Reduced Hepatitis B Virus (HBV)-Specific CD4⁺T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy

Abstract

Functional hepatitis B virus (HBV)-specific T cells are significantly diminished in individuals chronicallyinfected with HBV compared to individuals with self-limiting HBV infection or those on anti-HBV therapy. In individuals infected with human immunodeficiency virus type 1 (HIV-1), coinfection with HBV is associated with an increased risk of worsening liver function following antiviral therapy and of more rapid HBV disease progression. Total HBV-specific T-cell responses in subjects with diverse genetic backgrounds were characterized by using a library of 15-mer peptides overlapping by 11 amino acids and spanning all HBV proteins. The magnitude and breadth of CD4 ؉ and CD8 ؉ T-cell responses to HBV in peripheral blood were examined by flow cytometry to detect gamma interferon production following stimulation with HBV peptide pools. Chronic HBV carriers (n ‫؍‬ 34) were studied, including individuals never treated for HBV infection (n ‫؍‬ 7), HBV-infected individuals receiving anti-HBV therapy (n ‫؍‬ 13), and HIV-1-HBV-coinfected individuals receiving anti-HBV therapy (n ‫؍‬ 14). CD4؉ and CD8 ؉ HBV-specific T-cell responses were more frequently detected and the CD8 ؉ T-cell responses were of greater magnitude and breadth in subjects on anti-HBV treatment than in untreated chronic HBV carriers. There was a significant inverse correlation between detection of a HBVspecific T-cell response and HBV viral load. HBV-specific CD4؉ and CD8 ؉ T-cell responses were significantly (fivefold) reduced compared with HIV-specific responses. Although, the frequency and breadth of HBV-specific CD8 ؉ T-cell responses were comparable in the monoinfected and HIV-1-HBV-coinfected groups, HBV-specific CD4 ؉ T-cell responses were significantly reduced in HIV-1-HBV-coinfected individuals. Therefore, HIV-1 infection has a significant and specific effect on HBV-specific T-cell immunity.There are 350 million individuals chronically infected with hepatitis B virus (HBV) worldwide (36,42,59). Each year 1 million to 1.5 million carriers die from HBV-related liver disease and liver cancer such as hepatocellular carcinoma (36,48). In the United States, Europe, and Australia, approximately 6 to 7% of individuals infected with human immunodeficiency virus type 1 (HIV-1) are also coinfected with HBV (23, 41). Liver disease is now a major comorbidity in HIV-1-infected individuals (11,66). Although hepatitis C virus (HCV)-HIV-1 coinfection is more common than HBV infection, liver failure occurs more frequently with persistent HBV infection (60, 63). Coinfection of HBV with HIV-1 leads to elevated HBV DNA levels, a lower rate of seroconversion to HBeAg, and lower alanine aminotransferase (ALT) levels than those in HBV monoinfection (21, 31). Spontaneous flares and HBeAg seroconversion occur in 5% of HBV-monoinfected individuals; however, in the setting of HIV-1-HBV coinfection, spontaneous flares or seroconversion to HBeAg is rare (18). In individuals infected with HIV-1 who subsequently acquire HBV infection, there is an increased risk of persisten...

The phenotype of hepatitis B virus-specific T cells differ in the liver and blood in chronic hepatitis B virus infection

“…4 However, despite detection of interferon-gamma (IFN-␥) HBV-specific T cells in blood, the magnitude of CD4 ϩ and CD8 ϩ HBV-specific T cells in chronic HBV infection was still significantly lower than that observed in other chronic infections such as human immunodeficiency virus (HIV)-1. 3,4 Previous studies using tetramer staining suggested a larger population of HBV-specific T cells being sequestered within the liver than in circulation. 2,5,6 Although a useful tool to quantify virus-specific T cells, the use of tetramers will detect virus-specific T cells regardless of their function or ability to produce cytokine.…”

“…[1][2][3] We recently developed a sensitive method to assess HBV-specific T cells using an overlapping peptide library and intracellular cytokine staining (ICS). 4 However, despite detection of interferon-gamma (IFN-␥) HBV-specific T cells in blood, the magnitude of CD4 ϩ and CD8 ϩ HBV-specific T cells in chronic HBV infection was still significantly lower than that observed in other chronic infections such as human immunodeficiency virus (HIV)-1. 3,4 Previous studies using tetramer staining suggested a larger population of HBV-specific T cells being sequestered within the liver than in circulation.…”

“…ICS was performed on whole blood as previously described, 4,11,12 with some minor modifications to include anti-IFN-␥-fluorescein isothiocyanate (clone B27) and anti-tumor necrosis factor-␣-Allophycocyanin (MAb11) or anti-interleukin-2 (IL-2)-fluorescein isothiocyanate (clone MQ1-17H12) and anti-interleukin-10 (IL-10)-Allophycocyanin (clone JES3-19F1; all from BD Biosciences). The same ICS method was also used with expanded PBMCs and LILs resuspended at 1 ϫ 10 6 cells/well in 200 l RPMI 1640, 10% human AB serum, and penicillin/streptomycin/glutamine.…”

“…The cutoff of 0.05% was determined using the mean plus 2 standard deviations of responses detected in 8 healthy controls as previously described. 4 The total magnitude of the HBV-specific T cell response to all 8 HBV peptide pools was calculated by adding the magnitude of cytokine-producing cells for each pool (above the 0.05% cutoff). The responses were also examined qualitatively by defining a "responder" as an individual who produced a particular cytokine to at least 1 peptide pool.…”

“…To examine total HBV-specific T cell responses, an overlapping peptide library was made as previously described. 4 The 15-residue peptides overlapping by 11 amino acids were combined to create 8 HBV peptide pools, according to the relevant protein, with each peptide represented at equal concentrations. The peptide pools therefore included peptides from precore/core [hepatitis B e antigen (HBeAg)/hepatitis B core antigen], X protein, hepatitis B surface antigen, and polymerase.…”