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.
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.
|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|
|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|
|Wang, Yizhong; Li, Jieliang; Wang, Xu et al. (2014) Hepatitis C virus impairs TLR3 signaling and inhibits IFN-? 1 expression in human hepatoma cell line. Innate Immun 20:3-11|
|Li, Jieliang; Wang, Yizhong; Wang, Xu et al. (2013) Immune activation of human brain microvascular endothelial cells inhibits HIV replication in macrophages. Blood 121:2934-42|
|Wang, Yizhong; Wang, Xu; Li, Jieliang et al. (2013) RIG-I activation inhibits HIV replication in macrophages. J Leukoc Biol 94:337-41|
|Wang, Yizhong; Li, Jieliang; Wang, Xu et al. (2013) Hepatic stellate cells, liver innate immunity, and hepatitis C virus. J Gastroenterol Hepatol 28 Suppl 1:112-5|
|Zhou, Yu; Bao, Rong; Haigwood, Nancy L et al. (2013) SIV infection of rhesus macaques of Chinese origin: a suitable model for HIV infection in humans. Retrovirology 10:89|
|Wang, Y; Li, J; Wang, X et al. (2013) Induction of interferon-? contributes to Toll-like receptor-3-activated hepatic stellate cell-mediated hepatitis C virus inhibition in hepatocytes. J Viral Hepat 20:385-94|
|Wang, Yizhong; Ye, Li; Wang, Xu et al. (2013) Retinoic acid inducible gene-I (RIG-I) signaling of hepatic stellate cells inhibits hepatitis C virus replication in hepatocytes. Innate Immun 19:193-202|
|Li, Jieliang; Ye, Li; Wang, Xu et al. (2012) Induction of interferon-? contributes to Toll-like receptor 3-mediated herpes simplex virus type 1 inhibition in astrocytes. J Neurosci Res 90:399-406|
Showing the most recent 10 out of 32 publications