The Journal of Experimental Medicine
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Published online 12 April 2004 doi:10.1084/jem.20031869
Rockefeller University Press, 0022-1007 $8.00
JEM, Volume 199, Number 8, 1053-1063
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Identification of Cryptic MHC I–restricted Epitopes Encoded by HIV-1 Alternative Reading Frames

Sylvain Cardinaud1, Arnaud Moris2, Michèle Février3, Pierre-Simon Rohrlich1, Laurence Weiss4, Pierre Langlade-Demoyen1, François A. Lemonnier1, Olivier Schwartz2, and André Habel1

1 Unité di' Immunité Cellulaire Antivirale, 2 Groupe Virus et Immunité, and 3 Unité Immunopathologie Virale, Unité Associé de Recherche, Associé Centre National de la Recherche Scientifique 1930, Institut Pasteur, 75724 Paris, Cedex 15, France
4 Hôpital Européen Georges Pompidou, Service d'Immunologie Clinique, 75908 Paris, Cedex 15, France

Address correspondence to François Lemonnier, Unité Cellulaire Antivirale, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris Cedex 15, France. Phone: 33-1-45-68-85-75; Fax: 33-1-45-68-89-42; email: flemonn{at}pasteur.fr; or Olivier Schwartz, Groupe Virus et Immunité, Institut Pasteur, 28 Rue du Dr. Roux, 75724 Paris, Cedex 15, France. Phone: 33-1-45-68-83-53; Fax: 33-1-40-61-34-65; email: schwartz{at}pasteur.fr

Human immunodeficiency virus (HIV) 1 major histocompatibility complex (MHC) I–restricted epitopes are widely believed to be derived from viral proteins encoded by primary open reading frames. However, the HIV-1 genome contains alternative reading frames (ARFs) potentially encoding small polypeptides. We have identified a panel of epitopes encoded by ARFs within the gag, pol, and env genes. The corresponding epitopic peptides were immunogenic in mice humanized for MHC-I molecules. In addition, cytotoxic T lymphocytes recognizing these epitopes were found in HIV-infected patients. These results reveal the existence of atypical mechanisms of HIV-1 epitope generation. They indicate that the repertoire of epitopes recognized by the cellular anti–HIV-1 immune response is broader than initially thought. This should be taken into account when designing vaccine strategies aimed at activating these responses.

Key Words: HLA-B7 • CTL • transgenic mice • KO mice

The present address of A. Habel is Intercell AG, Campus Vienna Biocenter 6, A-1030 Vienna, Austria.

Abbreviations used in this paper: ARF, alternative reading frame; ARFP, ARF polypeptide; HCV, hepatitis C virus; ORF, open reading frame.


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