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M9490610.TXT
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1994-09-24
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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).