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Identification of the transcripts associated with spontaneous HCV clearance in individuals co-infected with HIV and HCV

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ABSTRACT

Background: Infection with human immunodeficiency virus (HIV) influences the outcome and natural disease progression of hepatitis C virus (HCV) infection. While the majority of HCV mono-infected and HCV/HIV co-infected subjects develop chronic HCV infection, 20–46% of mono- and co-infected subjects spontaneously clear HCV infection. The mechanism underlying viral clearance is not clearly understood. Analysis of differential cellular gene expression (mRNA) between HIV-infected patients with persistent HCV infection or spontaneous clearance could provide a unique opportunity to decipher the mechanism of HCV clearance.

Methods: Plasma RNA from HIV/HCV co-infected subjects who cleared HCV and those who remained chronically infected with HCV was sequenced using Ion Torrent technology. The sequencing results were analyzed to identify transcripts that are associated with HCV clearance by measuring differential gene expression in HIV/HCV co-infected subjects who cleared HCV and those who remained chronically infected with HCV.

Results: We have identified plasma mRNA, the levels of which are significantly elevated (at least 5 fold, False Discovery Rate (FDR) <0.05) before HCV infection in subjects who cleared HCV compared to those who remained chronically infected. Upon further analysis of these differentially expressed genes, before and after HCV infection, we found that before HCV infection 12 genes were uniquely upregulated in the clearance group compared to the chronically infected group. Importantly, a number of these 12 genes and their upstream regulators (such as CCL3, IL17D, LBP, SOCS3, NFKBIL1, IRF) are associated with innate immune response functions.

Conclusions: These results suggest that subjects who spontaneously clear HCV may express these unique genes associated with innate immune functions.

No MeSH data available.


Related in: MedlinePlus

Differentially expressed genes before HCV infection in clearance group compared to chronic group. a The heatmap was generated with the statistical differentially expressed genes between clearance group and chronic group before HCV infection. The numbers on X-axis represent individual subjects. Green stands for the clearance group and blue stands for the chronic group. b Pie chart illustrates the percentage of the DEGs, which encode proteins involved in different functions
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Fig2: Differentially expressed genes before HCV infection in clearance group compared to chronic group. a The heatmap was generated with the statistical differentially expressed genes between clearance group and chronic group before HCV infection. The numbers on X-axis represent individual subjects. Green stands for the clearance group and blue stands for the chronic group. b Pie chart illustrates the percentage of the DEGs, which encode proteins involved in different functions

Mentions: Plasma transcriptome analysis was performed in HCV infected individuals who cleared virus and those who remained chronically infected. A schematic diagram of the approaches for measurement of differentially expressed genes from the patients’ plasma samples collected before and after HCV infection and those cleared HCV and those who remained chronically infected is shown in Fig. 1. A comparison of transcriptomes before HCV infection between the HCV clearance group (TR1B, Fig. 1) and the chronically HCV infected group (TR 2B, Fig. 1) showed that the expression levels of 32 genes were significantly higher (5–563 fold) and expression level of one gene (LL22NC03–63E9.3) was significantly lower in the clearance group (Table 2). To further assess the clustering of subjects within the chronic and clearance groups and across the groups, hierarchical clustering was performed using the differentially expressed genes (Fig. 2a). Four of the eight chronically infected participants clustered together indicating a distinct gene expression pattern whereas the other four samples did not show a similar pattern. On the other hand, three of the five participants in the clearance group clustered indicating similar gene expression and the remaining two subjects had different gene expression. In both clearance and chronic groups, the characteristics of the samples that did not aggregate with the rest of the samples in the respective groups were not different with respect to HIV viral load or IL28B polymorphism. This suggests that HIV viral load and IL28B polymorphism may not have an independent effect on the pattern of the gene expression.Fig. 1


Identification of the transcripts associated with spontaneous HCV clearance in individuals co-infected with HIV and HCV
Differentially expressed genes before HCV infection in clearance group compared to chronic group. a The heatmap was generated with the statistical differentially expressed genes between clearance group and chronic group before HCV infection. The numbers on X-axis represent individual subjects. Green stands for the clearance group and blue stands for the chronic group. b Pie chart illustrates the percentage of the DEGs, which encode proteins involved in different functions
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5120459&req=5

Fig2: Differentially expressed genes before HCV infection in clearance group compared to chronic group. a The heatmap was generated with the statistical differentially expressed genes between clearance group and chronic group before HCV infection. The numbers on X-axis represent individual subjects. Green stands for the clearance group and blue stands for the chronic group. b Pie chart illustrates the percentage of the DEGs, which encode proteins involved in different functions
Mentions: Plasma transcriptome analysis was performed in HCV infected individuals who cleared virus and those who remained chronically infected. A schematic diagram of the approaches for measurement of differentially expressed genes from the patients’ plasma samples collected before and after HCV infection and those cleared HCV and those who remained chronically infected is shown in Fig. 1. A comparison of transcriptomes before HCV infection between the HCV clearance group (TR1B, Fig. 1) and the chronically HCV infected group (TR 2B, Fig. 1) showed that the expression levels of 32 genes were significantly higher (5–563 fold) and expression level of one gene (LL22NC03–63E9.3) was significantly lower in the clearance group (Table 2). To further assess the clustering of subjects within the chronic and clearance groups and across the groups, hierarchical clustering was performed using the differentially expressed genes (Fig. 2a). Four of the eight chronically infected participants clustered together indicating a distinct gene expression pattern whereas the other four samples did not show a similar pattern. On the other hand, three of the five participants in the clearance group clustered indicating similar gene expression and the remaining two subjects had different gene expression. In both clearance and chronic groups, the characteristics of the samples that did not aggregate with the rest of the samples in the respective groups were not different with respect to HIV viral load or IL28B polymorphism. This suggests that HIV viral load and IL28B polymorphism may not have an independent effect on the pattern of the gene expression.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Infection with human immunodeficiency virus (HIV) influences the outcome and natural disease progression of hepatitis C virus (HCV) infection. While the majority of HCV mono-infected and HCV/HIV co-infected subjects develop chronic HCV infection, 20–46% of mono- and co-infected subjects spontaneously clear HCV infection. The mechanism underlying viral clearance is not clearly understood. Analysis of differential cellular gene expression (mRNA) between HIV-infected patients with persistent HCV infection or spontaneous clearance could provide a unique opportunity to decipher the mechanism of HCV clearance.

Methods: Plasma RNA from HIV/HCV co-infected subjects who cleared HCV and those who remained chronically infected with HCV was sequenced using Ion Torrent technology. The sequencing results were analyzed to identify transcripts that are associated with HCV clearance by measuring differential gene expression in HIV/HCV co-infected subjects who cleared HCV and those who remained chronically infected with HCV.

Results: We have identified plasma mRNA, the levels of which are significantly elevated (at least 5 fold, False Discovery Rate (FDR) <0.05) before HCV infection in subjects who cleared HCV compared to those who remained chronically infected. Upon further analysis of these differentially expressed genes, before and after HCV infection, we found that before HCV infection 12 genes were uniquely upregulated in the clearance group compared to the chronically infected group. Importantly, a number of these 12 genes and their upstream regulators (such as CCL3, IL17D, LBP, SOCS3, NFKBIL1, IRF) are associated with innate immune response functions.

Conclusions: These results suggest that subjects who spontaneously clear HCV may express these unique genes associated with innate immune functions.

No MeSH data available.


Related in: MedlinePlus