Alcohol consumption effect on antiretroviral therapy and HIV-1 pathogenesis: role of cytochrome P450 isozymes

Abstract

Introduction: Alcohol consumption, which is highly prevalent in HIV-infected individuals, poses serious concerns in terms of rate of acquisition of HIV-1 infection, HIV-1 replication, response to highly active antiretroviral therapy (HAART) and AIDS/neuroAIDS progression. However, little is known about the mechanistic pathways by which alcohol exerts these effects, especially with respect to HIV-1 replication and the patient's response to HAART.

Areas covered: In this review, the authors discuss the effects of alcohol consumption on HIV-1 pathogenesis and its effect on HAART. They also describe the role of cytochrome P450 2E1 (CYP2E1) in alcohol-mediated oxidative stress and toxicity, and the role of CYP3A4 in the metabolism of drugs used in HAART (i.e., protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRTI)). Based on the most recent findings the authors discuss the role of CYP2E1 in alcohol-mediated oxidative stress in monocytes/macrophages and astrocytes, as well as the role of CYP3A4 in alcohol-PI interactions leading to altered metabolism of PI in these cells.

Expert opinion: The authors propose that alcohol and PI/NNRTI interact synergistically in monocytes/macrophages and astrocytes through the CYP pathway leading to an increase in oxidative stress and a decrease in response to HAART. Ultimately, this exacerbates HIV-1 pathogenesis and neuroAIDS.

Conflict of interest statement

Declaration of interest

The authors declare no other conflicts of interest.

Figures

Figure 1. Cells or organs that are involved in HIV-1 pathogenesis or neuroAIDS, as well as which are sites of action of antiretroviral therapy (ART) drugs

Some of these cells or organs, e.g., liver, are also involved in the metabolism of alcohol and ART drugs such as non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI).

Figure 2. Pathway showing the effect of alcohol on oxidative stress-mediated HIV-1 pathogenesis through CYP pathway

The PKC/MEK/Nrf-2 pathway is activated by oxidative stress generated from CYP2E1-mediated metabolism of alcohol. Nrf2 then activates the expression of CYP2A6 enzyme in these cells, which in turn metabolizes nicotine and produces oxidative stress. MEK: Mitogen-activated kinase kinase; Nrf-2: Nuclear factor E2-related factor 2; NNK: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; PKC: Protein kinase C.

Figure 3. Ethanol–CYP3A4–PI three-way interaction model with type II PI (TII-PI, blue), and spectrally unbound PI (UB-PI, red)

This model was derived from the data obtained using recombinant purified CYP3A4 enzyme. Ethanol (EtOH) differentially alters the inhibition of CYP3A4 by PI. Ethanol and type II PI interact simultaneously with CYP3A4 at the same site leading to a decrease in the IC50 of type II PI. Ethanol and spectrally unbound PI interact simultaneously with CYP3A4 at different sites leading to an increase in the IC50 of spectrally unbound PI. The altered CYP3A4–PI interactions by ethanol may lead to altered metabolism of PI and NNRTI.

Figure 4. Proposed strategy to study alcohol–ART interactions using recombinant CYP3A4 enzyme, HIV-infected macrophages and astrocytes, as well as hepatocytes and neurons

Alcohol–ART interaction may additively/synergistically enhance induction of CYP enzymes leading to increased metabolism of alcohol and ART thereby decreased bioavailability and efficacy of ART (red). This interaction is also expected to increase alcohol- and ART-mediated toxicity. Similarly, alcohol–ART physical interaction may differentially alter the binding and inhibition of CYP3A4 leading to altered metabolism of ART (increase or decrease), which may also alter the efficacy of ART and increase ART toxicity (blue). A decrease in the response to ART and an increased toxicity may eventually increase HIV-1 pathogenesis. In this case ART represents only PI and NNRTI. ART: Antiretroviral therapy; MTB: Metabolites; ROS: Reactive oxygen species.