HIV-Derived Cytotoxic T Lymphocyte (CTL) Epitopes

HIV-Derived Cytotoxic T Lymphocyte (CTL) Epitopes
for the Study of CTL Escape, Functional Avidity and
Viral Evolution
Nicole Frahma, Brett Bakera, Christian Brandera
I-A-1 Associations between T cell
specificity and viral control: cause
or effect?
Despite ongoing efforts into the characterization of immune
correlates of controlled HIV infection, the impact
of antigen specificity, viral sequence variation and variant
cross-recognition on the control of viral replication
and HIV disease progression remains unknown. While
a steadily growing number of reports confirm the association
between T cell responses directed against the HIV
Gag protein and reduced viral load [Zuñiga et al., 2006;
Brumme et al., 2008; Kiepiela et al., 2007; Masemola
et al., 2004a; Rolland et al., 2008], and despite some
reports showing a rapid re-presentation of Gag-derived
antigen from the incoming virus [Sacha et al., 2007], it
remains unclear whether a) these associations reflect the
cause or the consequences of otherwise controlled infection
and b) whether, and if so, which regions outside
of Gag would present effective targets of the host cellular
immune response to HIV. Similarly, although a
number of recent reports have established strong associations
between reduced viral replicative fitness and specific
viral sequence changes in Gag epitopes restricted by
HLA alleles associated with relative protection [Brockman
et al., 2007; Schneidewind et al., 2007; Martinez-
Picado et al., 2006], these analyses urgently need to be expanded
to other, broadly distributed HLA alleles and targets
located in viral proteins other than Gag. In addition,
the consequences of sequence variation on T cell recognition,
often assumed to reflect effective T cell escape,
aPartners AIDS Research Center, Massachusetts General Hospital,
Harvard Medical School, Boston, Mass., USA
In HIV Molecular Immunology 2008. Bette T. M. Korber, Christian
Brander, Barton F. Haynes, Richard Koup, John P. Moore, Bruce
D. Walker, and David I. Watkins, editors. Publisher: Los Alamos National
Laboratory, Theoretical Biology and Biophysics, Los Alamos,
New Mexico. p. 3–24.
will need to be more carefully assessed, ideally including
approaches such as viral inhibition assays and testing for
different T cell effector functions to discriminate between
partial agonistic variants, antagonistic or superagonistic
sequence changes, or true CTL escape due to abrogated
HLA binding, missing TCR interaction or severely impaired
antigen processing.
I-A-2 The role of functional avidity in the
control of highly variable pathogens
A rapidly growing number of reports have also started to
assess the role of T cell receptor repertoire diversity, TCR
functional avidity and variant recognition [Price et al.,
2005; Turnbull et al., 2006; Messaoudi et al., 2002]. Recently
published data in HCV infection has linked the
presence of T cell responses of high functional avidity
with a superior ability to cross-react with sequence variants
[Yerly et al., 2008]. Although these high avidity
HCV-specific T cell populations were mainly found in
subjects that spontaneously cleared HCV infection, it remains
unclear whether individuals who went on to become
chronically infected initially also had such high
avidity responses which, for unknown reasons, got lost
over time, similarly to what has recently been described
in longitudinal analyses in HIV infection. Emerging data
in HIV infection confirms the analyses in HCV as Frahm
et al. (unpublished data) and likely others have identified
particularly highly avid and broadly cross-reactive T cell
populations in HIV controllers, but less so in individuals
with progressive HIV disease. It thus appears likely
that an effective HIV vaccine (and HCV, too) would likely
profit from the induction of such high avidity responses.