Immunologic evidence for lack of heterologous protection following resolution of HCV in patients with non–genotype 1 infection

Abstract

Chronic hepatitis C virus (HCV) infectionis typically characterized by a lack of virus-specific CD4 ؉ T-cell-proliferative responses, but strong responses have been described in a subset of persons with persistent viremia. One possible explanation for these responses is that they were primed by an earlier resolved infection and do not recognize the current circulating virus. We defined all targeted epitopes using overlapping peptides corresponding to a genotype 1a strain in 44 patients chronically infected with different HCV genotypes (GT). Surprisingly, more HCVspecific CD4 ؉ T-cell responses were detected in patients with chronic non-GT1 infection compared with patients with chronic GT1 infection (P ‫؍‬ .017). Notably, we found serologic evidence of a previous exposure to GT1 in 4 patients with non-GT1 infection, and these persons also demonstrated significantly more responses than non-GT1 patients in whom genotype and HCV serotype were identical (P < .

Sustained Virological Response after Early Antiviral Treatment of Acute Hepatitis C Virus and HIV Coinfection

“…Although it remains to be elucidated whether these HCV-specific responses are of any clinical relevance, they are immunological markers that provide proof that HCV-specific T cells were indeed primed and preserved (potentially by early antiviral therapy) even during primary HIV infection. This notion is underlined by the fact that these CD4 + T cell responses are usually not detected in patients chronically monoinfected with HCV [13,14] or chronically coinfected with HIV and HCV [18,36]. In accordance with earlier work, we were able to detect HCVspecific CD4 + T cell responses only in the 2 HIV-infected patients with a nadir CD4 + cell count 1200 cells/mL [15].…”

“…No significant responses were detectable for patient J020 (right graph). Fresh CD4 + T cells of patients H014, I003, and J020 were stimulated with a set of 25 previously described [13], frequently recognized HCV-specific 20mer peptides (concentration, 1 mg/mL) and were cultured in the presence of interleukin-2 for 14 days, as previously described [13,14]. HCV-specific CD4 + T cell cultures were then tested for HCV-specific responses (interferon-g) in overnight single-peptide Elispot assays (controls not shown).…”

“…All patients enrolled gave written informed consent for this study, which was approved by the Institutional Review Board of the University Medical Center Hamburg-Eppendorf. Patients with HCV monoinfection, as well as healthy individuals, served as controls for the validation of the immunological tests [13,14]. HIV-1 viral load was determined using COBAS AMPLICOR assays with a limit of detection of !50 RNA copies/mL, and quantitative HCV viremia was determined by an HCV Monitor assay with a limit of detection of !300 IU/mL (both Roche Diagnostik).…”

“…HCV-specific CD4 + T cell lines were generated as described elsewhere [13,14,17]. Briefly, cell lines were generated via stimulation of fresh PBMCs with R10 medium supplemented with recombinant interleukin-2 (50 U/mL) and the respective HCV 20mer peptides at a concentration of 1 mg/mL.…”

Escape from a Dominant HLA-B*15-Restricted CD8 + T Cell Response against Hepatitis C Virus Requires Compensatory Mutations outside the Epitope

“…Rather, we hypothesize that these responses represent memory CD8 T cells against a previous genotype 1b infection, which is in line with the ability to rapidly expand them from PBMCs in vitro. Immunological evidence of exposure to different HCV genotypes was previously described for such high-risk groups for HCV infection (13,45). Although there is a large body of evidence that escape mutations are frequently selected in highly variable RNA viruses such as HIV and HCV, their overall role in viral persistence and immune control is less clear.…”