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T lymphocytes from chronic HCV-infected patients are primed for activation-induced apoptosis and express unique pro-apoptotic gene signature.

Zhao BB, Zheng SJ, Gong LL, Wang Y, Chen CF, Jin WJ, Zhang D, Yuan XH, Guo J, Duan ZP, He YW - PLoS ONE (2013)

Bottom Line: Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes.We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures.These results provide novel insights to the pathogenesis of chronic HCV infection.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biology of Pathogens, Ministry of Health, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, R. P. China.

ABSTRACT
Although extensive studies have demonstrated the functional impairment of antigen-specific CD4(+) and CD8(+) T-cells during chronic hepatitis C virus (HCV) infection, the functional status of global CD4(+) and CD8(+) T-cells remains unclear. In this report, we recruited 42 long-term (~20 years) treatment-naïve chronic HCV (CHC) patients and 15 healthy donors (HDs) to investigate differences in global CD4(+) and CD8(+) T-cells function. We show that CD4(+) and CD8(+) T-cells from CHC patients underwent increased apoptosis after TCR stimulation. Furthermore, IFN-γ, IL-9 and IP-10 were elevated in CHC patients' plasma and promoted activation-induced T-cells death. Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures. Importantly, the gene expression patterns of CD4(+) and CD8(+) T-cells from CHC patients differ from those in CD4(+) and CD8(+) T-cells from human immunodeficiency virus type 1 (HIV-1) or hepatitis B virus (HBV) infected individuals. Our results indicate that chronic HCV infection causes a systemic change in cytokine levels that primes T-cells for activation-induced apoptosis. Furthermore, HCV infection programs unique apoptosis-related gene expression profiles in CD4(+) and CD8(+) T-cells, leading to their enhanced activation-induced apoptosis. These results provide novel insights to the pathogenesis of chronic HCV infection.

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Expression patterns of apoptosis-related genes in T-cells from patients infected with HCV, HIV-1, and HBV.(A), Relative expression levels of apoptosis-related genes in CD4+ T-cells during HCV or HIV-1 infection. (B), Relative expression levels of apoptosis-related genes in CD8+ T-cells during HCV, HIV-1, or HBV infection. The gene expression levels in T-cells from HDs were defined as 1, and fold changes are shown.
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pone-0077008-g007: Expression patterns of apoptosis-related genes in T-cells from patients infected with HCV, HIV-1, and HBV.(A), Relative expression levels of apoptosis-related genes in CD4+ T-cells during HCV or HIV-1 infection. (B), Relative expression levels of apoptosis-related genes in CD8+ T-cells during HCV, HIV-1, or HBV infection. The gene expression levels in T-cells from HDs were defined as 1, and fold changes are shown.

Mentions: An important feature of untreated HIV infection is the gradual loss of global CD4+ T-cells via apoptosis [25]. We compared the gene expression profiles of CD4+ and CD8+ T-cells from CHC patients to those of HIV or HBV patients using published microarray data [9–11]. Interestingly, the expression of 65 genes was significantly changed in both CHC and HIV patients (Table S3). Despite these commonly changed genes, the T-cells gene expression patterns in these two groups of patients differed greatly. First, the expression of interferon-stimulated genes (ISGs) including interferon alpha-inducible protein 6 (IFI6), interferon alpha-inducible protein 27 (IFI27), interferon-inducible protein 44 (IFI44), 2'-5'-oligoadenylate synthetase 1 (OAS1), and myxovirus resistance protein 1 (MX1), was upregulated early during the acute phase of HIV-1 infection and maintained through the chronic phase but was not upregulated in CD4+ T-cells from CHC patients. Second, many apoptosis-related gene expression changes in CD4+ T-cells from CHC patients were not observed in CD4+ T-cells from HIV-1 infected patients (Figure 7A and Table S3). These results suggest that HCV and HIV infection have different impacts on the expression profiles of apoptosis-related genes in total CD4+ T-cells.


T lymphocytes from chronic HCV-infected patients are primed for activation-induced apoptosis and express unique pro-apoptotic gene signature.

Zhao BB, Zheng SJ, Gong LL, Wang Y, Chen CF, Jin WJ, Zhang D, Yuan XH, Guo J, Duan ZP, He YW - PLoS ONE (2013)

Expression patterns of apoptosis-related genes in T-cells from patients infected with HCV, HIV-1, and HBV.(A), Relative expression levels of apoptosis-related genes in CD4+ T-cells during HCV or HIV-1 infection. (B), Relative expression levels of apoptosis-related genes in CD8+ T-cells during HCV, HIV-1, or HBV infection. The gene expression levels in T-cells from HDs were defined as 1, and fold changes are shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3794995&req=5

pone-0077008-g007: Expression patterns of apoptosis-related genes in T-cells from patients infected with HCV, HIV-1, and HBV.(A), Relative expression levels of apoptosis-related genes in CD4+ T-cells during HCV or HIV-1 infection. (B), Relative expression levels of apoptosis-related genes in CD8+ T-cells during HCV, HIV-1, or HBV infection. The gene expression levels in T-cells from HDs were defined as 1, and fold changes are shown.
Mentions: An important feature of untreated HIV infection is the gradual loss of global CD4+ T-cells via apoptosis [25]. We compared the gene expression profiles of CD4+ and CD8+ T-cells from CHC patients to those of HIV or HBV patients using published microarray data [9–11]. Interestingly, the expression of 65 genes was significantly changed in both CHC and HIV patients (Table S3). Despite these commonly changed genes, the T-cells gene expression patterns in these two groups of patients differed greatly. First, the expression of interferon-stimulated genes (ISGs) including interferon alpha-inducible protein 6 (IFI6), interferon alpha-inducible protein 27 (IFI27), interferon-inducible protein 44 (IFI44), 2'-5'-oligoadenylate synthetase 1 (OAS1), and myxovirus resistance protein 1 (MX1), was upregulated early during the acute phase of HIV-1 infection and maintained through the chronic phase but was not upregulated in CD4+ T-cells from CHC patients. Second, many apoptosis-related gene expression changes in CD4+ T-cells from CHC patients were not observed in CD4+ T-cells from HIV-1 infected patients (Figure 7A and Table S3). These results suggest that HCV and HIV infection have different impacts on the expression profiles of apoptosis-related genes in total CD4+ T-cells.

Bottom Line: Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes.We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures.These results provide novel insights to the pathogenesis of chronic HCV infection.

View Article: PubMed Central - PubMed

Affiliation: Key Laboratory of Systems Biology of Pathogens, Ministry of Health, Institute of Pathogen Biology, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, R. P. China.

ABSTRACT
Although extensive studies have demonstrated the functional impairment of antigen-specific CD4(+) and CD8(+) T-cells during chronic hepatitis C virus (HCV) infection, the functional status of global CD4(+) and CD8(+) T-cells remains unclear. In this report, we recruited 42 long-term (~20 years) treatment-naïve chronic HCV (CHC) patients and 15 healthy donors (HDs) to investigate differences in global CD4(+) and CD8(+) T-cells function. We show that CD4(+) and CD8(+) T-cells from CHC patients underwent increased apoptosis after TCR stimulation. Furthermore, IFN-γ, IL-9 and IP-10 were elevated in CHC patients' plasma and promoted activation-induced T-cells death. Global CD4(+) and CD8(+) T-cells also showed unique transcriptional profiles in the expression of apoptosis-related genes. We identified BCL2, PMAIP1, and CASP1 in CD4(+) T-cells and IER3 and BCL2A1 in CD8(+) T-cells from CHC patients as HCV-specific gene signatures. Importantly, the gene expression patterns of CD4(+) and CD8(+) T-cells from CHC patients differ from those in CD4(+) and CD8(+) T-cells from human immunodeficiency virus type 1 (HIV-1) or hepatitis B virus (HBV) infected individuals. Our results indicate that chronic HCV infection causes a systemic change in cytokine levels that primes T-cells for activation-induced apoptosis. Furthermore, HCV infection programs unique apoptosis-related gene expression profiles in CD4(+) and CD8(+) T-cells, leading to their enhanced activation-induced apoptosis. These results provide novel insights to the pathogenesis of chronic HCV infection.

Show MeSH
Related in: MedlinePlus