Cocaine serves as a cofactor for susceptibility to HIV infection and AIDS progression. Cocaine also increases HIV-1 replication in peripheral blood mononuclear cells and enhances viral load in animal models. Furthermore, HIV positive cocaine users have lower CD4+ T cell counts and have a significant acceleration of decline of CD4+ T cells. Since CD4+ T cells are primary targets for HIV-1 infection and replication in vivo, it is imperative to understand the effects of cocaine on CD4+ T cell biology. This application proposes a potentially novel mechanism by which cocaine may increase HIV-1 replication. It has been proposed that cocaine enhances HIV-1 replication by regulating viral entry. Our preliminary data suggest modulation of HIV-1 post entry steps by cocaine. Our data also reveal that cocaine down regulates two anti-HIV cellular microRNAs (miRNAs), miR-125b and miR-328 in primary CD4+ T cells. Since these miRNAs target the 3'UTR of HIV-1 mRNA, we believe cocaine may target post-transcription steps of HIV-1 replication. Therefore, we hypothesize that enhanced HIV-1 replication and increased viral load by cocaine is mediated by down regulation of cellular anti-HIV miRNAs. Since HIV infected cocaine users have higher viral loads and increased risk of progression to AIDS, our findings will have far reaching implications in drug use and HIV biology. We will test our hypothesis by focusing on two aims.
Aim 1 : Determine effects of cocaine-induced down-regulation of anti-HIV cellular miRNAs on HIV-1 replication.
Aim 2 : Examine whether cocaine-induced down-regulation of anti-HIV cellular miRNAs activate latently infected HIV-1.

Public Health Relevance

Drug use remains the second most common mode of exposure to HIV and illicit drugs serve as cofactors for susceptibility to HIV infection and disease progression. Although cocaine has been shown to enhance HIV infection and replication, the underlying mechanism remains unclear. Therefore, the focus of this proposal is to delineate the mechanism by which cocaine contributes to HIV/AIDS.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
5R03DA033892-02
Application #
8449077
Study Section
Special Emphasis Panel (ZRG1-AARR-D (58))
Program Officer
Pollock, Jonathan D
Project Start
2012-04-01
Project End
2014-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
2
Fiscal Year
2013
Total Cost
$139,680
Indirect Cost
$43,680
Name
Meharry Medical College
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041438185
City
Nashville
State
TN
Country
United States
Zip Code
37208
Swepson, Chelsie; Ranjan, Alok; Balasubramaniam, Muthukumar et al. (2016) Cocaine Enhances HIV-1 Transcription in Macrophages by Inducing p38 MAPK Phosphorylation. Front Microbiol 7:823
Kaneshiro, Bliss; Edelman, Alison; Dash, Chandravanu et al. (2016) Effect of oral contraceptives and doxycycline on endometrial MMP-2 and MMP-9 activity. Contraception 93:65-9
Addai, Amma B; Pandhare, Jui; Paromov, Victor et al. (2015) Cocaine modulates HIV-1 integration in primary CD4+ T cells: implications in HIV-1 pathogenesis in drug-abusing patients. J Leukoc Biol 97:779-90
Beni, Yousef; Dash, Chandravanu; Parang, Keykavous (2015) Synthesis of β-triphosphotriester pronucleotides. Tetrahedron Lett 56:2247-2250
Pandhare, Jui; Dash, Sabyasachi; Jones, Bobby et al. (2015) A Novel Role of Proline Oxidase in HIV-1 Envelope Glycoprotein-induced Neuronal Autophagy. J Biol Chem 290:25439-51
Dash, Sabyasachi; Balasubramaniam, Muthukumar; Villalta, Fernando et al. (2015) Impact of cocaine abuse on HIV pathogenesis. Front Microbiol 6:1111
Passaro, Ryan Colby; Pandhare, Jui; Qian, Han-Zhu et al. (2015) The Complex Interaction Between Methamphetamine Abuse and HIV-1 Pathogenesis. J Neuroimmune Pharmacol 10:477-86
Pandhare, Jui; Addai, Amma B; Mantri, Chinmay K et al. (2014) Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients. Am J Pathol 184:927-36
Mantri, Chinmay K; Mantri, Jyoti V; Pandhare, Jui et al. (2014) Methamphetamine inhibits HIV-1 replication in CD4+ T cells by modulating anti-HIV-1 miRNA expression. Am J Pathol 184:92-100
Mantri, Chinmay K; Pandhare Dash, Jui; Mantri, Jyoti Velamarti et al. (2012) Cocaine enhances HIV-1 replication in CD4+ T cells by down-regulating MiR-125b. PLoS One 7:e51387

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