Impaired Quality of the Hepatitis B Virus (HBV)-Specific T-Cell Response in Human Immunodeficiency Virus Type 1-HBV Coinfection

Abstract

Hepatits B virus (HBV)-specific T cells play a key role both in the control of HBV replication and in the pathogenesis of liver disease. Human immunodeficiency virus type 1 (HIV-1) coinfection and the presence or absence of HBV e (precore) antigen (HBeAg) significantly alter the natural history of chronic HBV infection. We examined the HBV-specific T-cell responses in treatment-naïve HBeAg-positive and HBeAg-negative HIV-1-HBV-coinfected (n ‫؍‬ 24) and HBV-monoinfected (n ‫؍‬ 39) Asian patients. Peripheral blood was stimulated with an overlapping peptide library for the whole HBV genome, and tumor necrosis factor alpha and gamma interferon cytokine expression in CD8 ؉ T cells was measured by intracellular cytokine staining and flow cytometry. There was no difference in the overall magnitude of the HBV-specific T-cell responses, but the quality of the response was significantly impaired in HIV-1-HBV-coinfected patients compared with monoinfected patients. In coinfected patients, HBV-specific T cells rarely produced more than one cytokine and responded to fewer HBV proteins than in monoinfected patients. Overall, the frequency and quality of the HBV-specific T-cell responses increased with a higher CD4 ؉ T-cell count (P ‫؍‬ 0.018 and 0.032, respectively). There was no relationship between circulating HBV-specific T cells and liver damage as measured by activity and fibrosis scores, and the HBV-specific T-cell responses were not significantly different in patients with either HBeAg-positive or HBeAg-negative disease. The quality of the HBV-specific T-cell response is impaired in the setting of HIV-1-HBV coinfection and is related to the CD4 ؉ T-cell count.

HBV and HIV co-infection: Impact on liver pathobiology and therapeutic approaches

“…In a closely related clinical study of HIV and hepatitis C virus co-infection cases, liver cirrhosis was found associated with higher systemic markers of gut-microbial translocation [31] that could be also true for HBV. Further, the activation of HBV-specific CD8 + cells, crucial in controlling HBV replication as well as the liver pathogenesis [32] , is shown to be clearly impaired during HIV secondary infection. This might partially explain the tendency of progression of acute hepatitis B towards chronicity in HIV co-infection cases [33] .…”

No Increase in Hepatitis B Virus (HBV)-Specific CD8+T Cells in Patients with HIV-1-HBV Coinfections following HBV-Active Highly Active Antiretroviral Therapy

“…We have previously shown that the HBV-specific T-cell response is impaired in HIV-HBV coinfection (7,9). In one small observational study (n ϭ 5), HBV-active HAART was associated with the recovery of CD8 ϩ HBV-specific T cells (19); however, in this study, two patients had received prior HAART, and the HBV-specific T-cell responses were examined only during the first 24 weeks of treatment (19).…”

“…Intracellular cytokine staining (ICS) was performed as previously described (7). Briefly, 200 l of fresh whole blood was incubated for 6 h at 37°C with an overlapping HBV peptide library that covered the entire HBV genome and was designed for the genotype A consensus sequence and included additional peptides for genotypes B, C, and D in areas of high variability (8,9) or with HIV-1 Gag peptides (obtained through the AIDS Research and Reference Reagent Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health) and either DMSO as a negative control or pokeweed mitogen (PWM; Sigma) and staphylococcal enterotoxin B (SEB; St. Louis, MO) as positive controls (Fig.…”

Hepatitis B virus (HBV)-specific T-cell responses to recombinant HBV core protein in patients with normal liver function and co-infected with chronic HBV and human immunodeficiency virus 1 (HIV-1)

“…Additionally, we found that HBeAg-positive individuals had stronger HBV-specific T-cell responses than HBeAg-negative patients at 3 and 12 months after the onset of acute HIV-1 infection. These findings are contradictory to the Chang et al study which reported that the magnitude of the HBV-specific IFN-γ –positive CD8 + T-cell response was not significantly different between HBeAg-positive and -negative patients in HIV/HBV co-infected, ART naïve patients [15]. The distinct immunogenicity of stimulus antigens used in the two studies may have led to the different outcomes.…”

“…The distinct immunogenicity of stimulus antigens used in the two studies may have led to the different outcomes. Chang et al [15] used a 15 amino acid peptide pool of four proteins, however 14–22 amino acid peptides are typically used to induce either CD4 + or CD8 + T-cell responses [16] and mainly induce a CD8 + T-cell response [17]. Recombinant whole protein can be used to detect CD4-mediated responses and a limited CD8-mediated response [16,18].…”