Coinfection with HIV and HCV is a rapidly growing public health issue. HIV/HCV coinfection is common in injection drug users (IDUs), the single largest group for HCV infection in the USA. HCV coinfection is becoming even more significant, as HIV-infected people are living longer with HAART. However, we have limited and conflicting information about the interactions between opioids, host innate immunity and HIV/HCV. Importantly, no study to date has addressed combined effects of heroin use and HCV on HIV infection as well as on TLR3/RIG-I-mediated innate immunity, which is a major barrier of fundamental understanding of the immunopathogenesis of HIV disease in HIV and/or HCV-infected IDUs. The goal of this proposal is to address our overarching hypothesis that the negative impact of opioids (heroin, morphine) on the antiviral innate immunity is crucial in facilitating HIV or HCV infection. We will investigate the impact of heroin use and/or HCV on host innate immunity and HIV/HCV infection. We will determine previously unrecognized mechanisms by which opioids compromise TLR3/RIG-I (the key sensors of viral infection)-mediated innate immunity against HIV/HCV infection. We propose the following specific aims:
Aim 1. Determine in vivo impact of heroin and/or HCV infection on plasma and PBMC levels of HIV, CD4 T cell counts and antiviral cellular factors related to HIV or HCV infection;
Aim 2. Determine the ex vivo effects of heroin and/or HIV/HCV infection on the activation of TLR3/RIG-I signaling pathways;
Aim 3. Determine the mechanism(s) by which morphine and/or HIV/HCV infection compromise TLR3/RIG-I signaling- mediated anti-HIV/HCV effects in primary macrophages and hepatocytes. Data arising from this study using the specimens from the unique Chinese heroin-dependent subjects with or without HIV and/or HCV infection will be clinically relevant and important in our understanding of the in vivo interplays between opioids, host innate immunity and viral infections. Long term goal of this project is to develop host innate immunity-based treatment and prevention strategies for HIV/HCV-infected opioid-abusers.

Public Health Relevance

HIV and/or HCV prevalence is a major and growing public health problem in the World. This project proposes in vitro, ex vivo and in vivo studies using a unique subject population, Chinese heroin dependent subjects infected with HIV with or without HCV, to address the impact of opiates and/or HCV on HIV infection and previously unrecognized impact and mechanisms by which opioids (heroin or morphine) and/or the viruses compromise the specific host innate immunity against HIV and HCV.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01DA022177-08
Application #
8704399
Study Section
NeuroAIDS and other End-Organ Diseases Study Section (NAED)
Program Officer
Purohit, Vishnudutt
Project Start
Project End
Budget Start
Budget End
Support Year
8
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Temple University
Department
Pathology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Zhou, Yu; Sun, Li; Wang, Xu et al. (2016) Short Communication: HIV-1 Infection Suppresses Circulating Viral Restriction microRNAs. AIDS Res Hum Retroviruses 32:386-9
Zhou, Yu; Wang, Xu; Sun, Li et al. (2016) Toll-like receptor 3-activated macrophages confer anti-HCV activity to hepatocytes through exosomes. FASEB J 30:4132-4140
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
Ma, Tong-Cui; Zhou, Run-Hong; Wang, Xu et al. (2016) Soybean-derived Bowman-Birk Inhibitor (BBI) Inhibits HIV Replication in Macrophages. Sci Rep 6:34752
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. (2015) Comparison of antiviral activity of lambda-interferons against HIV replication in macrophages. J Interferon Cytokine Res 35:213-21
Liu, Man-Qing; Zhao, Min; Kong, Wen-Hua et al. (2015) Antiretroviral Therapy Fails to Restore Levels of HIV-1 Restriction miRNAs in PBMCs of HIV-1-infected MSM. Medicine (Baltimore) 94:e2116
Dai, Ming; Wang, Xu; Li, Jie-Liang et al. (2015) Activation of TLR3/interferon signaling pathway by bluetongue virus results in HIV inhibition in macrophages. FASEB J 29:4978-88
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

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