's sarcoma pathogenesis prompted us to study whether the mechanisms implicated in genotoxic effects of clastogenic factors (CFs) (i.e., chromosome damaging materials released by cells under conditions of oxidant stress) can play a role in HIV-1 expression and whether exogenous superoxide dismutase can inhibit the clastogenic and HIV-inducing effects of CFs. CFs were found in the plasma of all HIV-1 infected patients (n = 21) of this study group, in asymptomatic (CDC II) as well as in symptomatic patients (CDC IV). In addition to their chromosome damaging effect, CFs are able to upregulate HIV-1 expression in U1 cells and in PBMCs activated with PHA and IL2 at all time points (p < .05). Their formation, therefore, is an early event in the disease. It occured despite antiviral medication in these patients. Superoxide dismutase inhibited the clastogenic and the viral inducing effects (p < .05). On the basis of our findings, association of SOD mimetics or superoxide scavengers with antiviral drugs may be a new therapeutic approach. This polytherapy, if started early enough after infection, may prolong the latency period and limit the emergence of drug-resistant viral strains.
Subject(s)
Acquired Immunodeficiency Syndrome/blood , HIV-1/physiology , Mutagens/pharmacology , Superoxide Dismutase/pharmacology , Virus Replication , Humans , Interleukin-2/pharmacology , Mutagens/metabolism , Phytohemagglutinins/pharmacologyABSTRACT
We recently demonstrated that exogenous copper-zinc superoxide dismutase (SOD) reduced HIV replication in tumor necrosis factor alpha activated chronically HIV-infected promonocytic U1 cell line and in peripheral blood mononuclear cells coculture. However, whether exogenous SOD penetrates the cellular membrane or acts extracellularly has been remained controversial. SOD has been considered as not to penetrate the cellular membrane because of its high molecular weight, thus the main site of action is presumed to be extracellular. In order to determine whether exogenous SOD penetrates inside the cell, we utilized a gentle immunocytochemical method to detect Mn and Cu,Zn SOD in peripheral blood lymphocytes incubated with various concentrations of exogenous carrier-free Cu,Zn SOD without prior permeabilization of cell membranes. After 24 hrs. the total SOD activity and immunocytochemical studies were performed. Here we demonstrate clearly that a large amount of carrier-free Cu,Zn SOD, added exogenously, penetrates the cellular membrane and increases total SOD activity.
