Tobacco smoking effect on HIV-1 pathogenesis: role of cytochrome P450 isozymes

Abstract

Introduction Tobacco smoking is highly prevalent among the HIV-1-infected population. In addition to diminished immune response, smoking has been shown to increase HIV-1 replication and decrease response to antiretroviral therapy, perhaps through drug–drug interaction. However, the mechanism by which tobacco/nicotine increases HIV-1 replication and mediates drug–drug interaction is poorly understood. Areas covered In this review, the authors discuss the effects of smoking on HIV-1 pathogenesis. Since they propose a role for the cytochrome P450 (CYP) pathway in smoking-mediated HIV-1 pathogenesis, the authors briefly converse the role of CYP enzymes in tobacco-mediated oxidative stress and toxicity. Finally, the authors focus on the role of CYP enzymes, especially CYP2A6, in tobacco/nicotine metabolism and oxidative stress in HIV-1 model systems monocytes/macrophages, lymphocytes, astrocytes and neurons, which may be responsible for HIV-1 pathogenesis. Expert opinion Recent findings suggest that CYP-mediated oxidative stress is a novel pathway that may be involved in smoking-mediated HIV-1 pathogenesis, including HIV-1 replication and drug–drug interaction. Thus, CYP and CYP-associated oxidative stress pathways may be potential targets to develop novel pharmaceuticals for HIV-1-infected smokers. Since HIV-1/TB co-infections are common, future study involving interactions between antiretroviral and antituberculosis drugs that involve CYP pathways would also help treat HIV-1/TB co-infected smokers effectively.

Enhanced Nicotine Metabolism in HIV-1–Positive Smokers Compared with HIV-Negative Smokers: Simultaneous Determination of Nicotine and its Four Metabolites in Their Plasma Using a Simple and Sensitive Electrospray Ionization Liquid Chromatography–Tandem Mass Spectrometry Technique

“…This may lead to an increased risk of cancer in HIV-1-positive smokers compared with HIV-negative smokers. Indeed, our recent study showed an increase in oxidative DNA damage and viral load in the plasma of HIV-1-positive smokers compared to HIV-1-positive non-smokers (data not shown; Ande et al, 2013). We also reported enhanced oxidative stress that was correlated with an increase in the viral load in HIV-1-positive smokers compared with HIV-1-positive nonsmokers (Ande et al, 2013).…”

“…Indeed, our recent study showed an increase in oxidative DNA damage and viral load in the plasma of HIV-1-positive smokers compared to HIV-1-positive non-smokers (data not shown; Ande et al, 2013). We also reported enhanced oxidative stress that was correlated with an increase in the viral load in HIV-1-positive smokers compared with HIV-1-positive nonsmokers (Ande et al, 2013). Previous reports also suggest a role of smoking in increased viral replication and a possible association with increased oxidative stress (Boelaert et al, 1996;Israel and GougerotPocidalo, 1997;Aquaro et al, 2007).…”

“…Enhanced nicotine metabolism is known to increase ROS and reactive metabolites, leading to increased cell toxicity and cancer of the lungs, esophagus, and liver (Ande et al, 2013). This may lead to an increased risk of cancer in HIV-1-positive smokers compared with HIV-negative smokers.…”

Impact of HIV infection and smoking on lung immunity and related disorders

“…Such a contention is plausible based on findings that the magnitude of HIV replication is a strong predictor of the rate of progression to AIDS [68] and is supported by several in vitro studies, mentioned earlier, which have shown that smoking enhances HIV-1 replication in alveolar macrophages, microglia and T-cells [58][59][60]. It has been suggested that iron and oxidative stress are possible mechanisms of enhanced production of HIV-1 by alveolar macrophages in cigarette smokers [69,70]. In contrast, a number of clinical studies has failed to confirm accelerated disease progression in smokers [71][72][73][74][75][76][77][78], most probably because they were restricted to specific high-risk groups, such as men who have sex with men and injection-drug users.…”

“…Notwithstanding the counteracting immunosuppressive effect of HIV/smoking on the efficacy of therapy, other possible causes of smoking-related interference with HAART include 1) smoking is a surrogate marker of a noncompliant disposition [81,82]; 2) higher frequencies of side-effects in smokers, including neuropsychiatric symptoms associated with efavirenz-based HAART regimens [83]; 3) negative effects of smoking-related activation of cytochrome P450 enzymes, such as the CPY1A1-m1 variant, which promote oxidative conversion of smoke-derived toxicants to DNA adducts, causing activation of genes that support HIV replication [70,84]; 4) altered pharmacokinetics of antiretroviral agents, possibly related to smoking-mediated induction of CYP3A4 and aryl-hydrocarbon-hydroxylases [85,86], which metabolise many protease and non-nucleoside reverse transcriptase inhibitors [87,88]; and 5) smoking-induced mitochondrial oxidative stress [89], which may exacerbate the adverse effects of antiretroviral drugs that induce mitochondrial toxicity, such as drugs from the nucleoside reverse transcriptase inhibitor class [90].…”