       Document 0610
 DOCN  M9490610
 TI    Impaired cytotoxic T lymphocyte recognition due to genetic variations in
       the main immunogenic region of the human immunodeficiency virus 1 NEF
       protein [see comments]
 DT    9411
 AU    Couillin I; Culmann-Penciolelli B; Gomard E; Choppin J; Levy JP; Guillet
       JG; Saragosti S; Institut National de la Sante el de la Recherche
       Medicale, Unit; *363, Paris, France.
 SO    J Exp Med. 1994 Sep 1;180(3):1129-34. Unique Identifier : AIDSLINE
       MED/94342829
 CM    Comment in: J Exp Med 1994 Sep 1;180(3):779-82
 AB    Human immunodeficiency virus (HIV) induces strong responses from human
       histocompatibility leukocyte antigen (HLA) class I-restricted cytotoxic
       T lymphocytes (CTL). In a previous report we identified an
       immunodominant region (amino acids 73-144) in the NEF protein that was
       recognized by CD8+ class I-restricted CTL of most asymptomatic
       individuals. Analysis of the 73-144 region by peptide sensitization,
       experiments using overlapping peptides corresponding to the LAI isolate
       identified the peptide sequences located between residues 73 and 82 or
       84 and 92 and the peptide sequence between residues 134 and 144 as
       cognate peptides for HLA-A11- and HLA-B18-restricted epitopes,
       respectively. This report describes the variable demonstrable
       reactivities of CTL obtained from HLA-A11 or HLA-B18 seropositive,
       asymptomatic patients who all had a response to the virus NEF protein,
       but who did not always recognize appropriate cognate peptides. The high
       mutation rate of HIV probably facilitates the selection of mutants that
       can avoid the cellular immune response. We therefore analyzed the
       variability of these epitopes restricted by HLA-A11 and HLA-B18. We
       sequenced several viral isolates from HLA-A11 and HLA-B18 donors who
       recognized certain HLA-peptide complexes and from those who did not. A
       CTL sensitization assay was used to show that some mutations led to a
       great reduction in CTL activity in vitro. This might be due to failure
       of the mutated epitope to bind major histocompatibility complex class I
       molecule. A simple assay was used to detect peptides that promoted the
       assembly of class I molecules. Some of these mutations at major anchor
       positions prevented HLA-A11/peptide binding, and consequently impaired
       recognition of the HLA-peptide complex by the T cell receptor.
 DE    Amino Acid Sequence  Antigenic Determinants/*GENETICS  Base Sequence
       Gene Products, nef/GENETICS/*IMMUNOLOGY  Human
       HIV-1/GENETICS/*IMMUNOLOGY  HLA-A Antigens/PHYSIOLOGY  HLA-B
       Antigens/PHYSIOLOGY  Molecular Sequence Data  *Mutation  Support,
       Non-U.S. Gov't  T-Lymphocytes, Cytotoxic/*IMMUNOLOGY  JOURNAL ARTICLE

       SOURCE: National Library of Medicine.  NOTICE: This material may be
       protected by Copyright Law (Title 17, U.S.Code).

