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Virus-specific immune response in HBeAg-negative chronic hepatitis B: relationship with clinical profile and HBsAg serum levels.

Loggi E, Bihl FK, Cursaro C, Granieri C, Galli S, Brodosi L, Furlini G, Bernardi M, Brander C, Andreone P - PLoS ONE (2013)

Bottom Line: The total breadth and magnitude of HBV-specific T cell responses did not differ significantly between the four groups.The same inverse association between anti-core T cell response and HBsAg levels was found in treated patients.Especially, robust anti-core T cell responses were found in the presence of reduced HBsAg serum levels, suggesting that core-specific T cell responses can mediate a protective effect on HBV control.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical and Surgical Scinces, University of Bologna, Bologna, Italy.

ABSTRACT

Background aims: The immune impairment characterizing chronic hepatitis B (cHBV) infection is thought to be the consequence of persistent exposure to viral antigens. However, the immune correlates of different clinical stages of cHBV and their relation with different levels of HBsAg have not been investigated. The aim of the present study was to evaluate the relationship between HBV-specific T cells response and the degree of in vivo HBV control and HBsAg serum levels in HBeAg-HBeAb+ cHBV.

Methods: Peripheral blood mononuclear cells from 42 patients with different clinical profiles (treatment-suppressed, inactive carriers and active hepatitis) of cHBV, 6 patients with resolved HBV infection and 10 HBV-uninfected individuals were tested with overlapping peptides spanning the entire HBV proteome. The frequency and magnitude of HBV-specific T cell responses was assessed by IFNγ ELISPOT assay. Serum HBsAg was quantified with a chemiluminescent immunoassay.

Results: The total breadth and magnitude of HBV-specific T cell responses did not differ significantly between the four groups. However, inactive carriers targeted preferentially the core region. In untreated patients, the breadth of the anti-core specific T cell response was inversely correlated with serum HBsAg concentrations as well as HBV-DNA and ALT levels and was significantly different in patients with HBsAg levels either above or below 1000 IU/mL. The same inverse association between anti-core T cell response and HBsAg levels was found in treated patients.

Conclusions: Different clinical outcomes of cHBV infection are associated with the magnitude, breadth and specificity of the HBV-specific T cell response. Especially, robust anti-core T cell responses were found in the presence of reduced HBsAg serum levels, suggesting that core-specific T cell responses can mediate a protective effect on HBV control.

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HBV-core specific T cell response and HBV serovirological markers in untreated patients (IC and CHB).A) Correlation between the breadth of the HBV core specific T cell response (number of anti-core targeted peptides) and HBsAg serum levels (IU/mL) in the 26 treatment-naive patients (IC and CHB patients). Regression line, r coefficient and p value (Spearman Ranks test) are shown. HBsAg axis in logarithmic scale. B) Correlation between the breadth of the HBV core specific T cell response and HBV-DNA levels (IU/mL) in the 26 treatment-naive patients (IC and CHB patients). Regression line, and r coefficient and p value (Spearman Ranks test) are shown. HBV-DNA axis in logarithmic scale. C) Number of anti-core responses in the 26 treatment-naive patients, stratified by level of HBsAg antigenemia (<1000 and >1000 IU/mL). Each symbol represents an individual patient with bars representing the median per group. * = p value: 0.004 (Mann Whitney).
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pone-0065327-g003: HBV-core specific T cell response and HBV serovirological markers in untreated patients (IC and CHB).A) Correlation between the breadth of the HBV core specific T cell response (number of anti-core targeted peptides) and HBsAg serum levels (IU/mL) in the 26 treatment-naive patients (IC and CHB patients). Regression line, r coefficient and p value (Spearman Ranks test) are shown. HBsAg axis in logarithmic scale. B) Correlation between the breadth of the HBV core specific T cell response and HBV-DNA levels (IU/mL) in the 26 treatment-naive patients (IC and CHB patients). Regression line, and r coefficient and p value (Spearman Ranks test) are shown. HBV-DNA axis in logarithmic scale. C) Number of anti-core responses in the 26 treatment-naive patients, stratified by level of HBsAg antigenemia (<1000 and >1000 IU/mL). Each symbol represents an individual patient with bars representing the median per group. * = p value: 0.004 (Mann Whitney).

Mentions: To assess the potential relationship between antiviral immune profile and sero-virological parameters of HBV infection, the levels of serum HBsAg were compared to the frequency of protein-specific T cells response in the two treatment naive (IC and CHB) patient groups. The data show that the HBsAg serum levels were inversely correlated with the breadth of the anti-core specific T cell response (r = −0.569, p = 0.002, Figure 3A). Similarly, the HBV-DNA levels were also inversely related with the breadth of the core-specific T cell response (r = −0.568, p = 0.005, Figure 3B). In addition, serum ALT levels also positively correlated with HBsAg serum levels (r = 0.534, p = 0.006) and negatively with the anti-core response (r = −0.608, p = 0.001). The positive effect of core-specific T cell responses on HBV control was further manifested when the untreated patients in the IC and the CHB groups were stratified based on a HBsAg cut-off 1000 IU/mL, showing a significantly broader anti-core T cell response in patients with levels of HBsAg<1000 IU/mL than patients with HBsAg>1000 (median frequency 2,5 vs 0, respectively, p = 0.004, Figure 3C). Similarly, among the 15 individuals with core-specific T cell responses, the IC group was over-represented compared to the CHB (n = 11 out of 13 vs 4 out of 13, p = 0.001, Table 2).


Virus-specific immune response in HBeAg-negative chronic hepatitis B: relationship with clinical profile and HBsAg serum levels.

Loggi E, Bihl FK, Cursaro C, Granieri C, Galli S, Brodosi L, Furlini G, Bernardi M, Brander C, Andreone P - PLoS ONE (2013)

HBV-core specific T cell response and HBV serovirological markers in untreated patients (IC and CHB).A) Correlation between the breadth of the HBV core specific T cell response (number of anti-core targeted peptides) and HBsAg serum levels (IU/mL) in the 26 treatment-naive patients (IC and CHB patients). Regression line, r coefficient and p value (Spearman Ranks test) are shown. HBsAg axis in logarithmic scale. B) Correlation between the breadth of the HBV core specific T cell response and HBV-DNA levels (IU/mL) in the 26 treatment-naive patients (IC and CHB patients). Regression line, and r coefficient and p value (Spearman Ranks test) are shown. HBV-DNA axis in logarithmic scale. C) Number of anti-core responses in the 26 treatment-naive patients, stratified by level of HBsAg antigenemia (<1000 and >1000 IU/mL). Each symbol represents an individual patient with bars representing the median per group. * = p value: 0.004 (Mann Whitney).
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getmorefigures.php?uid=PMC3672146&req=5

pone-0065327-g003: HBV-core specific T cell response and HBV serovirological markers in untreated patients (IC and CHB).A) Correlation between the breadth of the HBV core specific T cell response (number of anti-core targeted peptides) and HBsAg serum levels (IU/mL) in the 26 treatment-naive patients (IC and CHB patients). Regression line, r coefficient and p value (Spearman Ranks test) are shown. HBsAg axis in logarithmic scale. B) Correlation between the breadth of the HBV core specific T cell response and HBV-DNA levels (IU/mL) in the 26 treatment-naive patients (IC and CHB patients). Regression line, and r coefficient and p value (Spearman Ranks test) are shown. HBV-DNA axis in logarithmic scale. C) Number of anti-core responses in the 26 treatment-naive patients, stratified by level of HBsAg antigenemia (<1000 and >1000 IU/mL). Each symbol represents an individual patient with bars representing the median per group. * = p value: 0.004 (Mann Whitney).
Mentions: To assess the potential relationship between antiviral immune profile and sero-virological parameters of HBV infection, the levels of serum HBsAg were compared to the frequency of protein-specific T cells response in the two treatment naive (IC and CHB) patient groups. The data show that the HBsAg serum levels were inversely correlated with the breadth of the anti-core specific T cell response (r = −0.569, p = 0.002, Figure 3A). Similarly, the HBV-DNA levels were also inversely related with the breadth of the core-specific T cell response (r = −0.568, p = 0.005, Figure 3B). In addition, serum ALT levels also positively correlated with HBsAg serum levels (r = 0.534, p = 0.006) and negatively with the anti-core response (r = −0.608, p = 0.001). The positive effect of core-specific T cell responses on HBV control was further manifested when the untreated patients in the IC and the CHB groups were stratified based on a HBsAg cut-off 1000 IU/mL, showing a significantly broader anti-core T cell response in patients with levels of HBsAg<1000 IU/mL than patients with HBsAg>1000 (median frequency 2,5 vs 0, respectively, p = 0.004, Figure 3C). Similarly, among the 15 individuals with core-specific T cell responses, the IC group was over-represented compared to the CHB (n = 11 out of 13 vs 4 out of 13, p = 0.001, Table 2).

Bottom Line: The total breadth and magnitude of HBV-specific T cell responses did not differ significantly between the four groups.The same inverse association between anti-core T cell response and HBsAg levels was found in treated patients.Especially, robust anti-core T cell responses were found in the presence of reduced HBsAg serum levels, suggesting that core-specific T cell responses can mediate a protective effect on HBV control.

View Article: PubMed Central - PubMed

Affiliation: Department of Medical and Surgical Scinces, University of Bologna, Bologna, Italy.

ABSTRACT

Background aims: The immune impairment characterizing chronic hepatitis B (cHBV) infection is thought to be the consequence of persistent exposure to viral antigens. However, the immune correlates of different clinical stages of cHBV and their relation with different levels of HBsAg have not been investigated. The aim of the present study was to evaluate the relationship between HBV-specific T cells response and the degree of in vivo HBV control and HBsAg serum levels in HBeAg-HBeAb+ cHBV.

Methods: Peripheral blood mononuclear cells from 42 patients with different clinical profiles (treatment-suppressed, inactive carriers and active hepatitis) of cHBV, 6 patients with resolved HBV infection and 10 HBV-uninfected individuals were tested with overlapping peptides spanning the entire HBV proteome. The frequency and magnitude of HBV-specific T cell responses was assessed by IFNγ ELISPOT assay. Serum HBsAg was quantified with a chemiluminescent immunoassay.

Results: The total breadth and magnitude of HBV-specific T cell responses did not differ significantly between the four groups. However, inactive carriers targeted preferentially the core region. In untreated patients, the breadth of the anti-core specific T cell response was inversely correlated with serum HBsAg concentrations as well as HBV-DNA and ALT levels and was significantly different in patients with HBsAg levels either above or below 1000 IU/mL. The same inverse association between anti-core T cell response and HBsAg levels was found in treated patients.

Conclusions: Different clinical outcomes of cHBV infection are associated with the magnitude, breadth and specificity of the HBV-specific T cell response. Especially, robust anti-core T cell responses were found in the presence of reduced HBsAg serum levels, suggesting that core-specific T cell responses can mediate a protective effect on HBV control.

Show MeSH
Related in: MedlinePlus