title: Characterization of cross-reactive CD8+ T-cell recognition of HLA-A2-restricted HIV-Gag (SLYNTVATL) and HCV-NS5b (ALYDVVSKL) epitopes in individuals infected with human immunodeficiency and hepatitis C viruses.
abstract: The immunologic mechanisms underlying the faster progression of hepatitis C virus (HCV) disease in the presence of human immunodeficiency virus (HIV) coinfection are not clearly understood. T-cell cross-reactivity between HCV and influenza virus-specific epitopes has been associated with rapid progression of HCV disease (S. Urbani, B. Amadei, P. Fisicaro, M. Pilli, G. Missale, A. Bertoletti, and C. Ferrari, J. Exp. Med. 201:675-680, 2005). We asked whether T-cell cross-reactivity between HCV and HIV could exist during HCV/HIV coinfection and affect pathogenesis. Our search for amino acid sequence homology between the HCV and HIV proteomes revealed two similar HLA-A2-restricted epitopes, HIV-Gag (SLYNTVATL [HIV-SL9]) and HCV-NS5b (ALYDVVSKL [HCV-AL9]). We found that 4 out of 20 HLA-A2-positive (HLA-A2(+)) HIV-infected individuals had CD8(+) T cells that recognized both the HIV-SL9 and HCV-AL9 epitopes. However, the AL9 epitope was generally shown to be a weak agonist. Although HCV-monoinfected individuals in our study did not show AL9-specific responses, we found that about half of HCV/HIV-coinfected individuals had dual responses to both epitopes. High dual T-cell recognition among coinfected subjects was usually due to separate T-cell populations targeting each epitope, as determined by pentamer staining. The one individual demonstrating cross-reactive T cells to both epitopes showed the most advanced degree of liver disease. In coinfected individuals, we observed a positive correlation between the magnitudes of T-cell responses to both the SL9 and the AL9 epitopes, which was also positively associated with the clinical parameter of liver damage. Thus, we find that HIV infection induces T cells that can cross-react to heterologous viruses or prime for T cells that are closely related in sequence. However, the induction of cross-reactive T cells may not be associated with control of disease caused by the heterologous virus. This demonstrates that degeneracy of HIV-specific T cells may play a role in the immunopathology of HCV/HIV coinfection.
authors.affiliation: Institute of Medical Science, University of Toronto, 1 King's College Circle, Toronto, Ontario M5S 1A8, Canada.
authors.forename: Bahareh
authors.initials: B
authors.lastname: Vali
authors.forename: Robert
authors.initials: R
authors.lastname: Tohn
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Cohen
authors.forename: Ali
authors.initials: A
authors.lastname: Sakhdari
authors.forename: Prameet M
authors.initials: PM
authors.lastname: Sheth
authors.forename: Feng Yun
authors.initials: FY
authors.lastname: Yue
authors.forename: David
authors.initials: D
authors.lastname: Wong
authors.forename: Colin
authors.initials: C
authors.lastname: Kovacs
authors.forename: Rupert
authors.initials: R
authors.lastname: Kaul
authors.forename: Mario A
authors.initials: MA
authors.lastname: Ostrowski
mesh_terms: D000595:Amino Acid Sequence; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000821:virology; D003429:Cross Reactions; D018984:Epitopes, T-Lymphocyte / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015683:Gene Products, gag / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D015658:HIV Infections / Q000150:complications* / Q000276:immunology / Q000821:virology; D015497:HIV-1 / Q000276:immunology; D015789:HLA-A2 Antigen / Q000235:genetics / Q000378:metabolism*; D016174:Hepacivirus / Q000276:immunology; D006526:Hepatitis C / Q000150:complications* / Q000276:immunology / Q000821:virology; D006801:Humans; D008969:Molecular Sequence Data; D017361:Viral Nonstructural Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology*; D012324:RNA-Dependent RNA Polymerase
chemical_list: D018984:Epitopes, T-Lymphocyte; D015683:Gene Products, gag; D015789:HLA-A2 Antigen; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase