An increase in chronic alcohol consumption in HIV-infected individuals is known to increase HIV-1 replication and decrease responses to highly active antiretroviral therapy (HAART). Alcohol is also known to disrupt blood-brain barrier, which further increases the CNS infiltration of HIV-infected monocytes/ macrophages (major viral reservoir), leading to development of neuroAIDS. However, the underlying mechanism(s) by which alcohol exposure results in increased HIV-1 replication and decreased response to HAART drugs, especially in monocytes/macrophages, is not known. Oxidative stress generated through various stimulants/pathways has been reported to be responsible for increased HIV-1 replication. The major chronic alcohol-mediated oxidative stress pathway in the liver is ethanol-induced expression of cytochrome P450 2E1 (CYP2E1). Since CYP3A4 is known to metabolize important HAART drugs, protease inhibitors (PIs), the role of CYP3A4 is considered critical in determining the bioavailability and efficacy of PIs. In addition, CYP3A4 is known to be induced by ethanol and PI, which could result in further increases in metabolism of PIs, thereby, decreasing their efficacy. There is relatively little known about the direct contribution of CYP pathways in alcohol-mediated oxidative damage, HIV-1 replication, and altered metabolism of PIs in monocytes/macrophages. Our long-term goal is to define the role of CYP pathways in alcohol-mediated oxidative stress, HIV-1 replication, and response to HAART in monocytes/macrophages, and their implications in pathogenesis of neuroAIDS. Our central hypothesis is that in monocytes/macrophages alcohol-mediated oxidative stress causes enhanced HIV-1 replication via pathways mediated through CYP2E1. In addition, alcohol-mediated decrease in the efficacy of PIs and increase in PIs-mediated toxicity concurrent with increase in the rates of HIV-1 replication is directly mediated through CYP3A4. To test our hypothesis, we propose two aims.
Aim 1 : Examine the contribution of CYP2E1 and CYP3A4 in ethanol-mediated efficacy of PI and HIV-1 replication in monocytes/ macrophages.
Aim 2 : Determine cellular, biochemical, and molecular changes unique to monocytes/ macrophages derived from alcoholic HIV-infected patients. Upon successful completion of the proposed research, we expect to have established that CYP2E1 is involved in ethanol-mediated oxidative stress and HIV-1 replication and that alcohol exposure alters PI-CYP3A4 interaction, thereby, decreasing the efficacy PI in alcoholic HIV+ individuals. These finding will open a new avenue in understanding HIV-1 pathogenesis and HAART treatment strategy among alcoholic/HIV+ individuals.
The proposal will determine the contribution of novel cytochrome P450 pathways by which alcohol alters HIV-1 pathogenesis and HAART efficacy in alcoholic HIV-1 patients. These findings would help optimize drug doses and/or find novel interventions for HIV+/alcoholic patients to improve treatment outcomes and decrease adverse effects.
|Midde, Narasimha M; Sinha, Namita; Lukka, Pradeep B et al. (2017) Alterations in cellular pharmacokinetics and pharmacodynamics of elvitegravir in response to ethanol exposure in HIV-1 infected monocytic (U1) cells. PLoS One 12:e0172628|
|Rahman, Mohammad A; Midde, Narasimha M; Wu, Xiaoxin et al. (2017) Kinetic characterizations of diallyl sulfide analogs for their novel role as CYP2E1 enzyme inhibitors. Pharmacol Res Perspect 5:|
|Midde, Narasimha M; Gong, Yuqing; Cory, Theodore J et al. (2017) Influence of Ethanol on Darunavir Hepatic Clearance and Intracellular PK/PD in HIV-Infected Monocytes, and CYP3A4-Darunavir Interactions Using Inhibition and in Silico Binding Studies. Pharm Res 34:1925-1933|
|Kumar, Santosh; Sinha, Namita; Gerth, Kelli A et al. (2017) Specific packaging and circulation of cytochromes P450, especially 2E1 isozyme, in human plasma exosomes and their implications in cellular communications. Biochem Biophys Res Commun 491:675-680|
|Midde, Narasimha M; Rahman, Mohammad A; Rathi, Chetan et al. (2016) Effect of Ethanol on the Metabolic Characteristics of HIV-1 Integrase Inhibitor Elvitegravir and Elvitegravir/Cobicistat with CYP3A: An Analysis Using a Newly Developed LC-MS/MS Method. PLoS One 11:e0149225|
|Rao, Pss; Ande, Anusha; Sinha, Namita et al. (2016) Effects of Cigarette Smoke Condensate on Oxidative Stress, Apoptotic Cell Death, and HIV Replication in Human Monocytic Cells. PLoS One 11:e0155791|
|Rao, P S S; Kumar, Santosh (2016) Chronic Effects of Ethanol and/or Darunavir/Ritonavir on U937 Monocytic Cells: Regulation of Cytochrome P450 and Antioxidant Enzymes, Oxidative Stress, and Cytotoxicity. Alcohol Clin Exp Res 40:73-82|
|Midde, Narasimha M; Patters, Benjamin J; Rao, Pss et al. (2016) Investigational protease inhibitors as antiretroviral therapies. Expert Opin Investig Drugs 25:1189-200|
|Midde, Narasimha M; Kumar, Santosh (2015) Development of NanoART for HIV Treatment: Minding the Cytochrome P450 (CYP) Enzymes. J Pers Nanomed 1:24-32|
|Ande, Anusha; Sinha, Namita; Rao, P S S et al. (2015) Enhanced oxidative stress by alcohol use in HIV+ patients: possible involvement of cytochrome P450 2E1 and antioxidant enzymes. AIDS Res Ther 12:29|
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