title: Anti-platelet-activating factor effects of highly active antiretroviral therapy (HAART): a new insight in the drug therapy of HIV infection?
abstract: Platelet-activating factor (PAF) is a potent inflammatory mediator, which seems to play a role in the pathogenesis of several AIDS manifestations such as AIDS dementia complex, Kaposi's sarcoma, and HIV-related nephropathy. PAF antagonists have been studied in these conditions with promising results. In order to examine the possible interactions between PAF and antiretroviral therapy, we studied the effect of nucleoside reverse transcriptase inhibitors, non-nucleoside reverse transcriptase inhibitors, and protease inhibitors against PAF biological activities and its basic biosynthetic enzymes dithiothreitol-insensitive PAF-cholinephosphotransferase (PAF-CPT) and lyso-PAF-acetyltransferase (Lyso-PAF-AT), as well as its main degradative enzyme PAF-acetylhydrolase, of human mesangial cell line (HMC). We also studied the effect of several backbones and highly active antiretroviral therapy (HAART) regimens against PAF activity. Among the drugs tested, several inhibited PAF-induced platelet aggregation in a concentration-depended manner, with tenofovir, efavirenz, and ritonavir exhibiting the higher inhibitory effect. In addition, when these drugs were combined in backbones and HAART regimens based on American antiretroviral therapy proposals, they also synergistically exhibited an inhibitory effect against PAF-induced platelet aggregation. Several of these drugs have also inhibited in vitro microsomal PAF-CPT activity, and concentrations of lopinavir-r or tenofovir-DF (similar to their IC(50) against PAF-induced platelet aggregation) exhibited the same effect against PAF-CPT and Lyso-PAF-AT when added in the cell medium of cultured HMC. In addition, in naïve patients treated with one of the most potent anti-PAF HAART regimens (efavirenz/emtricitabine/tenofovir-DF) for a period of 1 month, a significant reduction of the specific activity of PAF-CPT of washed human leukocytes of these patients was also observed, compared with its levels before the HAART treatment. These promising results need to be further studied and confirmed by additional in vivo tests in order to optimize HAART efficacy.
authors.affiliation: University of Athens, Faculty of Chemistry, Athens, Greece.
authors.forename: Alexandros B
authors.initials: AB
authors.lastname: Tsoupras
authors.forename: Maria
authors.initials: M
authors.lastname: Chini
authors.forename: Nickolaos
authors.initials: N
authors.lastname: Tsogas
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Fragopoulou
authors.forename: Tzortzis
authors.initials: T
authors.lastname: Nomikos
authors.forename: Athina
authors.initials: A
authors.lastname: Lioni
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Mangafas
authors.forename: Constantinos A
authors.initials: CA
authors.lastname: Demopoulos
authors.forename: Smaragdi
authors.initials: S
authors.lastname: Antonopoulou
authors.forename: Marios C
authors.initials: MC
authors.lastname: Lazanas
mesh_terms: D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase / Q000187:drug effects; D000123:Acetyltransferases / Q000187:drug effects; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D002478:Cells, Cultured; D002798:Diacylglycerol Cholinephosphotransferase / Q000187:drug effects; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects / Q000378:metabolism; D010972:Platelet Activating Factor / Q000187:drug effects* / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects
chemical_list: D044966:Anti-Retroviral Agents; D010972:Platelet Activating Factor; D000123:Acetyltransferases; C046035:1-alkylglycerophosphocholine acetyltransferase; D002798:Diacylglycerol Cholinephosphotransferase; D043203:1-Alkyl-2-acetylglycerophosphocholine Esterase