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J Virol, February 1998, p. 1403-1410, Vol. 72, No. 2
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Selection of Virus Variants and Emergence of Virus Escape Mutants after Immunization with an Epitope Vaccine

Lorenzo Mortara,1,* Franck Letourneur,2 Helene Gras-masse,3 Alain Venet,1 Jean-Gerard Guillet,1 and Isabelle Bourgault-Villada1

Laboratoire d'Immunologie des Pathologies Infectieuses et Tumorales, INSERM U445,1 and Unité de Séquençage UFR 18,2 Institut Cochin de Génétique Moléculaire, Université René Descartes, Hôpital Cochin, 75014 Paris, and Laboratoire de Chimie des Biomolécules, Université de Lille II, Institut Pasteur de Lille, 59019 Lille Cedex,3 France

Received 17 June 1997/Accepted 4 November 1997

In this report, we assessed the evolution of the cytotoxic T-lymphocyte (CTL) response induced by an epitope vaccine. In two macaques immunized with a mixture of lipopeptides derived from simian immunodeficiency virus (SIV) Nef and Gag proteins, CTL responses were directed against the same, single epitope of the Nef protein (amino acids 128 to 137) presenting an alanine at position 136 (Nef 128-137/136A). However, after 5 months of SIV infection, peripheral blood mononuclear cells from both macaques lost their ability to be stimulated by autologous SIV-infected cells while still retaining their capacity to generate cytotoxic responses after specific Nef 128-137/136A peptide stimulation. The sequences of the pathogenic viral isolate used for the challenge showed a mixture of several variants. Within the Nef epitopic sequence from amino acids 128 to 137, 82% of viral variants expressed the epitopic peptide Nef 128-137/136A; the remaining variants presented a threonine at position 136 (Nef 128-137/136T). In contrast, sequence analysis of cloned proviral DNA obtained from both macaques 5 months after SIV challenge showed a different pattern of quasi-species variants; 100% of clones presented a threonine at position 136 (Nef 128-137/136T), suggesting the disappearance of viral variants with an alanine at this position under antiviral pressure exerted by Nef 128-137/136A-specific CTLs. In addition, 12 months after SIV challenge, six of eight clones from one macaque presented a glutamic acid at position 131 (Nef 128-137/131E+136T), which was not found in the infecting isolate. Furthermore, CTLs generated very early after SIV challenge were able to lyse cells sensitized with the Nef 128-137/136A epitope. In contrast, lysis was significantly less effective or even did not occur when either the selected peptide Nef 128-137/136T or the escape variant peptide Nef 128-137/131E+136T was used in a target cell sensitization assay. Dose analysis of peptides used to sensitize target cells as well as a major histocompatibility complex (MHC)-peptide stability assay suggested that the selected peptide Nef 128-137/136T has an altered capacity to bind to the MHC. These data suggest that CTL pressure leads to the selection of viral variants and to the emergence of escape mutants and supports the fact that immunization should elicit broad CTL responses.

* Corresponding author. Mailing address: ICGM, INSERM U445, 27 rue du Faubourg Saint-Jacques, 75014 Paris, France. Phone: (33) 1 44 07 18 21. Fax: (33) 1 44 07 14 25. E-mail: mortara{at}icgm.cochin.inserm.fr.




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