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,
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Center for AIDS Research, Division of Infectious Diseases and Geographic Medicine, Stanford University Medical Center, Stanford, CA 94305;
Department of Microbiology and Immunology and Howard Hughes Institute, Stanford University, Stanford, CA 94305; and
Department of Microbiology and Immunology, Emory University, Atlanta, GA 30322
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and Vß TCR expression on CD8+ cells, was significantly
reduced after 8 wk of HAART (3). This finding provides indirect
evidence that lowering persistently high levels of viral replication
reduces the stimulus that maintains expanded CD8+ clones.
However, a recent study has shown that a highly perturbed
CD8+ TCR repertoire is not influenced by a reduction in
viral burden in patients receiving HAART (4). These data may reflect
persistent CTL expansion despite the suppression of virus, although the
Ag specificity of these cells was never examined. We have decided to
address this issue and to extend our earlier observation (3) by
investigating the frequency of epitope-specific CD8+ cells
using peptide/MHC tetrameric complexes (5). We wished to explore the
hypothesis that high levels of replicating HIV-1 are required to
maintain anti-HIV CD8+ cells. As it has been shown
functionally that a restricted anti-HIV CTL clonal repertoire
exists in infected individuals (6, 7), it is possible that a reduced
clonal repertoire during HAART could potentially result in broader CTL
responses to other Ags. Since the use of peptide/MHC tetramers was first reported (5), we have been investigating the relationship between the occurrence of these cells with CTL function in relation to HAART. Recent reports have shown that there is a good relationship between IL-7-driven in vitro-expanded CTL and tetramer staining (8), and that a significant relationship exists between freshly stained tetramer and fresh CTL lysis (9). This latter study also indicated that tetramer-positive cells had an inverse correlation with viral load in natural infection and concluded that the maintenance of CTL was driven by virus.
In this study, we have used peptide/MHC complexes to focus our investigation on CD8+ T cells that recognize two HLA-A*0201-restricted HIV-1 CTL epitopes. We have related the frequency of epitope-specific CD8+ cells with viral CTL epitope sequence changes, CTL function, and the effect of HAART; consequently, we were able to examine the effect of removing persistent HIV-1 replication. Our data suggest that the frequencies of CD8+ T cells binding peptide/MHC tetramers are likely to be memory CTLs rather than active effector cells. In turn, the relatively high frequency of these cells appears to be maintained by the presence of HIV-1 replication, because only when viral turnover is potently suppressed does the frequency of epitope-specific CD8+ T cells decline.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A total of 18 HLA-A*0201 patients were analyzed in a
cross-sectional manner to explore the relationship between the
frequency of Gag- and Pol-specific CD8+ T cells and the
variation in viral CTL epitope sequences. Table I
shows the details of treatment
history before the current investigation, estimated time of HIV-1
diagnosis, Centers for Disease Control and Prevention (CDC)
disease stage, CD4+ counts, and RNA copies per milliliter
at the time of investigation. The estimated time of HIV-1 diagnosis was
determined according to the first recorded p24 Ag. The cohort was
subdivided into three groups: six patients who never received any form
of treatment (treatment-naive); six patients who received either
glycoprotein 160 vaccine/placebo or allogeneic dendritic cell
(DC) therapy (10) that ended 12 mo before the current study
(drug-naive), and six patients who received combinations of
antiretroviral drug therapy with or without adjunctive immunotherapy. A
selection of these patients was further assessed for fresh and in
vitro-cultured CTL function and correlated to peptide/MHC tetramer
binding. Table II indicates which
patients were selected for this analysis.
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). Five of six patients in the first group were selected
(treatment-naive) to assess the effect of this regimen on patients
receiving drug treatment for the first time. The effect of HAART on
this group was compared with four other patients: P12, who had received
DC immunotherapy (drug naive), and P13, P15, and P17, who had received
protease inhibitor monotherapy followed by a triple HAART rescue
regimen (11). HLA typing
The selection of patients for study was made on the basis of HLA-A*0201 type, which was identified using standard class I serological methods.
PBMC preparation
Blood was collected in tubes containing acid citrate dextrose to prevent coagulation and PBMCs were isolated using Ficoll-Hypaque (Pharmacia, Piscataway, NJ). After washing to remove excess platelets, cells were resuspended in PBS at a concentration of 1 x 106 cells/ml.
Monoclonal Abs
The following FITC-conjugated mAbs were purchased: anti-CD69 and anti-CD45RA (Becton Dickinson, San Jose, CA); anti-CD28, anti-CD38, and anti-HLA-DR (Immunotech-Coulter, Hialeah, FL); and CyChrome-conjugated anti-CD8 (clone RPA-T8) (PharMingen, Cupertino, CA).
Tetrameric peptide/MHC complexes
The synthesis of the HLA-A*0201 tetrameric complexes used in this study has been described elsewhere (5) and was folded to express one epitope in the p17 region of Gag (SLYNTVATL) and the other in reverse transcriptase (ILKEPVHGV).
Cell staining and flow cytometry
Either freshly isolated, thawed from frozen, or peptide-stimulated cells (500,000) were resuspended in 15 µl of PBS plus 2.5% FCS, supplemented with 2 mM sodium azide, and incubated on ice for 45–60 min along with 25 µl of phycoerythrin-labeled HLA-A*0201 tetramers (4 µg). In addition, 5 µl of anti-CD8-CyChrome stock and one of a panel of FITC-conjugated Abs (5 µl) were added along with the tetramer complexes. Consequently, the total volume per stain was 50 µl, making the final tetramer concentration 2 µg/stain. Stained cells were washed twice in cold PBS/2.5% FCS and once with cold PBS and fixed in PBS plus 2% formaldehyde. After staining, cells were analyzed within 24 h using a FACScan flow cytometer. A CD8+ lymphocyte gate was made and 50,000 events were collected. Subset analysis was performed using either CellQuest (Becton Dickinson) or FlowJo software (TreeStar, Cupertino, CA). Color compensation settings were made with each round of staining using patient cells labeled singly with anti-CD8-FITC, -phycoerythrin, and -CyChrome.
Generation of EBV B lymphoblastoid cell line (B-LCL)
For each patient that was measured for CTL activity, EBV-B-LCLs
were generated 
6–8 wk before assay. These cells were used as
autologous targets in all CTL assays. EBV-B-LCLs were generated by
infecting 2x 106 PBMCs with EBV stock supernatants from
B95-8 cell lines (American Type Culture Collection, Manassas, VA) and
were cultured in the presence of cyclosporin A (14 µg/ml) in
media supplemented with 10% FCS. Transformation usually occurred after
2–3 wk, and lines were established after 6–8 wk.
CTL assays
Fresh CTL activity was assessed using a standard 6-h 51Cr release assay employing radioactively labeled autologous EBV-B-LCL as targets pulsed with Gag or Pol peptides. In vitro peptide-stimulated cells were assessed for CTL activity in a 4-h assay using EBV-B-LCL pulsed with peptides (4 µM) (10). Background 51Cr release was always <25%. Specific CTL lysis was calculated as follows: ([E - M]/[T - M]) x 100%, where E is the experimental release, M is the minimum release in the presence of media alone, and T is the maximum release after targets were lysed with 10% Triton X-100 detergent.
In vitro CTL cultures
Freshly isolated patient PBMCs (3–5 x 106) were incubated with 2 µmol/ml of either Gag or Pol peptide for 24 h, after which 50 U/ml rIL-2 (Life Technologies, Gaithersburg, MD) was added. The peptides SLYNTVATL and ILKEPVHGV were purchased from Quality Controlled Biochemicals (Hopkinton, MA) and were purified once by HPLC. Cultured cells were then fed with fresh media plus 50 U/ml rIL-2 every 3 days, and CTL activity was measured after 14 days.
Viral load
Plasma viral load was assessed using the Roche Amplicor kit (Burlington, NC), according to the manufacturer’s instructions.
Epitope sequencing
RNA was extracted from plasma using Qiagen Viral RNA Prep kits (Chatsworth, CA) according to the manufacturer’s instructions. The purified RNA was reverse-transcribed and amplified using Superscript One-Step reagent (Life Technologies) according to the manufacturer’s instructions. The primers for the Gag epitope were MAW-5 (GTG CGA GAG CGT CGG TA) and SK39 (TTT GGT CCT TGT CTT ATG TCC AGA ATG C); primers for the Pol epitope were B (GGA TGG AAA GGA TCA CC) and MAW-19 (GCT GGC TAC TAT TTC TTT TGC). The cycling parameters were 45°C for 30 min and 95°C for 2 min followed by 40 cycles at 94°C for 15 s, 55°C for 20 s, and 72°C for 2 min. A second-round PCR was performed using 5 µl of the first PCR reaction with 1x PCR buffer, 2.5 mM MgCl2, 2.5 U of Taq DNA polymerase (Life Technologies), 150 µM of deoxynucleoside triphosphate (Pharmacia), and 10 pmol of primer (Operon Technologies, Alameda, CA). The second-round primers for the Gag epitope were SK431 (TGC TAT GTC AGT TCC CCT TGG TTC TCT) and MAW-29 (AAC ATA TAG TAT GGG CAA G); second-round primers for the Pol epitope were MAW-15 (TTC CTT TGG ATG GGT TAT GA) and MAW-20 (TTC TTG GGC CTT ATC CTA TTC C). The cycling parameters were 35 cycles at 94°C for 15 s, 55°C for 20 s, and 72°C for 2 min. PCR products were then diluted 1/2–1/4 with water, and 10 µl was used in dichloro-rhodamine terminator reactions (Applied Biosystems, Foster City, CA) according to the manufacturer’s instructions. The sequencing primers for the Gag epitope were 77seq (AGC CTT CTC TTC TAC TAC TTT TAC) and MAW-7 (ACA ACC ATC CCT TCA GAC); sequencing primers for the Pol epitope were RT21 (CTG TAT TTC TGC TAT TAA GTC TTT TGA TGG G) and MAW-17 (TTG GGC AAG TCA GAT TTA CG). Data were collected on a model 377 DNA sequencer (Applied Biosystems) and edited manually. Mixtures were reported when a minority peak was 30% of the majority peak.
Statistical analysis
The strength of association between variables was measured using Spearman rank order correlation. Significant differences between values were measured using the paired or unpaired Student t test or the Wilcoxon test for unpaired data sets.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The frequency of peptide/MHC Gag and Pol tetramer-positive
CD8+ cells in the 18 HLA-A*0201 patients is shown in Fig. 1. The objective of this part of the
study was to observe the frequency of epitope-specific CD8+
T cells in a spread of patients. The Spearman rank correlation between
the frequency of either Gag or Pol tetramer binding and plasma viral
load showed a lack of association (r = -0.12 for
Gag; r = -0.17 for Pol); this finding is in contrast
to the observations of Ogg et al. (9), who showed a significant
negative correlation between viral load and pooled Gag and Pol tetramer
staining. It is likely that the heterogeneity of the treatment regimens
given to the patients before analysis in the current study may have
obscured any potential relationship between tetramer-positive
CD8+ cells and viral load.
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Viral epitope sequences
To determine whether frequencies of epitope-specific
CD8+ T cells were exerting anti-HIV pressure, plasma
virus was isolated from each patient and sequenced in regions of Gag
and Pol spanning the epitope sequences corresponding to the peptides
folded into each tetramer. Sequence analysis of the two epitopes showed
that 50% (9 of 18) of infected individuals had variant Gag epitopes
and 17% (3 of 18) had variant Pol epitopes when compared with the
peptides used in the construct (consensus sequence for subtype B) Fig. 1. Two patients (P2 and P8) showed a tyrosine for phenylalanine amino
acid substitution at position 3. Another two patients (P12 and P13) had
mixed viral populations shown by threonine + valine and leucine +
valine and at positions 8 and 2, respectively.
Relationship between tetramer binding and CTL function
To evaluate whether the frequency of tetramer binding related to
CTL function, we performed tetramer staining and measured CTL activity
from fresh PBMCs and after in vitro culture with peptide. The
relationship between the frequency of Gag and Pol tetramer-positive
CD8+ cells with fresh CTL activity failed to show a
significant correlation (Fig. 2,
A and B). Despite positive tetramer binding to
either Gag or Pol (ranging from 0 to 1.81% for Gag and from 0 to
0.72% for Pol), the corresponding fresh peptide-specific lysis was
often below the 5% 51Cr release cut-off; lysis was not
detectable in three individuals. Two of seven individuals displayed
fresh lysis above 5% 51Cr release against the Gag epitope
(Fig. 2A) and a further two against the Pol epitope (Fig. 2B). Stimulation of cells in vitro with specific peptide and
rIL-2 showed that tetramer-positive CD8+ cells could be
expanded, corresponding to peptide-specific CTL activity. Fig. 2C shows that a significant correlation (r =
0.76, p = 0.006) existed between the percentage of Pol
CTL lysis (25:1 E:T ratio) after in vitro culture and fresh Pol
tetramer stain before culture. Likewise, there was a highly significant
association between the percentage of Pol-specific CTL lysis and
corresponding tetramer staining after in vitro culture
(r = 0.96, p < 0.001; Fig. 2D). Correlation between fresh and in vitro-cultured Pol
tetramer staining (Fig. 2E) revealed a significant linear
relationship (r = 0.83, p = 0.005).
Similar restimulation experiments with the Gag epitope revealed that
only one of nine patients (P4) showed an expansion of Gag
tetramer-positive CD8+ cells that yielded high
peptide-specific lysis (Fig. 2F). In those patients in which
Gag tetramer-positive cells could not be expanded, alternative
stimulation strategies were employed. The addition of rIL-7 and a
different source of peptide (Bachem California, Torrance, CA)
yielded similar results (data not shown), and indicated that
Gag-specific cells could not always be propagated in culture despite
being detectable in fresh PBMCs.
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Fresh CD8+ cells binding peptide/MHC tetramers were
shown previously to display surface phenotypes characteristic of memory
cells (5). We have extended these observations to include the
coexpression of activation markers. Table III shows median values of the percent
expression of CD45RA, CD28, CD38, HLA-DR, and CD69 Ags on gated
CD8+ cells coexpressing either Gag or Pol tetramers. We
selected treatment- and drug-naive patients for analysis to avoid the
influence of antiretroviral drug therapy, which has been associated
with lower activation marker expression on CD8+ cells (1, 3). Of 12 patients (Table I), 11 showed Gag tetramer binding and 8
showed Pol binding (Fig. 1) and thus represented patient numbers for
phenotype analysis (Table III). Large proportions of Gag- or
Pol-expressing CD8+ cells were devoid of the CD45RA naive
cell marker, confirming that these cells were predominantly memory
cells (5). Coexpression of CD28 and HLA-DR on fresh cells appeared to
be more variable between patients, with CD28 coexpression found on both
Gag+ and Gag- CD8+
populations. A greater proportion of
CD8+Pol+ cells coexpressed CD28 and
HLA-DR (not significant); a representative example is shown in Fig. 3. Coexpression of activation markers
CD38 and CD69 on either CD8+Gag+ or
CD8+Pol+ cells revealed a lack of expression,
indicating that fresh tetramer-positive cells were not acutely
activated in these patients.
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, where fresh
CD8+Gag+ and CD8+Pol+
cells expressing costimulatory and activation markers are shown. In
this patient, there was differential expression of CD28 between Gag and
Pol CD8+ cells; discernible fresh CTL activity was apparent
only against autologous targets pulsed with the Pol peptide. After
stimulation with peptide in vitro, the frequency of
CD8+Pol+-binding cells increased 24-fold and
appeared to lose CD28 expression and gain expression of CD38 and
intermediate CD69 expression. Increased expression of these markers
corresponded to an enhanced Pol-specific CTL activity of 84% at a 25:1
E:T ratio. Changes in the frequency of tetramer-binding T cells during HAART
Fig. 4A shows changes in
the frequency of CD8+Gag+ or
CD8+Pol+ cells in six patients receiving HAART
for the first time over variable periods of 
28 wk. Consistent for all
patients was the sharp decline in plasma RNA copy numbers to below
detectable limits, irrespective of the initial starting viral load at
baseline. After 8 wk of HAART, five of six patients showed a
significant decline in the frequency of
CD8+Gag+ cells. P12 did not show this trend,
and there was a persistent and significant increase in the frequency of
CD8+Gag+ cells lasting for 28 wk
(representative FACS data is shown in Fig. 3 at 24 wk). The frequency
of CD8+Pol+ cells showed a similar trend in
this patient, but never to the same magnitude, indicating a significant
increase from 0.55 ± 0.06% to 0.95 ± 0.09% after 8 wk. P1
displayed an increased frequency of CD8+Gag+
cells in the first 2 wk of HAART; by 4 wk the frequency was
significantly reduced. Likewise, in P2 there was a significant increase
of CD8+Gag+ (0.66 ± 0.05% to 1.22
± 0.14%) in the first 4 wk; by 8 wk the frequency of CD8+
cells was significantly reduced (0.28 ± 0.02%) (Fig. 4A).
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B shows changes in the numbers of CD4+ and
CD8+ cells during HAART for these patients. All patients
showed increased CD4+ counts from a mean of 322 ± 206
cells/µl at baseline (n = 6) to 677 ± 219
cells/µl at wk 16 (n = 5). Likewise, CD8+
counts increased from a mean of 841 ± 429 cells/µl at baseline
to 943 ± 328 cells/µl at wk 16. Changes in CD8+Gag+ subsets during HAART
Closer analysis of the increased frequency of
CD8+Gag+ cells in P2 over the first 4 wk of
HAART is shown in Fig. 5. There was an
increase in the frequency of CD8+Gag+ cells
coexpressing CD38, HLA-DR, and CD69 (Fig. 5A). By 8 wk,
coexpression of these markers was lost. Fig. 5B shows the
emergence of these activated Gag-specific CD8+ cells as
contour FACS plots at 2 and 4 wk, with their disappearance at 16 wk.
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To assess changes of CD8+ tetramer-positive
frequencies over longer-term viral load changes, we analyzed three
patients who initially failed saquinavir (SQV) monotherapy (11) and
were provided with HAART as a rescue regimen. The frequencies of
CD8+Gag+ cells (P13 and P15) and
CD8+Pol+ cells (P17) are shown in Fig. 6, where each patient displayed
individualistic responses to the switch in treatment to triple-drug
HAART (represented by solid bars). Two patients showed a significant
reduction in the frequency of CD8+Gag+ cells
(P13) and CD8+Pol+ cells (P17) only when HAART
had commenced. One of these patients (P13) showed a significant
elevation of CD8+Gag+ cell frequencies that
oscillated for 24 wk during SQV monotherapy despite an initial
reduction in viral load (Fig. 6). After the commencement of HAART,
there was a further significant increase in
CD8+Gag+ frequencies after 2 wk, which then
fell to a nadir of 0.12% after 20 wk. There appeared to be more of a
consistent decline in the frequency CD8+Pol+
cells in P17, although only limited timepoints were available for
analysis. Contrary to these observations, P15 displayed an initial fall
in the frequency of CD8+Gag+ cells after 4 wk,
but values were significantly elevated above baseline during the HAART
regimen.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The lack of a significant correlation between tetramer-positive cells
and fresh discernible CTL activity suggests that the majority of
tetramer-binding T cells are more likely nonactive effectors. Although
the magnitude of fresh CTL lysis cannot be discounted (9), the
possibility that tetramer-binding cells are memory cells is supported
by restimulation experiments. Pol-specific CD8+ cells are
expanded by 20-fold when restimulated with peptide in culture, which
correlates significantly with CTL activity (Fig. 2). Phenotypically,
Pol-specific CD8+ cells gained expression of CD38 and CD69,
with a maintenance of HLA-DR and a loss of CD28 expression (Fig. 3);
this finding is compatible with activated CTL effectors (22, 23).
Consequently, we interpret the lack of substantial CD38 and CD69 Ag
expression on fresh circulating epitope-specific CD8+ cells
(Table III) as being compatible with a memory phenotype, thus providing
further support that these cells are not active effector CTLs.
When we measured the frequency of epitope-specific cells in patients
receiving potent antiretroviral therapy for the first time, five of six
showed a significant loss of tetramer-positive CD8+ cells
in parallel with a suppression of replicating HIV (Fig. 4). This
observation suggests that the maintenance of HIV-1-specific clones is
dependent upon the persistence of replicating virus. A reduction in
cell frequency was independent of gross CD4+ and
CD8+ changes (Fig. 4B) and was also not likely
due to mutations occurring in Gag or Pol epitopes that were measured in
the longer-term patient group receiving triple HAART: P13, P15, and P17
(data not shown). As most epitope-specific CD8+ T cells
were not acutely activated before drug therapy (Table III), a loss of
circulating tetramer-stained cells in response to HAART was unlikely
due to a decline in the gross activated CD8+ T cell pool.
There is also a possibility that a migration or redistribution of
Ag-specific CD8+ cells occurs from the periphery to
reservoir sites of HIV during HAART. It has been shown in natural HIV-1
infection that skewed CD8+ TCR repertoires are found within
lymphoid sites (24, 25), where intense viral replication and infection
are taking place. Conversely, it has also been shown that HIV-specific
CTL clones preferentially accumulate in the blood as opposed to the
lymph node (26). Therefore, it seems unlikely that such a
redistribution would take place, especially as the viral burden is also
reduced in lymphoid tissue during HAART (27). One patient in our study
(P12) was the only subject to show a continuous increase in
CD8+Gag+ cells, and to a lesser extent
CD8+Pol+ cells, during HAART. It is of interest
that this patient received DC immunotherapy 12 mo before receiving a
drug where some infusions of DCs were pulsed with both the Gag and Pol
epitopes (10). Intuitively, it would seem that expanded Gag-specific
cells during HAART may be potentially beneficial and that combined
immunotherapy with HAART may prove a useful approach (28). However,
these data may merely reflect an enrichment of a dominant clone that
may ultimately reduce the pool of functional T cells available to
control other infections and variations in HIV. Additional studies
would need to be designed that would critically evaluate this
possibility.
The observed increase in CD8+Gag+ cells in the first few weeks after HAART initiation in some patients (P1, P2, and P13) may reflect a redistribution of cells from lymphoid tissue sites into the periphery. A detailed analysis of one patient (P2) revealed that these cells were acutely activated, expressed CD38 and CD69, and were found in the circulation in the first 4 wk. It is likely that viral load suppression is accompanied by reduced inflammatory signals and more normal cytokine levels (2), allowing sequestered CD8+ CTLs to appear in the circulation (29, 30).
Collectively, these data may possibly reflect a scenario whereby a removal of Ag persistence reduces the requirement for protective immune responses (31, 32). For the maintenance of T cell memory and, hence, potential protective responses, a source of consistent Ag stimulation is thought to be crucial (31). This view has been upheld in studies in which adoptively transferred primed CD8+ CTLs appear to die unless rechallenged with specific Ag (33). Although there are opposing views for the maintenance of T cell memory (34), our findings are consistent with the notion that a reduction of viral antigenic stimulus is associated with decreased numbers of activated CD8+ cells (1, 3); without constant stimulation, Ag-specific CTLs disappear (35).
The data in this study may therefore support the view that high frequencies of Ag-specific CD8+ cells in asymptomatic HIV-1-infected individuals may merely reflect viral turnover rather than being determinants in the control of viral replication (35, 36).
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Clive M. Gray, AIDS Unit, National Institute for Virology, Private Bag x4, Sandringham 2131, Johannesburg, South Africa. E-mail address:
3 Abbreviations used in this paper: HAART, highly active antiretroviral therapy; B-LCL, B lymphoblastoid cell line; DC, dendritic cell; SQV, saquinavir.
Received for publication June 4, 1998. Accepted for publication October 15, 1998.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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J. E. Snyder-Cappione, A. A. Divekar, G. M. Maupin, X. Jin, L. M. Demeter, and T. R. Mosmann HIV-Specific Cytotoxic Cell Frequencies Measured Directly Ex Vivo by the Lysispot Assay Can Be Higher or Lower Than the Frequencies of IFN-{gamma}-Secreting Cells: Anti-HIV Cytotoxicity Is Not Generally Impaired Relative to Other Chronic Virus Responses J. Immunol., February 15, 2006; 176(4): 2662 - 2668. [Abstract] [Full Text] [PDF]
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I. M. Rouzine, R. A. Sergeev, and A. I. Glushtsov Two types of cytotoxic lymphocyte regulation explain kinetics of immune response to human immunodeficiency virus PNAS, January 17, 2006; 103(3): 666 - 671. [Abstract] [Full Text] [PDF]
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T. Koibuchi, T. M. Allen, M. Lichterfeld, S. K. Mui, K. M. O'Sullivan, A. Trocha, S. A. Kalams, R. P. Johnson, and B. D. Walker Limited Sequence Evolution within Persistently Targeted CD8 Epitopes in Chronic Human Immunodeficiency Virus Type 1 Infection J. Virol., July 1, 2005; 79(13): 8171 - 8181. [Abstract] [Full Text] [PDF]
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R. Chakraborty, A.-S. Morel, J. K. Sutton, V. Appay, R. M. Ripley, T. Dong, T. Rostron, S. Ogola, T. Palakudy, R. Musoke, et al. Correlates of Delayed Disease Progression in HIV-1-Infected Kenyan Children J. Immunol., June 15, 2005; 174(12): 8191 - 8199. [Abstract] [Full Text] [PDF]
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 A. Y. Kim, G. M. Lauer, K. Ouchi, M. M. Addo, M. Lucas, J. S. z. Wiesch, J. Timm, M. Boczanowski, J. E. Duncan, A. G. Wurcel, et al. The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1 Blood, February 1, 2005; 105(3): 1170 - 1178. [Abstract] [Full Text] [PDF]
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G. Ferrari, W. Neal, J. Ottinger, A. M. Jones, B. H. Edwards, P. Goepfert, M. R. Betts, R. A. Koup, S. Buchbinder, M. J. McElrath, et al. Absence of Immunodominant Anti-Gag p17 (SL9) Responses among Gag CTL-Positive, HIV-Uninfected Vaccine Recipients Expressing the HLA-A*0201 Allele J. Immunol., August 1, 2004; 173(3): 2126 - 2133. [Abstract] [Full Text] [PDF]
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J. Kan-Mitchell, B. Bisikirska, F. Wong-Staal, K. L. Schaubert, M. Bajcz, and M. Bereta The HIV-1 HLA-A2-SLYNTVATL Is a Help-Independent CTL Epitope J. Immunol., May 1, 2004; 172(9): 5249 - 5261. [Abstract] [Full Text] [PDF]
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N. Frahm, B. T. Korber, C. M. Adams, J. J. Szinger, R. Draenert, M. M. Addo, M. E. Feeney, K. Yusim, K. Sango, N. V. Brown, et al. Consistent Cytotoxic-T-Lymphocyte Targeting of Immunodominant Regions in Human Immunodeficiency Virus across Multiple Ethnicities J. Virol., March 1, 2004; 78(5): 2187 - 2200. [Abstract] [Full Text] [PDF]
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T. B. Campbell, K. Schneider, T. Wrin, C. J. Petropoulos, and E. Connick Relationship between In Vitro Human Immunodeficiency Virus Type 1 Replication Rate and Virus Load in Plasma J. Virol., November 15, 2003; 77(22): 12105 - 12112. [Abstract] [Full Text] [PDF]
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J. Cao, J. McNevin, U. Malhotra, and M. J. McElrath Evolution of CD8+ T Cell Immunity and Viral Escape Following Acute HIV-1 Infection J. Immunol., October 1, 2003; 171(7): 3837 - 3846. [Abstract] [Full Text] [PDF]
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 K. A. Mitchell and B. P. Lawrence Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) Renders Influenza Virus-Specific CD8+ T Cells Hyporesponsive to Antigen Toxicol. Sci., July 1, 2003; 74(1): 74 - 84. [Abstract] [Full Text] [PDF]
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G. Alter, G. Hatzakis, C. M. Tsoukas, K. Pelley, D. Rouleau, R. LeBlanc, J.-G. Baril, H. Dion, E. Lefebvre, R. Thomas, et al. Longitudinal Assessment of Changes in HIV-Specific Effector Activity in HIV-Infected Patients Starting Highly Active Antiretroviral Therapy in Primary Infection J. Immunol., July 1, 2003; 171(1): 477 - 488. [Abstract] [Full Text] [PDF]
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J. Cao, J. McNevin, S. Holte, L. Fink, L. Corey, and M. J. McElrath Comprehensive Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Specific Gamma Interferon-Secreting CD8+ T Cells in Primary HIV-1 Infection J. Virol., June 15, 2003; 77(12): 6867 - 6878. [Abstract] [Full Text] [PDF]
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 J. W. Smith II, E. B. Walker, B. A. Fox, D. Haley, K. P. Wisner, T. Doran, B. Fisher, L. Justice, W. Wood, J. Vetto, et al. Adjuvant Immunization of HLA-A2-Positive Melanoma Patients With a Modified gp100 Peptide Induces Peptide-Specific CD8+ T-Cell Responses J. Clin. Oncol., April 15, 2003; 21(8): 1562 - 1573. [Abstract] [Full Text] [PDF]
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N. Meidenbauer, J. Marienhagen, M. Laumer, S. Vogl, J. Heymann, R. Andreesen, and A. Mackensen Survival and Tumor Localization of Adoptively Transferred Melan-A-Specific T Cells in Melanoma Patients J. Immunol., February 15, 2003; 170(4): 2161 - 2169. [Abstract] [Full Text] [PDF]
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 S. Spira, M. A. Wainberg, H. Loemba, D. Turner, and B. G. Brenner Impact of clade diversity on HIV-1 virulence, antiretroviral drug sensitivity and drug resistance J. Antimicrob. Chemother., February 1, 2003; 51(2): 229 - 240. [Abstract] [Full Text] [PDF]
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S. Sabbaj, B. H. Edwards, M. K. Ghosh, K. Semrau, S. Cheelo, D. M. Thea, L. Kuhn, G. D. Ritter, M. J. Mulligan, P. A. Goepfert, et al. Human Immunodeficiency Virus-Specific CD8+ T Cells in Human Breast Milk J. Virol., June 27, 2002; 76(15): 7365 - 7373. [Abstract] [Full Text] [PDF]
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D. Valmori, V. Dutoit, V. Schnuriger, A.-L. Quiquerez, M. J. Pittet, P. Guillaume, V. Rubio-Godoy, P. R. Walker, D. Rimoldi, D. Lienard, et al. Vaccination with a Melan-A Peptide Selects an Oligoclonal T Cell Population with Increased Functional Avidity and Tumor Reactivity J. Immunol., April 15, 2002; 168(8): 4231 - 4240. [Abstract] [Full Text] [PDF]
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B. H. Edwards, A. Bansal, S. Sabbaj, J. Bakari, M. J. Mulligan, and P. A. Goepfert Magnitude of Functional CD8+ T-Cell Responses to the Gag Protein of Human Immunodeficiency Virus Type 1 Correlates Inversely with Viral Load in Plasma J. Virol., March 1, 2002; 76(5): 2298 - 2305. [Abstract] [Full Text] [PDF]
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G. M. Ortiz, J. Hu, J. A. Goldwitz, R. Chandwani, M. Larsson, N. Bhardwaj, S. Bonhoeffer, B. Ramratnam, L. Zhang, M. M. Markowitz, et al. Residual Viral Replication during Antiretroviral Therapy Boosts Human Immunodeficiency Virus Type 1-Specific CD8+ T-Cell Responses in Subjects Treated Early after Infection J. Virol., January 1, 2002; 76(1): 411 - 415. [Abstract] [Full Text] [PDF]
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W. Lu and J.-M. Andrieu In Vitro Human Immunodeficiency Virus Eradication by Autologous CD8+ T Cells Expanded with Inactivated-Virus-Pulsed Dendritic Cells J. Virol., October 1, 2001; 75(19): 8949 - 8956. [Abstract] [Full Text] [PDF]
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J. Lieberman, P. Shankar, N. Manjunath, and J. Andersson Dressed to kill? A review of why antiviral CD8 T lymphocytes fail to prevent progressive immunodeficiency in HIV-1 infection Blood, September 15, 2001; 98(6): 1667 - 1677. [Abstract] [Full Text] [PDF]
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V. Blazevic, S. Jankelevich, S. M. Steinberg, F. Jacobsen, R. Yarchoan, and G. M. Shearer Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Type 1-Infected Children: Analysis of Cellular Immune Responses Clin. Vaccine Immunol., September 1, 2001; 8(5): 943 - 948. [Abstract] [Full Text] [PDF]
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W. Lu, A. Achour, M. Arlie, L. Cao, and J.-M. Andrieu Enhanced Dendritic Cell-Driven Proliferation and Anti-HIV Activity of CD8+ T Cells by a New Phenothiazine Derivative, Aminoperazine J. Immunol., September 1, 2001; 167(5): 2929 - 2935. [Abstract] [Full Text] [PDF]
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C. L. Day, A. K. Shea, M. A. Altfeld, D. P. Olson, S. P. Buchbinder, F. M. Hecht, E. S. Rosenberg, B. D. Walker, and S. A. Kalams Relative Dominance of Epitope-Specific Cytotoxic T-Lymphocyte Responses in Human Immunodeficiency Virus Type 1-Infected Persons with Shared HLA Alleles J. Virol., July 15, 2001; 75(14): 6279 - 6291. [Abstract] [Full Text]
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J. P. Casazza, M. R. Betts, L. J. Picker, and R. A. Koup Decay Kinetics of Human Immunodeficiency Virus-Specific CD8+ T Cells in Peripheral Blood after Initiation of Highly Active Antiretroviral Therapy J. Virol., July 15, 2001; 75(14): 6508 - 6516. [Abstract] [Full Text]
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J. M. Faint, N. E. Annels, S. J. Curnow, P. Shields, D. Pilling, A. D. Hislop, L. Wu, A. N. Akbar, C. D. Buckley, P. A. H. Moss, et al. Memory T Cells Constitute a Subset of the Human CD8+CD45RA+ Pool with Distinct Phenotypic and Migratory Characteristics J. Immunol., July 1, 2001; 167(1): 212 - 220. [Abstract] [Full Text] [PDF]
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 E. J. Novak, S. A. Masewicz, A. W. Liu, A. Lernmark, W. W. Kwok, and G. T. Nepom Activated human epitope-specific T cells identified by class II tetramers reside within a CD4high, proliferating subset Int. Immunol., June 1, 2001; 13(6): 799 - 806. [Abstract] [Full Text] [PDF]
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V. Monsurro, M.-B. Nielsen, A. Perez-Diez, M. E. Dudley, E. Wang, S. A. Rosenberg, and F. M. Marincola Kinetics of TCR Use in Response to Repeated Epitope-Specific Immunization J. Immunol., May 1, 2001; 166(9): 5817 - 5825. [Abstract] [Full Text] [PDF]
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A. Hosmalin, A. Samri, M.-J. Dumaurier, Y. Dudoit, E. Oksenhendler, M. Karmochkine, B. Autran, S. Wain-Hobson, and R. Cheynier HIV-specific effector cytotoxic T lymphocytes and HIV-producing cells colocalize in white pulps and germinal centers from infected patients Blood, May 1, 2001; 97(9): 2695 - 2701. [Abstract] [Full Text] [PDF]
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G. Gorochov, A. U. Neumann, C. Parizot, T. Li, C. Katlama, and P. Debre Down-regulation of CD8+ T-cell expansions in patients with human immunodeficiency virus infection receiving highly active combination therapy Blood, March 15, 2001; 97(6): 1787 - 1795. [Abstract] [Full Text] [PDF]
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 R. M. Welsh Assessing CD8 T Cell Number and Dysfunction in the Presence of Antigen J. Exp. Med., March 5, 2001; 193(5): F19 - F22. [Full Text] [PDF]
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M. A. Altfeld, B. Livingston, N. Reshamwala, P. T. Nguyen, M. M. Addo, A. Shea, M. Newman, J. Fikes, J. Sidney, P. Wentworth, et al. Identification of Novel HLA-A2-Restricted Human Immunodeficiency Virus Type 1-Specific Cytotoxic T-Lymphocyte Epitopes Predicted by the HLA-A2 Supertype Peptide-Binding Motif J. Virol., February 1, 2001; 75(3): 1301 - 1311. [Abstract] [Full Text]
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M. Altfeld, E. S. Rosenberg, R. Shankarappa, J. S. Mukherjee, F. M. Hecht, R. L. Eldridge, M. M. Addo, S. H. Poon, M. N. Phillips, G. K. Robbins, et al. Cellular Immune Responses and Viral Diversity in Individuals Treated during Acute and Early HIV-1 Infection J. Exp. Med., January 8, 2001; 193(2): 169 - 180. [Abstract] [Full Text] [PDF]
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P. J.R. Goulder, M. A. Altfeld, E. S. Rosenberg, T. Nguyen, Y. Tang, R. L. Eldridge, M. M. Addo, S. He, J. S. Mukherjee, M. N. Phillips, et al. Substantial Differences in Specificity of HIV-specific Cytotoxic T Cells in Acute and Chronic HIV Infection J. Exp. Med., January 8, 2001; 193(2): 181 - 194. [Abstract] [Full Text] [PDF]
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G. Carcelain, R. Tubiana, A. Samri, V. Calvez, C. Delaugerre, H. Agut, C. Katlama, and B. Autran Transient Mobilization of Human Immunodeficiency Virus (HIV)-Specific CD4 T-Helper Cells Fails To Control Virus Rebounds during Intermittent Antiretroviral Therapy in Chronic HIV Type 1 Infection J. Virol., January 1, 2001; 75(1): 234 - 241. [Abstract] [Full Text]
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S. Reichstetter, R. A. Ettinger, A. W. Liu, J. A. Gebe, G. T. Nepom, and W. W. Kwok Distinct T Cell Interactions with HLA Class II Tetramers Characterize a Spectrum of TCR Affinities in the Human Antigen-Specific T Cell Response J. Immunol., December 15, 2000; 165(12): 6994 - 6998. [Abstract] [Full Text] [PDF]
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S. M. Smith, R. Brookes, M. R. Klein, A. S. Malin, P. T. Lukey, A. S. King, G. S. Ogg, A. V. S. Hill, and H. M. Dockrell Human CD8+ CTL Specific for the Mycobacterial Major Secreted Antigen 85A J. Immunol., December 15, 2000; 165(12): 7088 - 7095. [Abstract] [Full Text] [PDF]
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P. A. Goepfert, A. Bansal, B. H. Edwards, G. D. Ritter Jr., I. Tellez, S. A. McPherson, S. Sabbaj, and M. J. Mulligan A Significant Number of Human Immunodeficiency Virus Epitope-Specific Cytotoxic T Lymphocytes Detected by Tetramer Binding Do Not Produce Gamma Interferon J. Virol., November 1, 2000; 74(21): 10249 - 10255. [Abstract] [Full Text]
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P. Shankar, M. Russo, B. Harnisch, M. Patterson, P. Skolnik, and J. Lieberman Impaired function of circulating HIV-specific CD8+ T cells in chronic human immunodeficiency virus infection Blood, November 1, 2000; 96(9): 3094 - 3101. [Abstract] [Full Text] [PDF]
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A. Samri, G. Haas, J. Duntze, J.-M. Bouley, V. Calvez, C. Katlama, and B. Autran Immunogenicity of Mutations Induced by Nucleoside Reverse Transcriptase Inhibitors for Human Immunodeficiency Virus Type 1-Specific Cytotoxic T Cells J. Virol., October 1, 2000; 74(19): 9306 - 9312. [Abstract] [Full Text]
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T. Linnemann, G. Jung, and P. Walden Detection and Quantification of CD4+ T Cells with Specificity for a New Major Histocompatibility Complex Class II-Restricted Influenza A Virus Matrix Protein Epitope in Peripheral Blood of Influenza Patients J. Virol., September 15, 2000; 74(18): 8740 - 8743. [Abstract] [Full Text]
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G. M. A. Gillespie, M. R. Wills, V. Appay, C. O'Callaghan, M. Murphy, N. Smith, P. Sissons, S. Rowland-Jones, J. I. Bell, and P. A. H. Moss Functional Heterogeneity and High Frequencies of Cytomegalovirus-Specific CD8+ T Lymphocytes in Healthy Seropositive Donors J. Virol., September 1, 2000; 74(17): 8140 - 8150. [Abstract] [Full Text]
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M.-B. Nielsen, V. Monsurro, S. A. Migueles, E. Wang, A. Perez-Diez, K.-H. Lee, U. Kammula, S. A. Rosenberg, and F. M. Marincola Status of Activation of Circulating Vaccine-Elicited CD8+ T Cells J. Immunol., August 15, 2000; 165(4): 2287 - 2296. [Abstract] [Full Text] [PDF]
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L. Mollet, T.-S. Li, A. Samri, C. Tournay, R. Tubiana, V. Calvez, P. Debre, C. Katlama, and B. Autran Dynamics of HIV-Specific CD8+ T Lymphocytes with Changes in Viral Load J. Immunol., August 1, 2000; 165(3): 1692 - 1704. [Abstract] [Full Text] [PDF]
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J. C. Gea-Banacloche, S. A. Migueles, L. Martino, W. L. Shupert, A. C. McNeil, M. S. Sabbaghian, L. Ehler, C. Prussin, R. Stevens, L. Lambert, et al. Maintenance of Large Numbers of Virus-Specific CD8+ T Cells in HIV-Infected Progressors and Long-Term Nonprogressors J. Immunol., July 15, 2000; 165(2): 1082 - 1092. [Abstract] [Full Text] [PDF]
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V. Appay, D. F. Nixon, S. M. Donahoe, G. M.A. Gillespie, T. Dong, A. King, G. S. Ogg, H. M.L. Spiegel, C. Conlon, C. A. Spina, et al. HIV-specific CD8+ T Cells Produce Antiviral Cytokines but Are Impaired in Cytolytic Function J. Exp. Med., July 3, 2000; 192(1): 63 - 76. [Abstract] [Full Text] [PDF]
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 A. K. Sewell, D. A. Price, A. Oxenius, A. D. Kelleher, and R. E. Phillips Cytotoxic T Lymphocyte Responses to Human Immunodeficiency Virus: Control and Escape Stem Cells, July 1, 2000; 18(4): 230 - 244. [Abstract] [Full Text]
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P. J. R. Goulder, C. Brander, K. Annamalai, N. Mngqundaniso, U. Govender, Y. Tang, S. He, K. E. Hartman, C. A. O'Callaghan, G. S. Ogg, et al. Differential Narrow Focusing of Immunodominant Human Immunodeficiency Virus Gag-Specific Cytotoxic T-Lymphocyte Responses in Infected African and Caucasoid Adults and Children J. Virol., June 15, 2000; 74(12): 5679 - 5690. [Abstract] [Full Text]
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J.-F. Baurain, D. Colau, N. van Baren, C. Landry, V. Martelange, M. Vikkula, T. Boon, and P. G. Coulie High Frequency of Autologous Anti-Melanoma CTL Directed Against an Antigen Generated by a Point Mutation in a New Helicase Gene J. Immunol., June 1, 2000; 164(11): 6057 - 6066. [Abstract] [Full Text] [PDF]
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C. R. Rinaldo Jr., X.-L. Huang, Z. Fan, J. B. Margolick, L. Borowski, A. Hoji, C. Kalinyak, D. K. McMahon, S. A. Riddler, W. H. Hildebrand, et al. Anti-Human Immunodeficiency Virus Type 1 (HIV-1) CD8+ T-Lymphocyte Reactivity during Combination Antiretroviral Therapy in HIV-1-Infected Patients with Advanced Immunodeficiency J. Virol., May 1, 2000; 74(9): 4127 - 4138. [Abstract] [Full Text]
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D. Wodarz, R. M. May, and M. A. Nowak The role of antigen-independent persistence of memory cytotoxic T lymphocytes Int. Immunol., April 1, 2000; 12(4): 467 - 477. [Abstract] [Full Text] [PDF]
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A. Oxenius, D. A. Price, P. J. Easterbrook, C. A. O'Callaghan, A. D. Kelleher, J. A. Whelan, G. Sontag, A. K. Sewell, and R. E. Phillips Early highly active antiretroviral therapy for acute HIV-1 infection preserves immune function of CD8+ and CD4+ T lymphocytes PNAS, March 28, 2000; 97(7): 3382 - 3387. [Abstract] [Full Text] [PDF]
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 P. R Smith, J. D Cavenagh, T. Milne, D. Howe, S. J Wilkes, P. Sinnott, G. E Forster, and M. Helbert Benign monoclonal expansion of CD8+ lymphocytes in HIV infection J. Clin. Pathol., March 1, 2000; 53(3): 177 - 181. [Abstract] [Full Text] [PDF]
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H. Soudeyns, G. Campi, G. P. Rizzardi, C. Lenge, J. F. Demarest, G. Tambussi, A. Lazzarin, D. Kaufmann, G. Casorati, L. Corey, et al. Initiation of antiretroviral therapy during primary HIV-1 infection induces rapid stabilization of the T-cell receptor beta chain repertoire and reduces the level of T-cell oligoclonality Blood, March 1, 2000; 95(5): 1743 - 1751. [Abstract] [Full Text] [PDF]
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H. M. L. Spiegel, G. S. Ogg, E. DeFalcon, M. E. Sheehy, S. Monard, P. A. J. Haslett, G. Gillespie, S. M. Donahoe, H. Pollack, W. Borkowsky, et al. Human Immunodeficiency Virus Type 1- and Cytomegalovirus-Specific Cytotoxic T Lymphocytes Can Persist at High Frequency for Prolonged Periods in the Absence of Circulating Peripheral CD4+ T Cells J. Virol., January 1, 2000; 74(2): 1018 - 1022. [Abstract] [Full Text]
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D. Wodarz and M. A. Nowak Specific therapy regimes could lead to long-term immunological control of HIV PNAS, December 7, 1999; 96(25): 14464 - 14469. [Abstract] [Full Text] [PDF]
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K.-H. Lee, E. Wang, M.-B. Nielsen, J. Wunderlich, S. Migueles, M. Connors, S. M. Steinberg, S. A. Rosenberg, and F. M. Marincola Increased Vaccine-Specific T Cell Frequency After Peptide-Based Vaccination Correlates with Increased Susceptibility to In Vitro Stimulation But Does Not Lead to Tumor Regression J. Immunol., December 1, 1999; 163(11): 6292 - 6300. [Abstract] [Full Text] [PDF]
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A. E. Lukacher, J. M. Moser, A. Hadley, and J. D. Altman Visualization of Polyoma Virus-Specific CD8+ T Cells In Vivo During Infection and Tumor Rejection J. Immunol., September 15, 1999; 163(6): 3369 - 3378. [Abstract] [Full Text] [PDF]
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