Molecular Biology and Evolution, Vol 15, 1259-1268, Copyright © 1998 by Society for Molecular Biology and Evolution
J da Silva and AL Hughes
Host cytotoxic T lymphocytes (CTLs) that recognize specific viral peptides
(epitopes) are thought to provide the most effective control of viral
replication and spread. However, viruses may escape this recognition
through mutations in CTL epitopes. We tested the hypothesis that, as an
adaptation on the part of the host to constrain parasite escape from immune
control, class I major histocompatibility complex (MHC) molecules present
peptides that are derived from conserved regions of foreign proteins to
CTLs. We did this by estimating the relative conservation of CTL epitopes
of the functionally important Nef protein of human immunodeficiency virus 1
(HIV-1) and relating this to the structure and function of the protein. In
comparisons among sequences from several HIV-1 subtypes and both major
groups, CTL epitopes had lower rates of nonsynonymous nucleotide
substitution per site than did the remainder of the protein, indicating the
relative conservation of these epitopes. In contrast, helper T-cell
epitopes were as conserved as, and monoclonal antibody epitopes less
conserved than, the remainder of the protein. The conservation of CTL
epitopes is apparently due to their derivation from functionally important
domains of Nef, since CTL epitopes coincide with these domains and these
domains are conserved relative to the remainder of the protein, in contrast
to secondary structural elements, which are not. Recent studies provide
evidence of CTL selection on HIV-1 epitopes, but the variational range of
viral escape mutants appears to be limited by functional constraints on the
protein regions from which epitopes are derived. The presentation of
conserved foreign peptides to CTLs by class I MHC molecules may be a
general adaptation of vertebrate hosts to constrain the adaptation of their
intracellular parasites.
ORIGINAL ARTICLE
Conservation of cytotoxic T lymphocyte (CTL) epitopes as a host strategy to constrain parasite adaptation: evidence from the nef gene of human immunodeficiency virus 1 (HIV-1)
Department of Biology, Pennsylvania State University, University Park 16802, USA.
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