Biology Reference
In-Depth Information
Conversely, disease progression has been associated with HLA homozygosity
(Carrington et al., 1999), especially within either the A or B loci ( Tang et al.,
1999). This may be a result of limited antigen presentation and lack of im-
munodominance and/or a bias toward Th2 cytokine pro®les (Candore et al.,
1998). Thus, the choice of peptides for inclusion into a tetramer synthesis is
dependent on detailed knowledge of which CTL epitopes are restricted by a
particular HLA allele in individuals with a common HLA background. Identi-
®cation of immunodominant epitopes has been a major thrust of CTL research
by many groups and an up-to-date listing and database of epitopes restricted by
many HLA alleles is provided by the Los Alamos Immunology Database
( Korber et al., 1999). Although this database provides detailed information for
subtype B HIV-1 CTL sequences, it does not, as yet, have detailed informa-
tion of nonsubtype B HIV-1 sequences that may be restricted by HLA alleles
found in non-Caucasians. This lack of information will slowly be corrected as
more information on non-B subtype CTL sequences will become available from
Africa, Asia, and India, where >90% of global infections occur ( Karim and
Karim, 1999). More importantly, divergent HLA alleles across di¨erent geo-
graphic regions will in¯uence which CTL epitopes are immunodominant and
hence which peptides should be chosen for tetramer synthesis. The importance
of tetramer synthesis for tracking antigen-speci®c cells that recognize non-B
subtypes of HIV-1 is important for understanding the course of HIV-1 infection
in the context of intercurrent infections (such as Mycobacterium tuberculosis)
and for evaluating vaccine immunogenicity (see below).
There have been few longitudinal studies that have tracked the course of
antigen-speci®c CD8
cells during the natural history of HIV-1 infection. The
®rst such study tracked the course of Gag- and Pol-speci®c tetramer-positive
cells in 16 HLA-A*0201 untreated patients over 14 years (Ogg et al., 1999b).
High frequencies of Gag- or Pol-speci®c CD8
cells at 1±2 years after sero-
conversion are signi®cantly associated with slow disease progression. Lower
anti-HIV and anti-EBV CTL during disease progression was found to be due to
preferential loss of the CD27
CD45RO
CD8
cell subset (Ogg et al., 1999b).
A subsequent study showed the frequency of Gag ( p24) tetramer positive cells
in three HLA-B*2705 and ÿA*0201 positive patients over a 3±4 year period.
The immunodominant response appeared to be established prior to serocon-
version and tetramer staining reached up to 4.84% of CD8
T cells that were
closely associated with a signi®cant decline in viral load ( Wilson et al., 2000).
TRACKING ANTIGEN-SPECIFIC T CELLS DURING HIGHLY ACTIVE
ANTIRETROVIRAL THERAPY (HAART )
The impact of HAART on restoration of immunity has been extensively ana-
lyzed (Autran et al., 1997; Evans et al., 1998; Gray et al., 1998; Komanduri et
al., 1998; Kroon et al., 1998; Li et al., 1998; Oxenius et al., 2000; Roederer,
