The potential impact of cigarette smoking in HIV scenario can be gauged from the fact that the prevalence of smoking is estimated to be 50-70% in HIV+ population compared to 20% in the general population. Until recently, little attention was paid to the potential interaction between smoking and HIV-1/AIDS. Smoking and its main constituent, nicotine have been shown to enhance HIV-1 replication in alveolar macrophages and microglia, decrease immune responses, and decreased responses to antiretroviral therapy (ART). However, very little is known about the mechanism(s) by which nicotine causes these effects. Nicotine, its major metabolite, cotinine, and other important tobacco-specific compounds are predominantly metabolized by cytochrome P450 2A6 (CYP2A6), especially in the liver, and by lung-specific CYP2A13. This metabolic pathway is thought to increase oxidative stress and inflammation, resulting in liver damage, as well as lung, esophageal, and pancreatic cancers. Several studies, including ours, demonstrate that CYP2A6 is highly expressed in human monocyte-derived macrophages. Our preliminary studies show that CYP2A6 is induced by nicotine in U937 cell lines (HIV-1 model cell lines for macrophages). However, their clinical implications are unknown. Macrophages are one of the major cellular targets of HIV-1, crucial virus reservoirs, and carriers of HIV-1 infection to the brain (NeuroAIDS). Our goal is to examine the role of nicotine in CYP2A6-induced oxidative stress and HIV-1 replication in macrophages. Our hypothesis is that nicotine enhances HIV-1 replication in macrophages through CYP2A6-mediated nicotine metabolism and oxidative stress. To test the hypothesis, the study is designed with two specific aims.
Specific Aim 1 : To examine the role of nicotine on CYP2A6-mediated oxidative stress and HIV-1 replication in human primary macrophages.
Specific Aim 2 : To determine the effect of smoking on CYP2A6 expression, oxidative stress, and HIV-1 replication in HIV+ smokers. Upon successful completion of this project, we will have tested our hypothesis that nicotine enhances HIV-1 replication through CYP2A6-mediated oxidative stress in human macrophages. This would provide the first evidence of the effect of nicotine on HIV-1 replication in macrophages and the mechanism by which it occurs. This novel work would provide a new dimension in HIV-1/nicotine related research, and would provide an opportunity to develop novel therapeutic agents to treat HIV+ smokers effectively.
The proposal will examine the role of smoking/nicotine on CYP2A6-mediated oxidative stress in HIV-1 replication. The proposal would provide a new dimension to link substances of abuse, especially tobacco use and HIV-1, which is one of the major objectives of NIDA. In long term, this would provide an opportunity to develop novel therapeutic agents to treat HIV+ smokers effectively.
|Ande, Anusha; McArthur, Carole; Ayuk, Leo et al. (2015) Effect of mild-to-moderate smoking on viral load, cytokines, oxidative stress, and cytochrome P450 enzymes in HIV-infected individuals. PLoS One 10:e0122402|
|Earla, Ravinder; Ande, Anusha; McArthur, Carole et al. (2014) 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 ma Drug Metab Dispos 42:282-93|
|Kumar, Santosh (2013) Phytoremediation of Explosives using Transgenic Plants. J Pet Environ Biotechnol Suppl 4:11127|
|Jin, M; Ande, A; Kumar, A et al. (2013) Regulation of cytochrome P450 2e1 expression by ethanol: role of oxidative stress-mediated pkc/jnk/sp1 pathway. Cell Death Dis 4:e554|
|Ande, Anusha; McArthur, Carole; Kumar, Anil et al. (2013) Tobacco smoking effect on HIV-1 pathogenesis: role of cytochrome P450 isozymes. Expert Opin Drug Metab Toxicol 9:1453-64|
|Jin, Mengyao; Earla, Ravinder; Shah, Ankit et al. (2012) A LC-MS/MS method for concurrent determination of nicotine metabolites and role of CYP2A6 in nicotine metabolism in U937 macrophages: implications in oxidative stress in HIV + smokers. J Neuroimmune Pharmacol 7:289-99|
|Ande, Anusha; Earla, Ravinder; Jin, Mengyao et al. (2012) An LC-MS/MS method for concurrent determination of nicotine metabolites and the role of CYP2A6 in nicotine metabolite-mediated oxidative stress in SVGA astrocytes. Drug Alcohol Depend 125:49-59|
|Kumar, Santosh; Jin, Mengyao; Weemhoff, James L (2012) Cytochrome P450-Mediated Phytoremediation using Transgenic Plants: A Need for Engineered Cytochrome P450 Enzymes. J Pet Environ Biotechnol 3:|
|Kumar, Santosh; Jin, Mengyao; Ande, Anusha et al. (2012) Alcohol consumption effect on antiretroviral therapy and HIV-1 pathogenesis: role of cytochrome P450 isozymes. Expert Opin Drug Metab Toxicol 8:1363-75|
|Kumar, Santosh (2012) Challenges and Opportunities of Cytochrome P450-Mediated Phytoremediation. J Pet Environ Biotechnol 4:|
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