Research Summary: Increased Breadth and Depth of Cytotoxic T Lymphocytes Responses against HIV-1-B Nef by Inclusion of Epitope Variant Sequences


Different vaccine approaches cope with HIV-1
diversity, ranging from
centralized1–4 to
antigens. For all these strategies, a concern
remains: how does HIV-1 diversity impact epitope
recognition by the immune system? We studied the
relationship between HIV-1 diversity and
CD8+ T Lymphocytes (CTL) targeting
of HIV-1 subtype B Nef using 944 peptides (10-mers
overlapping by nine amino acids (AA)) that
corresponded to consensus peptides and their most
common variants in the HIV-1-B virus population.
IFN-γ ELISpot assays were performed using
freshly isolated PBMC from 26 HIV-1-infected
persons. Three hundred and fifty peptides elicited
a response in at least one individual. Individuals
targeted a median of 7 discrete regions. Overall,
33% of responses were directed against
viral variants but not elicited against
consensus-based test peptides. However, there was
no significant relationship between the frequency
of a 10-mer in the viral population and either its
frequency of recognition (Spearman’s
correlation coefficient
ρ = 0.24) or the
magnitude of the responses
(ρ = 0.16). We found that
peptides with a single mutation compared to the
consensus were likely to be recognized (especially
if the change was conservative) and to elicit
responses of similar magnitude as the consensus
peptide. Our results indicate that
cross-reactivity between rare and frequent
variants is likely to play a role in the expansion
of CTL responses, and that maximizing antigenic
diversity in a vaccine may increase the breadth
and depth of CTL responses. However, since there
are few obvious preferred pathways to virologic
escape, the diversity that may be required to
block all potential escape pathways may be too
large for a realistic vaccine to accommodate.
Furthermore, since peptides were not recognized
based on their frequency in the population, it
remains unclear by which mechanisms
variability-inclusive antigens (i.e., constructs
enriched with frequent variants) expand CTL


Publisher: Public Library of

Date Published: 28-March-2011

Author(s): Rolland M., Frahm N., Nickle D., Jojic N., Deng W., Allen T., Brander C., Heckerman D., Mullins J.


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