HIV infection increases HCV-induced hepatocyte apoptosis

Jang, Jae Young; Shao, Run–Xuan; Lin, Wenyu; Weinberg, Ethan M.; Chung, Woo Jin; Tsai, Wan-Ting; Zhao, Hong; Goto, Kaku; Zhang, Leiliang; Méndez-Navarro, Jorge; Jilg, Nikolaus; Peng, Leilei; Brockman, Mark A.; Chung, Raymond T.

doi:10.1016/j.jhep.2010.07.042

Cited by 49 publications

(49 citation statements)

References 44 publications

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“…We recently demonstrated that co-infection with HCV and HIV stimulates DR4 and DR5 gene expression and subsequently activates caspase-3 signaling pathway, resulting in induction of mitochondrial apoptosis of human hepatocytes [18]. In this study, we demonstrate the significant contribution of caspase-8 activation to HCV-induced DR4/DR5-dependent hepatocyte apoptosis.…”

Section: Introductionsupporting

confidence: 61%

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TRAIL Enhances Apoptosis of Human Hepatocellular Carcinoma Cells Sensitized by Hepatitis C Virus Infection: Therapeutic Implications

et al. 2014

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Hepatitis C virus (HCV) infection causes chronic liver diseases leading to hepatocellular carcinoma (HCC) and liver failure. We have previously shown that HCV sensitizes hepatocytes to mitochondrial apoptosis via the TRAIL death receptors DR4 and DR5. Although TRAIL and its receptors are selective targets for cancer therapy, their potential against HCC with chronic HCV infection has not been explored yet. Here we show that HCV induces DR4/DR5-dependent activation of caspase-8 leading to elevation of apoptotic signaling in infected cells and also present TRAIL effect in HCV-induced apoptotic signaling. HCV induced proteolytic cleavage of caspase-9 by stimulating DR4 and DR5, resulting in subsequent cleavage of caspase-3. Further, HCV-induced proteolytic cleavage in caspase-8, caspase-9, and caspase-3 was enhanced in the presence of recombinant TRAIL. HCV-induced cleavage in caspase-9 and increase in caspase-3/7 activity was completely suppressed by silencing of either DR4 or DR5. Perturbing DR4/DR5-caspase-8 signaling complex by silencing DR4 and DR5 or by chemical inhibitor specific to caspase-8 led to decrease of HCV-induced cleavage of poly(ADP-ribose) polymerase (PARP), a substrate for caspase-3 during apoptosis, indicating the functional role of caspase-8 in HCV-induced apoptotic signaling network. Furthermore, TRAIL enhanced PARP cleavage in apoptotic response induced by HCV infection, indicating the effect of TRAIL for the induction of selective apoptosis of HCC cells infected with HCV. Given the importance of apoptosis in HCC development, our data suggest that HCV-induced DR4 and DR5 may be considered as an attractive target for TRAIL therapy against HCC with chronic HCV infection.

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Section: Introductionsupporting

confidence: 61%

“…Cell culture-derived HCV JFH-1 (HCVcc) used in this study was propagated and prepared, as described previously [18].…”

Section: Methodsmentioning

confidence: 99%

TRAIL Enhances Apoptosis of Human Hepatocellular Carcinoma Cells Sensitized by Hepatitis C Virus Infection: Therapeutic Implications

et al. 2014

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“…[48] In addition, exposure of HCV-infected hepatocytes to HIV leads to increased apoptosis and expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and the TRAIL death receptors DR4 and DR5. [49, 50] Finally, infecting hepatocytes with HCV leads to induction of ROS and activation of p38 MAPK, JNK, ERK1/2 and NFκB pathways, which leads to increased TGF-β1. [51] In a similar manner, exposing hepatocytes to HIV directly leads to increased production of ROS, collagen, and tissue inhibitor of metalloproteinase 1 (TIMP1), an effect that is magnified by concurrent HCV exposure and can be blocked by ROS inhibition or siRNA to NFκB.…”

Section: Mechanisms Of Accelerated Fibrosismentioning

confidence: 99%

HCV and HIV co-infection: mechanisms and management

Chen

Feeney

Chung

2014

Nat Rev Gastroenterol Hepatol

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HCV and HIV co-infection is associated with accelerated hepatic fibrosis progression and higher rates of liver decompensation and death compared to HCV monoinfection, and liver disease is a leading cause of non-AIDS related mortality among HIV-infected patients. New insights have revealed multiple mechanisms by which HCV and HIV lead to accelerated disease progression, specifically that HIV infection increases HCV replication, augments HCV-induced hepatic inflammation, increases hepatocyte apoptosis, increases microbial translocation from the gut, and leads to an impairment of HCV-specific immune responses. Treatment of HIV with antiretroviral therapy and treatment of HCV have independently been shown to delay the progression of fibrosis and reduce complications from end-stage liver disease among co-infected patients. However, rates of sustained virologic response with PEG-IFN and ribavirin have been significantly inferior among co-infected patients compared to HCV monoinfected patients, and treatment uptake has remained low given the limited efficacy and tolerability of current HCV regimens. With multiple direct acting antivirals in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients, which incorporates data on fibrosis stage as well as potential drug interactions with antiretroviral therapy.

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“…Relative risks were similarly increased for all major NHL subtypes (Marcucci and Mele, 2011). Although the mechanism of the interaction between HIV and HCV is not completely known, HIV increases the progression of HCV (Singal and Anand, 2009;Jang et al, 2010).…”

Section: Non Hodgkin Lymphomamentioning

confidence: 94%

Geographical patterns of Kaposi’s sarcoma, nonHodgkin lymphomas, and cervical cancer associated with HIV infection in five African populations

Chaabna

Boniol

Vuyst³

et al. 2012

European Journal of Cancer Prevention

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The objective of this study is to describe the most recent geographical patterns of incidence of AIDS-related cancers, Kaposi's sarcoma (KS), nonHodgkin lymphoma (NHL), and cervical cancer in North African and subSaharan African populations. Data were extracted for the period 1998-2002 from five African population-based cancer registries: Kyadondo, Harare, Setif, Sousse, and Gharbiah. Age-standardized rates were calculated using the African standard population; a comparison was made between these populations by computing the standardized incidence ratio and 95% confidence intervals. The KS rate was found to be significantly higher in men than in women, and higher in Harare (women: 26.3/100,000; men: 50.4/100,000) and Kyadondo (women: 23.6/100,000; men: 30.2/100,000) than in the North African sites for both sexes (<0.3/100,000). In addition, the KS rate in women from Harare was similar to that for Kyadondo. Gharbiah presented the highest rates for NHL (women: 7 per 100,000; men: 11.9/100,000) for both sexes. We observed that Harare and Kyadondo had similar age-specific incidence in the high-risk age group for HIV/AIDS (15-49 years), and these rates were 4.5-fold higher in subSaharan populations than those in the North African sites. Thus, it was observed that the pattern of HIV prevalence is variable with the lowest prevalence in North African countries, intermediate prevalence in Uganda, and the highest prevalence in Zimbabwe. Our findings show that the incidence of NHL and cervical cancer, considered to be HIV/AIDS-related cancers, does not follow the pattern of HIV prevalence in the five studied African populations. Thus, the highest NHL incidence rate in both sexes in Gambia may be explained, at least in great part, by the highest hepatitis C virus prevalence observed there. Indeed, factors other than HIV infection likely contribute to their geographical patterns.

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HIV infection increases HCV-induced hepatocyte apoptosis

Cited by 49 publications

References 44 publications

TRAIL Enhances Apoptosis of Human Hepatocellular Carcinoma Cells Sensitized by Hepatitis C Virus Infection: Therapeutic Implications

TRAIL Enhances Apoptosis of Human Hepatocellular Carcinoma Cells Sensitized by Hepatitis C Virus Infection: Therapeutic Implications

HCV and HIV co-infection: mechanisms and management

Geographical patterns of Kaposi’s sarcoma, nonHodgkin lymphomas, and cervical cancer associated with HIV infection in five African populations

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