Methamphetamine (METH) abuse and human immunodeficiency virus (HIV) infection produce a """"""""double epidemic"""""""" in the United States, which is a serious global concern to public health. METH abuse and HIV infection are both recognized as major causes of neurocognitive diseases. METH use can increase the risk of acquiring HIV and enhance brain injury in the context of HIV infection. However, it is unclear about the mechanisms by which METH and/or HIV impair the central nervous system (CNS). Human brain microvascular endothelial cells (HBMEC) have been well known as main components of the blood-brain barrier (BBB) and play a key role in protecting the CNS from pathogen invasion. Recently, we identified HBMEC as an important bystander in inhibiting HIV replication in macrophages, as Toll-like receptor 3 (TLR3) signaling of HBMEC could activate IFN pathway, inducing the expression of the cellular HIV restriction factors. In the proposed studies, we will determine whether METH and/or HIV compromise TLR3 signaling-mediated immune activation of HBMEC and HBMEC-mediated anti-HIV activity. The overarching hypothesis of this R03 proposal is that METH and/or HIV impair TLR3 signaling of HBMEC, diminishing HBMEC-mediated innate immunity against HIV. We propose two specific aims: 1) to determine the effect of METH and/or HIV on TLR3 signaling of HBMEC-mediated anti-HIV activity;2) to examine the impact of METH and/or HIV on BBB permeability in the context of TLR3 signaling of HBMEC, and whether TLR3 signaling of HBMEC has protective effect on METH and/or HIV-mediated neuronal injury. Given the high prevalence of METH use and its implication in HIV-associated dementia, the proposed studies are timely and important, which should provide insight of the role of HBMEC in BBB innate immunity in the context of METH use and/or HIV infection.

Public Health Relevance

This project will provide new information about the role of human brain microvascular endothelial cells (HBMEC) in the BBB innate immunity and CNS homeostasis in the context of METH use and HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Small Research Grants (R03)
Project #
1R03DA036413-01A1
Application #
8659645
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Purohit, Vishnudutt
Project Start
2014-03-15
Project End
2016-02-29
Budget Start
2014-03-15
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$77,833
Indirect Cost
$27,833
Name
Temple University
Department
Pathology
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Zhou, Runhong; Wang, Xu; Liu, Hang et al. (2018) GalNAc-Specific Soybean Lectin Inhibits HIV Infection of Macrophages through Induction of Antiviral Factors. J Virol 92:
Sun, Li; Wang, Xu; Zhou, Yu et al. (2016) Exosomes contribute to the transmission of anti-HIV activity from TLR3-activated brain microvascular endothelial cells to macrophages. Antiviral Res 134:167-171
Liu, Jin-Biao; Zhou, Li; Wang, Yi-Zhong et al. (2016) Neuroprotective Activity of (-)-Epigallocatechin Gallate against Lipopolysaccharide-Mediated Cytotoxicity. J Immunol Res 2016:4962351
Wang, Yizhong; Li, Jieliang; Wang, Xu et al. (2016) (-)-Epigallocatechin-3-Gallate Enhances Hepatitis C Virus Double-Stranded RNA Intermediates-Triggered Innate Immune Responses in Hepatocytes. Sci Rep 6:21595
Liu, Jinbiao; Xiao, Qianhao; Zhou, Runhong et al. (2016) Comparative Analysis of Immune Activation Markers of CD8(+) T Cells in Lymph Nodes of Different Origins in SIV-Infected Chinese Rhesus Macaques. Front Immunol 7:371
Wang, Xu; Ma, Tong-Cui; Li, Jie-Liang et al. (2015) Heroin inhibits HIV-restriction miRNAs and enhances HIV infection of macrophages. Front Microbiol 6:1230
Li, Jie-Liang; Zhuang, Ke; Wu, Guang-Yao et al. (2015) Magnetic resonance imaging study of a simian/human immunodeficiency virus-infected Chinese rhesus macaque with HIV-associated dementia. AIDS Res Hum Retroviruses 31:272-3
Wang, Yizhong; Li, Jieliang; Wang, Xu et al. (2015) Comparison of antiviral activity of lambda-interferons against HIV replication in macrophages. J Interferon Cytokine Res 35:213-21
Mastrogiannis, Dimitrios S; Wang, Xu; Dai, Min et al. (2014) Alcohol enhances HIV infection of cord blood monocyte-derived macrophages. Curr HIV Res 12:301-8
Sang, Ming; Liu, Jin-Biao; Dai, Ming et al. (2014) Toll-like receptor 3 signaling inhibits simian immunodeficiency virus replication in macrophages from rhesus macaques. Antiviral Res 112:103-12