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Journal of Virology, December 2001, p. 11983-11991, Vol. 75, No. 24
Department of Internal Medicine, The
University of Texas Southwestern Medical Center, Dallas, Texas
75390-91131; Ecology & Evolution, ETH
Zurich, CH-8092 Zurich, Switzerland2; and
Vaccine and Gene Therapy Institute, Oregon Health Sciences
University, Portland, Oregon 97201-30983
Received 3 July 2001/Accepted 17 September 2001
Human immunodeficiency virus (HIV)-specific T-cell responses are
thought to play a key role in viral load decline during primary infection and in determining the subsequent viral load set point. The
requirements for this effect are unknown, partly because comprehensive analysis of total HIV-specific CD4+ and CD8+
T-cell responses to all HIV-encoded epitopes has not been accomplished. To assess these responses, we used cytokine flow cytometry and overlapping peptide pools encompassing all products of the HIV-1 genome
to study total HIV-specific T-cell responses in 23 highly active
antiretroviral therapy naïve HIV-infected patients.
HIV-specific CD8+ T-cell responses were detectable in all
patients, ranging between 1.6 and 18.4% of total CD8+ T
cells. HIV-specific CD4+ T-cell responses were present in
21 of 23 patients, although the responses were lower (0.2 to 2.94%).
Contrary to previous reports, a positive correlation was identified
between the plasma viral load and the total HIV-, Env-, and
Nef-specific CD8+ T-cell frequency. No correlation
was found either between viral load and total or Gag-specific
CD4+ T-cell response or between the frequency of
HIV-specific CD4+ and CD8+ T cells. These
results suggest that overall frequencies of HIV-specific T cells are
not the sole determinant of immune-mediated protection in
HIV-infection.
Although infection by human
immunodeficiency virus (HIV) and its simian counterpart, simian
immunodeficiency virus (SIV), is persistent and ultimately progressive
in the vast majority of untreated hosts, there is increasing evidence
that HIV- or SIV-specific cellular immune responses play a major role
in determining the tempo of viral replication and thus the clinical
outcome of infection. The best evidence for this protective immune
function derives from the rhesus macaque model of SIV infection, where it has been shown that (i) interference with CD8+
T-cell function with a depleting monoclonal antibody significantly enhances viral replication (19, 27, 41) and (ii)
CD8+ cytotoxic T lymphocytes (CTL) are capable of
exerting significant selective pressure on the viral genome, as
evidenced by the rapid appearance of specific escape mutations in
epitope-encoding sequences (1, 12). Moreover, recent
studies have demonstrated that vaccine strategies capable of eliciting
viral specific CD8+ T-cell responses can control
viral replication and prevent the onset of disease (3, 5,
42).
In humans, evidence supporting a protective effect of cellular immune
responses in HIV infection is less direct. The initial appearance of
HIV-specific CD8+ T cells is closely associated
with the drop in plasma viremia that occurs during acute infection
(26), and the loss of HIV-specific CD8+ T cells has been linked to rapid progression
to AIDS (23). HIV-specific CD8+ T
cells elicit potent selective pressure on the virus, in many cases
resulting in the appearance of epitope escape mutations (8, 18,
38). Long-term nonprogressive infection has been associated with
both strong virus-specific CTL and with robust gag
p24-specific CD4+ T-cell proliferative responses
(23, 35, 37, 40). Indeed, some studies have reported a
direct inverse correlation between viral load and HIV-specific T-cell
responses in untreated HIV-infected subjects. Specifically, using two
different HIV peptide-major histocompatibility complex (MHC) class I
tetramers, Ogg et al. demonstrated such an association between viral
load and HIV-specific CD8+ T-cell immunity
(33). Additionally, a similar inverse relationship was
observed between HIV Gag-specific CD4+ T-cell
proliferative responses and viral load (40). However, subsequent studies analyzing cytokine production by HIV-specific T
cells in response to a larger, but still limited, array of potential epitopes have not been able to confirm these relationships (14, 15, 37).
To date, studies correlating the HIV-specific immune response and
parameters of viral infection have been restricted to the T-cell
responses against single epitopes (33), panels of selected epitopes (6, 14), or selected HIV proteins
(15). This approach implies that such selected responses
give an accurate representation of the total HIV-specific immune
response. We have recently provided evidence that the correlation of
particular restricting HLA alleles and epitope immunodominance is not
absolute (6), a finding that contradicts the assumption
that such selected responses are representative of the total response.
Thus, an appreciation of the overall immune response to HIV and its
relationship to parameters of viral infection would best be truly
achieved by examining the response to every potential HIV epitope in
the absence of assumptions of immunodominance.
We have therefore adopted the strategy of using overlapping peptide
panels that span every encoded HIV protein to examine the total T-cell
response to all potential epitopes in a group of 23 untreated
HIV-infected patients. Our results show that high levels of
HIV-specific CD4+ and CD8+
T cells are present in nearly all chronically HIV-infected patients. We
find no significant correlation between the frequency of HIV-specific CD4+ T cells and HIV-specific
CD8+ T cells, or between HIV-specific
CD4+ T-cell frequency and HIV plasma viral load.
Interestingly, however, our data indicate that the total frequency of
HIV-specific CD8+ T cells is positively
correlated with viral load in the absence of therapy. These results
suggest that the high frequency of HIV-specific CD8+ T cells is in fact the result of high
antigen load and that the absolute magnitude of either the
CD8+ or CD4+ T-cell
response to HIV is not by itself an adequate predictor of the ability
of the immune system to control HIV infection.
Patient cohort.
Twenty-three HIV-1 infected patients were
recruited into this study at the Amelia Court HIV Clinic at the
University of Texas Southwestern Medical Center. This cohort consists
of both men and women and various ethnic groups, including Caucasian,
Hispanic, and African American subjects. These patients were recruited
on the basis of having no previous history of antiretroviral therapy, although after study samples were obtained, many of the patients began
highly active antiretroviral therapy (HAART). As detailed in Table
1, this cohort included patients who were
recently infected, chronically infected, or long-term
nonprogressors. The viral loads in these patients varied from
undetectable (<50 viral RNA copies/ml) to 635,000 viral RNA copies/ml.
Viral loads were determined using either the Roche Amplicor Monitor
assay or the Roche Ultradirect assay. The patients all gave informed
consent prior to entry into this study.
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.24.11983-11991.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Analysis of Total Human Immunodeficiency Virus (HIV)-Specific
CD4+ and CD8+ T-Cell Responses: Relationship
to Viral Load in Untreated HIV Infection
ABSTRACT
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
INTRODUCTION
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
MATERIALS AND METHODS
Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
TABLE 1.
Patient cohort characteristics at time of analysis
Peptides. Three different sets of HIV peptides were utilized in these experiments: (i) optimally defined epitopes from 8 to 11 amino acids in length derived from HIV Gag, Pol, Env, and Nef, as described in the Los Alamos Molecular Immunology Database (24); (ii) 15-mer peptides overlapping by 11 amino acids corresponding to sequences of chimeric HIV strain HXBc2/Bal R5 (Gag, Pol, Env, or Nef) or HIV strain SF2 (Tat, Rev, Vif, Vpr, and Vpu); and (iii) 20-mer peptides overlapping by 10 amino acids corresponding to strain HXB2 Gag and strain MN Env proteins (obtained through the NIH AIDS Research and Reference Reagent Program). The peptides were synthesized as free acids and were more than 80% pure. Lyophilized peptides were resuspended in dimethyl sulfoxide (DMSO; Sigma, St. Louis, Mo.) at 100 mg/ml for peptide mixtures. The addition of small amounts of DMSO (0.5 to 1% final concentration) does not affect antigen-specific CD4+ or CD8+ T-cell responses (data not shown). Four different pools of the optimally defined 8 to 11 amino acid peptides were made corresponding to peptide origin (37 Gag, 18 Pol, 20 Env, and 20 Nef peptides). The overlapping 15-mers were also grouped together in pools corresponding to antigen, and for HIV Pol and Env, the peptides were grouped into two separate pools (122 Gag, 248 Pol, 211 Env, 49 Nef, 27 Rev, 23 Tat, 46 Vif, 22 Vpr, and 7 Vpu peptides; total, 746). The overlapping 20-mer peptides were grouped into a Gag pool (49 peptides) and an Env pool (80 peptides). The concentration of each single peptide within a pool was 400 µg/ml. The final concentration of any single peptide was 2 µg/106 cells in all experiments.
Cell stimulation.
Peripheral blood mononuclear cells (PBMC)
were isolated using Ficoll-Hypaque (Pharmacia, Uppsala, Sweden) density
centrifugation. In some instances PBMC were frozen (90% fetal calf
serum-10% DMSO) at 
140°C until use. Stimulation was performed
with fresh or frozen PBMC as described elsewhere (6, 37).
Briefly, 106 PBMC were incubated with 1 µg each
of costimulatory antibodies against CD28 and CD49d and 5 µl of each
peptide mixture (final concentration, 2 µg/ml/peptide). In every
experiment a negative control (anti-CD28-CD49d) was included to control
for spontaneous production of gamma interferon (IFN-
), as well as a
positive control (Staphylococcus enterotoxin B; final
concentration, 1 µg/ml) to ensure that the cells were responsive. The
cultures were incubated for 1 h at 37°C in a 5%
CO2 incubator, followed by an additional 5 h
in the presence of the secretion inhibitor Brefeldin A (10 µg/ml;
Sigma). The cells were than placed at 4°C overnight and
stained the next day.
Immunofluorescent staining.
Stimulated PBMC were washed once
(1,200 rpm for 5 min) with FACS buffer (1% bovine serum albumin, 0.1%
sodium azide). The cells were then surface stained for 20 min on ice
with antibodies directly conjugated to CD3 and CD8. The cells were
washed as above and then fixed and permeabilized using 750 µl
of 2× fixation-permeablization solution (Becton Dickinson
Immunocytometry Systems, San Jose, Calif.). After a 10-min incubation
(25°C in darkness), the cells were washed twice in FACS buffer (1,800 rpm for 8 min) and stained intracellularly with antibodies directly
conjugated to CD69 and IFN-. The cells were washed a final time
(1,800 rpm for 8 min) and resuspended in 1% paraformaldehyde (Electron
Microscopy Systems, Fort Washington, Pa.) in phosphate-buffered saline.
Flow cytometric analysis.
Six-parameter flow cytometric
analysis was preformed using a FACScalibur flow cytometer (Becton
Dickinson Immunocytometry Systems). Fluorescein isothiocyanate,
phycoerythrin, peridinin-chlorophyll protein, and allophycocyanin (APC)
were used as the fluorescent parameters. Between 100,000 and 130,000 live CD3+ lymphocytes were collected. The
list-mode data files were analyzed with PAINT-A-GATE software (Becton
Dickinson Immunocytometry Systems). In all data shown, the percentages
represent the number of IFN-+
CD69+CD3+CD8+
or CD8
cells that responded to each
peptide or control. In general, the background (anti CD28-CD49d alone)
was less than 0.1% of total T cells (for exceptions, see the legend to
Fig. 2).
Antibodies.
Unconjugated mouse anti-human CD28, unconjugated
mouse anti-human CD49d, fluorescein isothiocyanate-conjugated mouse
anti-human IFN-, phycoerythrin-conjugated mouse anti-human CD69,
peridinin-chlorophyll protein-conjugated mouse-anti-human CD3, and
APC-conjugated mouse anti-human CD8 monoclonal antibodies were obtained
from Becton Dickinson Immunocytometry Systems.
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RESULTS |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Use of overlapping peptides in the intracellular cytokine
assay.
To assess total CD4+ and
CD8+ T-cell responses to HIV by measuring
intracellular cytokine production, we first had to establish a method
to determine these responses in the most efficient manner, using a
minimum number of PBMC while examining a maximum number of potential
peptides. We examined whether a mixture of peptides 15 amino acids in
length, overlapping by 11 amino acids, and derived from HIV-1 Gag (122 peptides) could be recognized simultaneously by both
CD4+ and CD8+ T cells, as
depicted in Fig. 1. To quantify
Gag-specific T-cell responses, we examined IFN- production in PBMC
from CD3+CD8+ and
CD3+CD8 (hereafter
referred to as CD4+) T cells. While examining
CD4+ responses in this manner may theoretically
underestimate the total CD4+ T-cell response,
comparative analysis of responding
CD3+CD8 and
CD3+CD4+ T-cell populations
to the HIV-gag 15-mer mixture shows that they are directly equivalent
(data not shown). To determine if the 15-mer peptides were of optimal
length for both CD4+ and
CD8+ T-cell responses, we compared the
CD4+ and CD8+ T-cell
responses to different HIV Gag peptide mixtures (optimized 8- to
11-mers, overlapping 15-mers, and overlapping 20-mers; data not shown).
The CD4+ T-cell responses to the overlapping
15-mer and 20-mer Gag peptide mixtures were nearly identical, while
more CD8+ T cells recognized the Gag 15-mer
peptide mixture than the Gag 20-mer mixture in samples from 10 patients
examined. CD8+ T-cell responses to the optimized
Gag 8- to 11-mers and the Gag 15-mers, however, were more disparate,
potentially due to a number of factors, including the location of the
recognized sequence within the 15-mer (i.e., peptide overhang length
and location) as well as sequence differences (data not shown). This
discrepancy suggests that while the 15-mer peptides are recognized,
they may underestimate the CD8+ T-cell response
slightly in some patients. However, since the optimal Gag peptide
mixture only contains 37 different epitopes that bind to a limited
array of HLA alleles, it is unlikely to encompass the entire repertoire
of Gag peptides recognized in every patient. Because the overlapping
15-mers theoretically contain every possible T-cell epitope (patient
sequence variation notwithstanding), they can be used to quantify total
T-cell responses independently of the patient's MHC haplotype.
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Quantification of total HIV-specific T-cell responses using
overlapping peptide mixtures.
Having established that the 15-mer
peptides provided the best assessment of both
CD4+ and CD8+ T-cell
responses, we used the overlapping 15-mer peptide mixtures to quantify
the total HIV-specific T-cell responses in the 23 untreated
HIV-positive patients (Fig. 2).
Significant IFN- production (
0.05% above background) to the
various HIV 15-mer peptide mixtures was detected in the
CD4+ T lymphocyte subset in 21 of 23 patients
(Fig. 2A), varying from 0.2 to 2.94% (mean frequency, 0.74%) of total
CD4+ T lymphocytes. Responses to the Gag peptide
mixture were observed in most patients (21 of 23) and ranged between
0.06 and 1.3% of total CD4+ T lymphocytes,
comparable to previous findings (37). Although detected in
most of the patients, HIV Gag-specific CD4+
T-cell responses were only dominant in 11 of 21 responding patients. CD4+ T-cell responses specific for other
HIV-peptide mixtures besides Gag were found in every responding patient
(Pol, 11 of 21; Env, 11 of 21, Nef, 8 of 23; Tat, 6 of 21; Rev, 8 of
21; Vif, 4 of 21; Vpr, 6 of 21; Vpu, 4 of 21). These results indicate
that any HIV protein can be the target of CD4+ T
cells, although responses directed at HIV Gag, Pol, and Env are the
most common. Furthermore, in agreement with previous studies, substantial numbers of HIV-specific CD4+ T cells
are present in most of the HIV-infected patients regardless of disease
progression status (37). Because longitudinal information on the rates of disease progression were unavailable for most of the
patients in this cohort, we were unable to examine the relationship
between progression and the frequency of responding HIV-specific
CD4+ T cells. There was no correlation between
absolute CD4+ T-cell count and the total
HIV-specific CD4+ T-cell response or the response
to any individual HIV protein (data not shown). Interestingly, patient
21, with a CD4+ T-cell count of 181 cells/mm3, had the highest total
CD4+ T-cell response detected, indicating that
substantially strong CD4+ T-cell responses can be
present even in individuals with advanced disease.
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0.1% in all patients
except for patients 15 (0.15%), 17 (0.37%), and 22 (0.2%).
Background IFN-
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Correlation between viral load and responding HIV-specific
CD4+ and CD8+ T-cell frequency.
Previous
studies have suggested that there is an inverse correlation between HIV
Gag-specific CD4+ T-cell lymphoproliferative
activity and HIV viral load (20, 40), a finding not
confirmed by another study where the HIV gag p55-specific
CD4+ T-cell frequency and viral load were
compared (37). Our results also suggest that there is no
correlation between the frequency of responding HIV Gag-specific
CD4+ T cells and viral load (Fig.
4A). It is possible that there is no
direct correlation between the CD4+ T-cell
response to a single HIV protein, since the CD4+
T-cell response to HIV is specific for multiple HIV proteins in most
people (Fig. 2A). We therefore examined the relationship between the
total HIV-specific CD4+ T-cell frequency and
viral load, as these may be closely related. Our results, however,
failed to indicate a direct correlation between the total frequency of
responding HIV-specific CD4+ T cells and viral
load (Fig. 4B).
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DISCUSSION |
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Top
Abstract
Introduction
Materials and Methods
Results
Discussion
References
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Recent developments in the ability to accurately quantify
antigen-specific T cells have led to significant advancements in our
understanding of the strength and specificity of T-cell responses to
HIV. Here we have utilized one such technique, intracellular cytokine
staining, to quantify the total CD4+ and
CD8+ T-cell response to HIV. Rather than focus on
single peptides or combinations of epitopes as a representation of the
HIV-specific response, we have examined the T-cell response to a panel
of overlapping 15-mer peptides that cover every HIV protein. This
system has a considerable advantage over existing tetramer technologies
in that it examines the response to all potential HIV epitopes,
regardless of the HLA haplotype of the infected individual. There is a
strong correlation between the frequency of peptide-specific
IFN--producing CD8+ T cells and
tetramer-positive CD8+ T cells (17,
29), suggesting that these two assays examine the same cell
populations and that therefore either can be used to accurately
quantify antigen-specific T-cell responses to single peptides. Using
intracellular cytokine staining, we have found that markedly high
frequencies of CD4+ and
CD8+ T cells specific for multiple different HIV
proteins are present in nearly every untreated HIV-infected individual.
Our results are novel in that this is the first report to examine both
the CD4+ and CD8+ T-cell
response to every potential HIV epitope. Previous attempts to quantify
the total HIV-specific CD8+ T-cell response to
HIV only examined the responses to the HIV Gag, Pol, Env, and Nef
proteins (15) or panels of selected epitopes (14). Although the overlapping 15-mer panels may slightly
underestimate the total HIV-specific response due to the effects of
amino acid overlaps and potential sequence differences between peptides
and autologous virus, our results nevertheless provide the most
comprehensive assessment of the total T-cell response to HIV performed
to date.
We found that CD4+ T cells specific for multiple
HIV proteins are readily detectable in the majority of chronically
infected patients, in agreement with a previous report that examined
HIV p55-specific CD4+ T-cell responses
(37). These results indicate that HIV-specific CD4+ T cells are generated and persist during
ongoing virus replication in untreated individuals. Previous evidence
has suggested that there is a positive correlation between
CD4+ T-cell proliferative responses and the
frequency of HIV-specific CD8+ T cells
(20), as well as a negative correlation between
CD4+ T-cell proliferative responses and viral
load (40). We failed to find these relationships by
intracellular cytokine staining to directly quantify total HIV-specific
CD4+ and CD8+ T-cell
frequencies. This discrepancy can be explained by a number of factors.
First, proliferative assays do not precisely quantify responder cell
frequencies but provide an overall "bulk" view of a complex
cellular response that depends on a number of factors, including
absolute numbers of CD4+ T cells, responding cell
frequency and/or proliferative ability, APC function, and assay culture
conditions. Indeed, recent data suggest that there is inconsistency
between HIV-specific CD4+ T-cell proliferative
responses and the frequency of IFN--producing CD4+ T cells (44). Other studies
have demonstrated that in vitro proliferative responses to HIV antigens
are abrogated during viremia, yet HIV-specific IFN--producing
CD4+ T cells persist, calling into question
whether the absence of these responses should be used as a proxy for
absent virus-specific T cell help in HIV infection (M. Connors,
personal communication). Thus, proliferation assays may correlate with
viral load via an indirect association between viral replication,
hyperactivation, and in vitro apoptosis and not through a direct
connection with the number or frequency of functional HIV-specific
CD4+ T cells. Animal models have established the
importance of virus-specific CD4+ T cells in
initiating and maintaining CD8+ T-cell effector
function (46), but our data suggest that in HIV infection
this relationship is more complex than a simple linear correlation
between the frequencies of HIV-specific CD4+ and
either CD8+ T cells or viral load.
Our results show that a positive correlation exists between the total HIV-specific CD8+ T-cell response and viral load. This is in contrast to a previous report that identified an inverse correlation between the frequency of CD8+ T cells specific for two individual HIV epitopes restricted by HLA-A2 (as measured by tetramer analysis) and plasma viral load (33). As was recently shown, a limited examination of the HIV-specific CD8+ response in HLA-A2-positive patients is not likely to be representative of the entire HIV-specific CD8+ T-cell response (6, 16). Other studies utilizing precursor frequency analysis and standard 51Cr release assays have also demonstrated an inverse correlation between viral load and HIV-specific CD8+ T-cell activity (7, 30). However, because precursor frequency assays often underestimate CD8+ T-cell responses (17, 29) and 51Cr release assays are at best semiquantitative, the validity of these findings is somewhat questionable. In fact, two recent studies that examined a panel of optimized HIV epitopes or selected vaccinia virus-expressed HIV proteins by intracellular cytokine staining were unable to find an inverse correlation between HIV-specific CD8+ T-cell frequency and viral load (14, 15).
A massive expansion of HIV-specific CD8+ T cells in response to increasing HIV load has been shown to occur during acute HIV infection (26). This expansion of antigen-specific CD8+ T cells occurs in other viral infection as well, for example in lymphocytic choriomeningitis virus infection in mice (29) and Epstein-Barr virus infection in humans (9). Although evidence suggests that HIV-specific CD8+ T cells play a significant role in delaying progression to AIDS (19, 23, 39, 41), it is clear that in the vast majority of infected individuals, HIV-specific CD8+ T-cell responses are by themselves insufficient to effectively contain viral replication. Because of the complex feedback between HIV-specific CD8+ T cells and viral load, the interpretation of correlations between these two quantities is difficult and controversial. While it has been argued that a negative correlation is indicative of control of virus replication by the CD8+ T-cell response (33), it has also been reported on theoretical grounds that a negative correlation indicates that the virus actively impairs the immune response (45). Additional support for a positive correlation between HIV load and HIV-specific CD8+ T cells comes from HAART-treated patients. Shortly after therapy initiation, the viral titer in these individuals rapidly decreases, accompanied by a rapid decrease in the frequency of HIV-specific CD8+ T cells (32, 34). Interestingly, after the viral load drops below detection limits in HAART-treated individuals, at which time the decay rate of the viral reservoir becomes lower (13, 36), the HIV-specific CD8+ T-cell frequency also appears to decay at a much lower rate (10), again reflecting the positive relationship between viral load and HIV-specific CD8+ T-cell frequency.
Taken together, these results suggest that the relationship between
HIV-1-specific CD8+ T-cell frequencies and viral
load is more reflective of viral replication driving T-cell expansion
than of CTL controlling viral replication. This implies that the
frequency of HIV-specific CD8+ T cells is not the
sole predictor of the ability of the immune system to control HIV
replication. Given the ample evidence of the antiviral activity of
CD8+ T cells
most critically, that removal of
CD8+ T cells from SIV-infected macaques leads to
increased viral replication and rapid progression (19,
41)this observation does not invalidate a role for
CD8+ CTL in viral control but does suggest that
the functional ability of HIV-specific CD8+ T
cells to control viral replication must be linked to parameters other
than frequency alone. One possibility is that the diversity of HIV
peptides recognized by CD8+ T cells may be linked
to control of viral replication (2). The enormous rate of
viral replication, in concert with a high incidence of tolerable
mutations endows HIV with the ability to rapidly escape from
immunological pressure, or the so-called epitope escape (18,
38). Recognition of a broad array of viral epitopes might
prevent such escape, both by providing backup recognition if mutations
nullify one or two responses and by providing a higher likelihood of
immune recognition of obligate wild-type epitopes (viral protein
sequences critical to function and nontolerant of mutation). However,
given the capacity of HIV to make compensatory mutations, it is likely
that even relatively conserved areas can tolerate mutations
(22). Given the associations between rapid progression or
nonprogression and HLA haplotype (21, 31), it is also
possible that recognition of particular HIV epitopes in context of
certain HLA molecules plays a significant role in the ability of
CD8+ T cells to control viral replication
(28).
Other parameters of the CD8 response may also be relevant to viral control. In addition to which epitopes are recognized, the number of distinct T-cell receptor-defined clonotypes recognizing each epitope may be pertinent. A broad array of clonotypes might provide resistance to escape mutation, as well as a higher likelihood of including high avidity responses, which might enhance function by allowing recognition of epitopes with a lower level of MHC class I affinity or decreased expression levels. It has also been suggested that the functional differentiation of HIV-specific CD8+ T cells may be impaired in HIV infection, such that the cytokine-producing cells present lack efficient cytolytic function (4, 11). Since the CD27 phenotype has been associated with functionally efficient CTL, it is possible that frequencies of HIV-specific CTL with this phenotype show a different relationship with viral load (4, 25).
Of course, any or all of these mechanisms could presumably operate, making determination of protective thresholds complex. Moreover, immunological protection is a dynamic process where the frequencies, specificities, and functional activities of CD8+ T-cell clonotypes change in concert with evolution of viral species during the course of infection. In reaction to mutations at dominant epitopes, the immune system could mount a response (i) with the same CD8+ T-cell clones, (ii) with newly elicited clones to such mutant epitopes, or (iii) with newly elicited clones to previously cryptic or subdominant clones. This would likely cause expansion in the overall breadth and frequency of the CD8+ T-cell response, which would, in turn, result in further immunological pressure on the virus and subsequent epitope escape. The overall effect would be one of action and reaction: viral expansion driving CD8+ T-cell expansion, driving viral mutation, and driving further CD8+ T-cell expansion. Thus, a positive correlation between CD8+ T-cell frequency and viral load would ensue until sufficient depletion of CD4+ T cells by the action of virus and/or CD8+ T cells rendered the CD8+ T cells ineffective (46). In addition to the concept of action and reaction, one can envision a situation in which the specificity of certain CD8+ T-cell clones is against viral epitopes that cannot tolerate mutation, possibly for reasons of viral fitness. In this situation one might find a genuine negative correlation between viral load and CD8+ T-cell response. Thus, determination of protective correlates in HIV infection will likely require quantitative measurement of various parameters of CD8+ T-cell-mediated immune responses (patterns of epitope recognition, clonotypic complexity, phenotype, and function) and of viral infection over the course of untreated early infection. Approaches outlined in this report, particularly the use of cytokine flow cytometry and overlapping pan-genome peptides, will allow such dissection of the response, and will constitute a powerful tool in this effort.
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ACKNOWLEDGMENTS |
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We thank Gary Nabel for providing the overlapping HIV 15-mer peptide panels.
This work was supported by the following grants: AI 47603 (R.A.K.), AI 43638 (R.A.K.), AI 35522 (R.A.K.), and AI 47606 (L.J.P.). S.B. is supported by a grant from the Swiss National Science Foundation, no. 631-62898.
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FOOTNOTES |
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* Corresponding author. Mailing address: Vaccine Research Center, NIAID/NIH, Building 40, Room 3614B, 40 Convent Dr., MSC 3022, Bethesda, MD 20892. Phone: (301) 594-8612. Fax: (301) 480-2779. E-mail: mbetts{at}nih.gov.
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REFERENCES |
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Abstract
Introduction
Materials and Methods
Results
Discussion
References
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| 1. | Allen, T. M., D. H. O'Connor, P. Jing, J. L. Dzuris, B. R. Mothe, T. U. Vogel, E. Dunphy, M. E. Liebl, C. Emerson, N. Wilson, K. J. Kunstman, X. Wang, D. B. Allison, A. L. Hughes, R. C. Desrosiers, J. D. Altman, S. M. Wolinsky, A. Sette, and D. I. Watkins. 2000. Tat-specific cytotoxic T lymphocytes select for SIV escape variants during resolution of primary viraemia. Nature 407:386-390[CrossRef][Medline]. |
| 2. |
Altfeld, M.,
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,
P. E. Sax,
S. Boswell,
J. O. Kahn,
C. Brander,
P. J. Goulder,
J. A. Levy,
J. I. Mullins, and B. D. Walker.
2001.
Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection.
J. Exp. Med.
193:169-180 |
| 3. |
Amara, R. R.,
F. Villinger,
J. Altman,
S. L. Lydy,
S. P. O'Neil,
S. I. Staprans,
D. C. Montefiori,
Y. Xu,
J. G. Herndon,
L. S. Wyatt,
M. A. Candido,
N. L. Kozyr,
P. L. Earl,
J. M. Smith,
H.-L. Ma,
B. D. Grimm,
M. L. Hulsey,
J. Miller,
H. M. McClure,
J. M. McNicholl,
B. Moss, and H. L. Robinson.
2001.
Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine.
Science
292:69-74 |
| 4. |
Appay, V.,
D. F. Nixon,
S. M. Donahoe,
G. M. Gillespie,
T. Dong,
A. King,
G. S. Ogg,
H. M. Spiegel,
C. Conlon,
C. A. Spina,
D. V. Havlir,
D. D. Richman,
A. Waters,
P. Easterbrook,
A. J. McMichael, and S. L. Rowland-Jones.
2000.
HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function.
J. Exp. Med.
192:63-75 |
| 5. |
Barouch, D. H.,
S. Santra,
J. E. Schmitz,
M. J. Kuroda,
T. M. Fu,
W. Wagner,
M. Bilska,
A. Craiu,
X. X. Zheng,
G. R. Krivulka,
K. Beaudry,
M. A. Lifton,
C. E. Nickerson,
W. L. Trigona,
K. Punt,
D. C. Freed,
L. Guan,
S. Dubey,
D. Casimiro,
A. Simon,
M. E. Davies,
M. Chastain,
T. B. Strom,
R. S. Gelman,
D. C. Montefiori, and M. G. Lewis.
2000.
Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination.
Science
290:486-492 |
| 6. |
Betts, M. R.,
J. P. Casazza,
B. A. Patterson,
S. Waldrop,
W. Trigona,
T.-M. Fu,
F. Kern,
L. J. Picker, and R. A. Koup.
2000.
Putative immunodominant human immunodeficiency virus-specific CD8+ T-cell responses cannot be predicted by major histocompatibility complex class I haplotype.
J. Virol.
74:9144-9151 |
| 7. | Betts, M. R., J. F. Krowka, T. B. Kepler, M. Davidian, C. Christopherson, S. Kwok, L. Louie, J. Eron, H. Sheppard, and J. A. Frelinger. 1999. Human immunodeficiency virus type 1-specific cytotoxic T lymphocyte activity is inversely correlated with HIV type 1 viral load in HIV type 1-infected long-term survivors. AIDS Res. Hum. Retrovir. 15:1219-1228[CrossRef][Medline]. |
| 8. | Borrow, P., H. Lewicki, X. P. Wei, M. S. Horwitz, N. Peffer, H. Meyers, J. A. Nelson, J. E. Gairin, B. H. Hahn, M. B. A. Oldstone, and G. M. Shaw. 1997. Antiviral pressure exerted by HIV-1-specific cytotoxic T lymphocytes (CTLs) during primary infection demonstrated by rapid selection of CTL escape virus. Nat. Med. 3:205-211[CrossRef][Medline]. |
| 9. | Callan, M. F., N. Steven, P. Krausa, J. D. Wilson, P. A. Moss, G. M. Gillespie, J. I. Bell, A. B. Rickinson, and A. J. McMichael. 1996. Large clonal expansions of CD8+ T cells in acute infectious mononucleosis. Nat. Med. 2:906-911[CrossRef][Medline]. |
| 10. |
Casazza, J. P.,
M. R. Betts,
L. J. Picker, and R. A. Koup.
2001.
Decay kinetics of HIV-specific CD8+ T cells in peripheral blood after initiation of highly active antiretroviral therapy.
J. Virol.
75:6508-6516 |
| 11. | Champagne, P., G. S. Ogg, A. S. King, C. Knabenhans, K. Ellefsen, M. Nobile, V. Appay, G. P. Rizzardi, S. Fleury, M. Lipp, R. Forster, S. Rowland-Jones, R. P. Sekaly, A. J. McMichael, and G. Pantaleo. 2001. Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410:106-111[CrossRef][Medline]. |
| 12. |
Chen, Z. W.,
A. Craiu,
L. Shen,
M. J. Kuroda,
U. C. Iroku,
D. I. Watkins,
G. Voss, and N. L. Letvin.
2000.
Simian immunodeficiency virus evades a dominant epitope-specific cytotoxic T lymphocyte response through a mutation resulting in the accelerated dissociation of viral peptide and MHC class I.
J. Immunol.
164:6474-6479 |
| 13. | Chun, T. W., L. Carruth, D. Finzi, X. Shen, J. A. DiGiuseppe, H. Taylor, M. Hermankova, K. Chadwick, J. Margolick, T. C. Quinn, Y. H. Kuo, R. Brookmeyer, M. A. Zeiger, P. Barditch-Crovo, and R. F. Siliciano. 1997. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature 387:183-188[CrossRef][Medline]. |
| 14. |
Dalod, M.,
M. Dupuis,
J. C. Deschemin,
D. Sicard,
D. Salmon,
J. F. Delfraissy,
A. Venet,
M. Sinet, and J. G. Guillet.
1999.
Broad, intense anti-human immunodeficiency virus (HIV) ex vivo CD8+ responses in HIV type 1-infected patients: comparison with anti-Epstein-Barr virus responses and changes during antiretroviral therapy.
J. Virol.
73:7108-7116 |
| 15. |
Gea-Banacloche, J. C.,
S. A. Migueles,
L. Martino,
W. L. Shupert,
A. C. McNeil,
M. S. Sabbaghian,
L. Ehler,
C. Prussin,
R. Stevens,
L. Lambert,
J. Altman,
C. W. Hallahan,
J. C. de Quiros, and M. Connors.
2000.
Maintenance of large numbers of virus-specific CD8+ T cells in HIV-infected progressors and long-term nonprogressors.
J. Immunol.
165:1082-1092 |
| 16. |
Goulder, P. J.,
M. A. Altfeld,
E. S. Rosenberg,
T. Nguyen,
Y. Tang,
R. L. Eldridge,
M. M. Addo,
S. He,
J. S. Mukherjee,
M. N. Phillips,
M. Bunce,
S. A. Kalams,
R. P. Sekaly,
B. D. Walker, and C. Brander.
2001.
Substantial differences in specificity of HIV-specific cytotoxic T cells in acute and chronic HIV infection.
J. Exp. Med.
193:181-194 |
| 17. |
Goulder, P. J.,
Y. Tang,
C. Brander,
M. R. Betts,
M. Altfeld,
K. Annamalai,
A. Trocha,
S. He,
E. S. Rosenberg,
G. Ogg,
C. A. O'Callaghan,
S. A. Kalams,
R. E. McKinney,
K. Mayer,
R. A. Koup,
S. I. Pelton,
S. K. Burchett,
K. McIntosh, and B. D. Walker.
2000.
Functionally inert HIV-specific cytotoxic T lymphocytes do not play a major role in chronically infected adults and children.
J. Exp. Med.
192:1819-1832 |
| 18. | Goulder, P. J. R., R. E. Phillips, R. A. Colbert, S. McAdam, G. Ogg, M. A. Nowak, P. Giangrande, G. Luzzi, B. Morgan, A. Edwards, A. J. McMichael, and S. Rowland-Jones. 1997. Late escape from an immunodominant cytotoxic T lymphocytes response associated with progression to AIDS. Nat. Med. 3:212-217[CrossRef][Medline]. |
| 19. |
Jin, X.,
D. E. Bauer,
S. E. Tuttleton,
S. Lewin,
A. Gettie,
J. Blanchard,
C. E. Irwin,
J. T. Safrit,
J. Mittler,
L. Weinberger,
L. G. Kostrikis,
L. Zhang,
A. S. Perelson, and D. D. Ho.
1999.
Dramatic rise in plasma viremia after CD8(+) T cell depletion in simian immunodeficiency virus-infected macaques.
J. Exp. Med.
189:991-998 |
| 20. |
Kalams, S. A.,
S. P. Buchbinder,
E. S. Rosenberg,
J. M. Billingsley,
D. S. Colbert,
N. G. Jones,
A. K. Shea,
A. K. Trocha, and B. D. Walker.
1999.
Association between virus-specific cytotoxic T-lymphocyte and helper responses in human immunodeficiency virus type 1 infection.
J. Virol.
73:6715-6720 |
| 21. | Kaslow, R. A., M. Carrington, R. Apple, L. Park, A. Munoz, A. J. Saah, J. J. Goedert, C. Winkler, S. J. O'Brien, C. Rinaldo, R. Detels, W. Blattner, J. Phair, H. Erlich, and D. L. Mann. 1996. Influence of combinations of human major histocompatibility complex genes on the course of HIV-1 infection. Nat. Med. 2:405-411[CrossRef][Medline]. |
| 22. |
Kelleher, A. D.,
C. Long,
E. C. Holmes,
R. L. Allen,
J. Wilson,
C. Conlon,
C. Workman,
S. Shaunak,
K. Olson,
P. Goulder,
C. Brander,
G. Ogg,
J. S. Sullivan,
W. Dyer,
I. I. Jones,
A. J. McMichael,
S. Rowland-Jones, and R. E. Phillips.
2001.
Clustered mutations in HIV-1 gag are consistently required for escape from HLA-B27-restricted cytotoxic T lymphocyte responses.
J. Exp. Med.
193:375-386 |
| 23. |
Klein, M. R.,
C. A. van Baalen,
A. M. Holwerda,
S. R. Kerkhof Garde,
R. J. Bende,
I. P. M. Keet,
J.-K. M. Eeftinck-Schattenkerk,
A. D. M. E. Osterhaus,
H. Schuitemaker, and F. Miedema.
1995.
Kinetics of gag-specific cytotoxic T lymphocyte responses during the clinical course of HIV-1 infection: a longitudinal analysis of rapid progressors and long-term asymptomatics.
J. Exp. Med.
181:1365-1372 |
| 24. | Korber, B. T. M., C. Brander, B. D. Walker, R. A. Koup, J. P. Moore, B. F. Haynes, and G. Myers. 1998. HIV molecular immunology database. Los Alamos National Laboratory, Los Alamos, N.Mex. |
| 25. | Kostense, S., G. S. Ogg, E. H. Manting, G. Gillespie, J. Joling, K. Vandenberghe, E. Z. Veenhof, D. van Baarle, S. Jurriaans, M. R. Klein, and F. Miedema. 2001. High viral burden in the presence of major HIV-specific CD8(+) T cell expansions: evidence for impaired CTL effector function. Eur. J. Immunol. 31:677-686[CrossRef][Medline]. |
| 26. |
Koup, R. A.,
J. T. Safrit,
Y. Cao,
C. A. Andrews,
Y. Wu,
G. McLeod,
W. Borkowsky,
C. Farthing, and D. D. Ho.
1994.
Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome.
J. Virol.
68:4650-4655 |
| 27. |
Metzner, K. J.,
X. Jin,
F. V. Lee,
A. Gettie,
D. E. Bauer,
M. Di Mascio,
A. S. Perelson,
P. A. Marx,
D. D. Ho,
L. G. Kostrikis, and R. I. Connor.
2000.
Effects of in vivo CD8(+) T cell depletion on virus replication in rhesus macaques immunized with a live, attenuated simian immunodeficiency virus vaccine.
J. Exp. Med.
191:1921-1931 |
| 28. |
Migueles, S. A.,
M. S. Sabbaghian,
W. L. Shupert,
M. P. Bettinotti,
F. M. Marincola,
L. Martino,
C. W. Hallahan,
S. M. Selig,
D. Schwartz,
J. Sullivan, and M. Connors.
2000.
HLA B*5701 is highly associated with restriction of virus replication in a subgroup of HIV-infected long term nonprogressors.
Proc. Natl. Acad. Sci. USA
97:2709-2714 |
| 29. | Murali-Krishna, K., J. D. Altman, M. Suresh, D. J. Sourdive, A. J. Zajac, J. D. Miller, J. Slansky, and R. Ahmed. 1998. Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection. Immunity 8:177-187[CrossRef][Medline]. |
| 30. |
Musey, L.,
J. Hughes,
T. Schacker,
T. Shea,
L. Corey, and M. J. McElrath.
1997.
Cytotoxic-T-cell responses, viral load, and disease progression in early human immunodeficiency virus type 1 infection.
N. Engl. J. Med.
337:1267-1274 |
| 31. |
Nelson, G. W.,
R. Kaslow, and D. L. Mann.
1997.
Frequency of HLA allele-specific peptide motifs in HIV-1 proteins correlates with the allele's association with relative rates of disease progression after HIV-1 infection.
Proc. Natl. Acad. Sci. USA
94:9802-9807 |
| 32. | Nixon, D. F., D. Douek, P. J. Kuebler, X. Jin, M. Vesanen, S. Bonhoeffer, Y. Cao, R. A. Koup, D. D. Ho, and M. Markowitz. 1999. Molecular tracking of an human immunodeficiency virus nef specific cytotoxic T-cell clone shows persistence of clone-specific T-cell receptor DNA but not mRNA following early combination antiretroviral therapy. Immunol. Lett. 66:219-228[CrossRef][Medline]. |
| 33. |
Ogg, G. S.,
X. Jin,
S. Bonhoeffer,
P. R. Dunbar,
M. A. Nowak,
S. Monard,
J. P. Segal,
Y. Cao,
S. L. Rowland-Jones,
V. Cerundolo,
A. Hurley,
M. Markowitz,
D. D. Ho,
D. F. Nixon, and A. J. McMichael.
1998.
Quantitation of HIV-1-specific cytotoxic T lymphocytes and plasma load of viral RNA.
Science
279:2103-2106 |
| 34. |
Ogg, G. S.,
X. Jin,
S. Bonhoeffer,
P. Moss,
M. A. Nowak,
S. Monard,
J. P. Segal,
Y. Cao,
S. L. Rowland-Jones,
A. Hurley,
M. Markowitz,
D. D. Ho,
A. J. McMichael, and D. F. Nixon.
1999.
Decay kinetics of human immunodeficiency virus-specific effector cytotoxic T lymphocytes after combination antiretroviral therapy.
J. Virol.
73:797-800 |
| 35. |
Pantaleo, G.,
S. Menzo,
M. Vaccarezza,
C. Graziosi,
O. J. Cohen,
J. F. Demarest,
D. Montefiori,
J. M. Orenstein,
C. Fox,
L. K. Schrager, et al.
1995.
Studies in subjects with long-term nonprogressive human immunodeficiency virus infection.
N. Engl. J. Med.
332:209-216 |
| 36. | Perelson, A. S., P. Essunger, Y. Cao, M. Vesanen, A. Hurley, K. Saksela, M. Markowitz, and D. D. Ho. 1997. Decay characteristics of long-lived HIV-1-infected compartments during combination therapy. Nature 387:188-191[CrossRef][Medline]. |
| 37. | Pitcher, C. J., C. Quittner, D. M. Peterson, M. Connors, R. A. Koup, V. C. Maino, and L. J. Picker. 1999. HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat. Med. 5:518-525[CrossRef][Medline]. |
| 38. |
Price, D. A.,
P. J. Goulder,
P. Klenerman,
A. K. Sewell,
P. J. Easterbrook,
M. Troop,
C. R. Bangham, and R. E. Phillips.
1997.
Positive selection of HIV-1 cytotoxic T lymphocyte escape variants during primary infection.
Proc. Natl. Acad. Sci. USA
94:1890-1895 |
| 39. |
Rinaldo, C.,
X.-L. Huang,
Z. Fan,
M. Ding,
L. Beltz,
A. Logar,
D. Panicali,
G. Mazzara,
J. Liebmann,
M. Cottrill, and P. Gupta.
1995.
High levels of anti-human immunodeficiency virus type 1 (HIV-1) memory cytotoxic T-lymphocyte activity and low viral load are associated with lack of disease in HIV-1-infected long-term nonprogressors.
J. Virol.
69:5838-5842 |
| 40. |
Rosenberg, E.,
J. Billingsley,
A. Caliendo,
S. Boswell,
P. Sax,
S. Kalams, and B. Walker.
1997.
Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia.
Science
278:1447-1450 |
| 41. |
Schmitz, J. E.,
M. J. Kuroda,
S. Santra,
V. G. Sasseville,
M. A. Simon,
M. A. Lifton,
P. Racz,
K. Tenner-Racz,
M. Dalesandro,
B. J. Scallon,
J. Ghrayeb,
M. A. Forman,
D. C. Montefiori,
E. P. Rieber,
N. L. Letvin, and K. A. Reimann.
1999.
Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes.
Science
283:857-860 |
| 42. |
Seth, A.,
I. Ourmanov,
J. E. Schmitz,
M. J. Kuroda,
M. A. Lifton,
C. E. Nickerson,
L. Wyatt,
M. Carroll,
B. Moss,
D. Venzon,
N. L. Letvin, and V. M. Hirsch.
2000.
Immunization with a modified vaccinia virus expressing simian immunodeficiency virus (SIV) Gag-Pol primes for an anamnestic Gag-specific cytotoxic T-lymphocyte response and is associated with reduction of viremia after SIV challenge.
J. Virol.
74:2502-2509 |
| 43. | van Baalen, C. A., O. Pontesilli, R. C. Huisman, A. M. Geretti, M. R. Klein, F. de Wolf, F. Miedema, R. A. Gruters, and A. D. Osterhaus. 1997. Human immunodeficiency virus type 1 Rev- and Tat-specific cytotoxic T lymphocyte frequencies inversely correlate with rapid progression to AIDS. J. Gen. Virol. 78:1913-1918[Abstract]. |
| 44. | Wilson, J. D., N. Imami, A. Watkins, J. Gill, P. Hay, B. Gazzard, M. Westby, and F. M. Gotch. 2000. Loss of CD4+ T cell proliferative ability but not loss of human immunodeficiency virus type 1 specificity equates with progression to disease. J. Infect. Dis. 182:792-798[CrossRef][Medline]. |
| 45. | Wodarz, D., S. E. Hall, K. Usuku, M. Osame, G. S. Ogg, A. J. McMichael, M. A. Nowak, and C. R. Bangham. 2001. Cytotoxic T-cell abundance and virus load in human immunodeficiency virus type 1 and human T-cell leukaemia virus type 1. Proc. R. Soc. Biol. Sci. 268:1215-1221[Medline]. |
| 46. |
Zajac, A. J.,
J. N. Blattman,
K. Murali-Krishna,
D. J. Sourdive,
M. Suresh,
J. D. Altman, and R. Ahmed.
1998.
Viral immune evasion due to persistence of activated T cells without effector function.
J. Exp. Med.
188:2205-2213 |
Journal of Virology, December 2001, p. 11983-11991, Vol. 75, No. 24
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.24.11983-11991.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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[Abstract] [Full Text] -
Daucher, M., Price, D. A., Brenchley, J. M., Lamoreaux, L., Metcalf, J. A., Rehm, C., Nies-Kraske, E., Urban, E., Yoder, C., Rock, D., Gumkowski, J., Betts, M. R., Dybul, M. R., Douek, D. C.
(2008). Virological Outcome after Structured Interruption of Antiretroviral Therapy for Human Immunodeficiency Virus Infection Is Associated with the Functional Profile of Virus-Specific CD8+ T Cells. J. Virol.
82: 4102-4114
[Abstract] [Full Text] -
Rehr, M., Cahenzli, J., Haas, A., Price, D. A., Gostick, E., Huber, M., Karrer, U., Oxenius, A.
(2008). Emergence of Polyfunctional CD8+ T Cells after Prolonged Suppression of Human Immunodeficiency Virus Replication by Antiretroviral Therapy. J. Virol.
82: 3391-3404
[Abstract] [Full Text] -
Nilsson, C., Aboud, S., Karlen, K., Hejdeman, B., Urassa, W., Biberfeld, G.
(2008). Optimal Blood Mononuclear Cell Isolation Procedures for Gamma Interferon Enzyme-Linked Immunospot Testing of Healthy Swedish and Tanzanian Subjects. CVI
15: 585-589
[Abstract] [Full Text] -
Balamurugan, A., Lewis, M. J., Kitchen, C. M. R., Robertson, M. N., Shiver, J. W., Daar, E. S., Pitt, J., Ali, A., Ng, H. L., Currier, J. S., Yang, O. O.
(2008). Primary Human Immunodeficiency Virus Type 1 (HIV-1) Infection during HIV-1 Gag Vaccination. J. Virol.
82: 2784-2791
[Abstract] [Full Text] -
Li, H., Chien, P. C. Jr., Tuen, M., Visciano, M. L., Cohen, S., Blais, S., Xu, C.-F., Zhang, H.-T., Hioe, C. E.
(2008). Identification of an N-Linked Glycosylation in the C4 Region of HIV-1 Envelope gp120 That Is Critical for Recognition of Neighboring CD4 T Cell Epitopes. J. Immunol.
180: 4011-4021
[Abstract] [Full Text] -
Lewis, M. J., Balamurugan, A., Ohno, A., Kilpatrick, S., Ng, H. L., Yang, O. O.
(2008). Functional Adaptation of Nef to the Immune Milieu of HIV-1 Infection In Vivo. J. Immunol.
180: 4075-4081
[Abstract] [Full Text] -
Currier, J. R., Galley, L. M., Wenschuh, H., Morafo, V., Ratto-Kim, S., Gray, C. M., Maboko, L., Hoelscher, M., Marovich, M. A., Cox, J. H.
(2008). Peptide Impurities in Commercial Synthetic Peptides and Their Implications for Vaccine Trial Assessment. CVI
15: 267-276
[Abstract] [Full Text] -
Geldmacher, C., Gray, C., Nason, M., Currier, J. R., Haule, A., Njovu, L., Geis, S., Hoffmann, O., Maboko, L., Meyerhans, A., Cox, J., Hoelscher, M.
(2007). A High Viral Burden Predicts the Loss of CD8 T-Cell Responses Specific for Subdominant Gag Epitopes during Chronic Human Immunodeficiency Virus Infection. J. Virol.
81: 13809-13815
[Abstract] [Full Text] -
Frahm, N., Kaufmann, D. E., Yusim, K., Muldoon, M., Kesmir, C., Linde, C. H., Fischer, W., Allen, T. M., Li, B., McMahon, B. H., Faircloth, K. L., Hewitt, H. S., Mackey, E. W., Miura, T., Khatri, A., Wolinsky, S., McMichael, A., Funkhouser, R. K., Walker, B. D., Brander, C., Korber, B. T.
(2007). Increased Sequence Diversity Coverage Improves Detection of HIV-Specific T Cell Responses. J. Immunol.
179: 6638-6650
[Abstract] [Full Text] -
Mandl, J. N., Regoes, R. R., Garber, D. A., Feinberg, M. B.
(2007). Estimating the Effectiveness of Simian Immunodeficiency Virus-Specific CD8+ T Cells from the Dynamics of Viral Immune Escape. J. Virol.
81: 11982-11991
[Abstract] [Full Text] -
Hartigan-O'Connor, D. J., Abel, K., McCune, J. M.
(2007). Suppression of SIV-specific CD4+ T cells by infant but not adult macaque regulatory T cells: implications for SIV disease progression. JEM
204: 2679-2692
[Abstract] [Full Text] -
Almeida, J. R., Price, D. A., Papagno, L., Arkoub, Z. A., Sauce, D., Bornstein, E., Asher, T. E., Samri, A., Schnuriger, A., Theodorou, I., Costagliola, D., Rouzioux, C., Agut, H., Marcelin, A.-G., Douek, D., Autran, B., Appay, V.
(2007). Superior control of HIV-1 replication by CD8+ T cells is reflected by their avidity, polyfunctionality, and clonal turnover. JEM
204: 2473-2485
[Abstract] [Full Text] -
D'Souza, M., Fontenot, A. P., Mack, D. G., Lozupone, C., Dillon, S., Meditz, A., Wilson, C. C., Connick, E., Palmer, B. E.
(2007). Programmed Death 1 Expression on HIV-Specific CD4+ T Cells Is Driven by Viral Replication and Associated with T Cell Dysfunction. J. Immunol.
179: 1979-1987
[Abstract] [Full Text] -
Kianizad, K., Marshall, L. A., Grinshtein, N., Bernard, D., Margl, R., Cheng, S., Beermann, F., Wan, Y., Bramson, J.
(2007). Elevated Frequencies of Self-reactive CD8+ T Cells following Immunization with a Xenoantigen Are Due to the Presence of a Heteroclitic CD4+ T-Cell Helper Epitope. Cancer Res.
67: 6459-6467
[Abstract] [Full Text] -
Barry, A. P., Silvestri, G., Safrit, J. T., Sumpter, B., Kozyr, N., McClure, H. M., Staprans, S. I., Feinberg, M. B.
(2007). Depletion of CD8+ Cells in Sooty Mangabey Monkeys Naturally Infected with Simian Immunodeficiency Virus Reveals Limited Role for Immune Control of Virus Replication in a Natural Host Species. J. Immunol.
178: 8002-8012
[Abstract] [Full Text] -
Willberg, C. B., Pillai, S. K., Sharp, E. R., Rosenberg, M. G., Agudelo, J. D., Barbour, J. D., Nixon, D. F.
(2007). Rational Peptide Selection To Detect Human Immunodeficiency Virus Type 1-Specific T-Cell Responses under Resource-Limited Conditions. CVI
14: 785-788
[Abstract] [Full Text] -
Critchfield, J. W., Lemongello, D., Walker, D. H., Garcia, J. C., Asmuth, D. M., Pollard, R. B., Shacklett, B. L.
(2007). Multifunctional Human Immunodeficiency Virus (HIV) Gag-Specific CD8+ T-Cell Responses in Rectal Mucosa and Peripheral Blood Mononuclear Cells during Chronic HIV Type 1 Infection. J. Virol.
81: 5460-5471
[Abstract] [Full Text] -
Northfield, J. W., Loo, C. P., Barbour, J. D., Spotts, G., Hecht, F. M., Klenerman, P., Nixon, D. F., Michaelsson, J.
(2007). Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ TEMRA Cells in Early Infection Are Linked to Control of HIV-1 Viremia and Predict the Subsequent Viral Load Set Point. J. Virol.
81: 5759-5765
[Abstract] [Full Text] -
Connick, E., Mattila, T., Folkvord, J. M., Schlichtemeier, R., Meditz, A. L., Ray, M. G., McCarter, M. D., MaWhinney, S., Hage, A., White, C., Skinner, P. J.
(2007). CTL Fail to Accumulate at Sites of HIV-1 Replication in Lymphoid Tissue. J. Immunol.
178: 6975-6983
[Abstract] [Full Text] -
Biancotto, A., Grivel, J.-C., Iglehart, S. J., Vanpouille, C., Lisco, A., Sieg, S. F., Debernardo, R., Garate, K., Rodriguez, B., Margolis, L. B., Lederman, M. M.
(2007). Abnormal activation and cytokine spectra in lymph nodes of people chronically infected with HIV-1. Blood
109: 4272-4279
[Abstract] [Full Text] -
Ueno, T., Idegami, Y., Motozono, C., Oka, S., Takiguchi, M.
(2007). Altering Effects of Antigenic Variations in HIV-1 on Antiviral Effectiveness of HIV-Specific CTLs. J. Immunol.
178: 5513-5523
[Abstract] [Full Text] -
Lichterfeld, M., Yu, X. G., Mui, S. K., Williams, K. L., Trocha, A., Brockman, M. A., Allgaier, R. L., Waring, M. T., Koibuchi, T., Johnston, M. N., Cohen, D., Allen, T. M., Rosenberg, E. S., Walker, B. D., Altfeld, M.
(2007). Selective Depletion of High-Avidity Human Immunodeficiency Virus Type 1 (HIV-1)-Specific CD8+ T Cells after Early HIV-1 Infection. J. Virol.
81: 4199-4214
[Abstract] [Full Text] -
Honeyborne, I., Prendergast, A., Pereyra, F., Leslie, A., Crawford, H., Payne, R., Reddy, S., Bishop, K., Moodley, E., Nair, K., van der Stok, M., McCarthy, N., Rousseau, C. M., Addo, M., Mullins, J. I., Brander, C., Kiepiela, P., Walker, B. D., Goulder, P. J. R.
(2007). Control of Human Immunodeficiency Virus Type 1 Is Associated with HLA-B*13 and Targeting of Multiple Gag-Specific CD8+ T-Cell Epitopes. J. Virol.
81: 3667-3672
[Abstract] [Full Text] -
De Boer, R. J.
(2007). Understanding the Failure of CD8+ T-Cell Vaccination against Simian/Human Immunodeficiency Virus. J. Virol.
81: 2838-2848
[Abstract] [Full Text] -
McKinnon, L. R., Ball, T. B., Wachihi, C., McLaren, P. J., Waruk, J. L. M., Mao, X., Ramdahin, S., Anzala, A. O., Kamene, J., Luo, M., Fowke, K. R., Plummer, F. A.
(2007). Epitope Cross-Reactivity Frequently Differs between Central and Effector Memory HIV-Specific CD8+ T Cells. J. Immunol.
178: 3750-3756
[Abstract] [Full Text] -
Blankson, J. N., Bailey, J. R., Thayil, S., Yang, H.-C., Lassen, K., Lai, J., Gandhi, S. K., Siliciano, J. D., Williams, T. M., Siliciano, R. F.
(2007). Isolation and Characterization of Replication-Competent Human Immunodeficiency Virus Type 1 from a Subset of Elite Suppressors. J. Virol.
81: 2508-2518
[Abstract] [Full Text] -
Geldmacher, C., Currier, J. R., Herrmann, E., Haule, A., Kuta, E., McCutchan, F., Njovu, L., Geis, S., Hoffmann, O., Maboko, L., Williamson, C., Birx, D., Meyerhans, A., Cox, J., Hoelscher, M.
(2007). CD8 T-Cell Recognition of Multiple Epitopes within Specific Gag Regions Is Associated with Maintenance of a Low Steady-State Viremia in Human Immunodeficiency Virus Type 1-Seropositive Patients. J. Virol.
81: 2440-2448
[Abstract] [Full Text] -
Arrode, G., Hegde, R., Mani, A., Jin, Y., Chebloune, Y., Narayan, O.
(2007). Phenotypic and Functional Analysis of Immune CD8+ T Cell Responses Induced by a Single Injection of a HIV DNA Vaccine in Mice. J. Immunol.
178: 2318-2327
[Abstract] [Full Text] -
Rodriguez, A. R., Arulanandam, B. P., Hodara, V. L., McClure, H. M., Cobb, E. K., Salas, M. T., White, R., Murthy, K. K.
(2007). Influence of interleukin-15 on CD8+ natural killer cells in human immunodeficiency virus type 1-infected chimpanzees. J. Gen. Virol.
88: 641-651
[Abstract] [Full Text] -
Chung, C., Lee, W., Loffredo, J. T., Burwitz, B., Friedrich, T. C., Giraldo Vela, J. P., Napoe, G., Rakasz, E. G., Wilson, N. A., Allison, D. B., Watkins, D. I.
(2007). Not All Cytokine-Producing CD8+ T Cells Suppress Simian Immunodeficiency Virus Replication. J. Virol.
81: 1517-1523
[Abstract] [Full Text] -
Breton, M., Zhao, C., Ouellette, M., Tremblay, M. J., Papadopoulou, B.
(2007). A recombinant non-pathogenic Leishmania vaccine expressing human immunodeficiency virus 1 (HIV-1) Gag elicits cell-mediated immunity in mice and decreases HIV-1 replication in human tonsillar tissue following exposure to HIV-1 infection. J. Gen. Virol.
88: 217-225
[Abstract] [Full Text] -
Gauduin, M.-C., Yu, Y., Barabasz, A., Carville, A., Piatak, M., Lifson, J. D., Desrosiers, R. C., Johnson, R. P.
(2006). Induction of a virus-specific effector-memory CD4+ T cell response by attenuated SIV infection. JEM
203: 2661-2672
[Abstract] [Full Text] -
Adnan, S., Balamurugan, A., Trocha, A., Bennett, M. S., Ng, H. L., Ali, A., Brander, C., Yang, O. O.
(2006). Nef interference with HIV-1-specific CTL antiviral activity is epitope specific. Blood
108: 3414-3419
[Abstract] [Full Text] -
Le Priol, Y., Puthier, D., Lecureuil, C., Combadiere, C., Debre, P., Nguyen, C., Combadiere, B.
(2006). High Cytotoxic and Specific Migratory Potencies of Senescent CD8+CD57+ Cells in HIV-Infected and Uninfected Individuals. J. Immunol.
177: 5145-5154
[Abstract] [Full Text] -
VandeWoude, S., Apetrei, C.
(2006). Going Wild: Lessons from Naturally Occurring T-Lymphotropic Lentiviruses. Clin. Microbiol. Rev.
19: 728-762
[Abstract] [Full Text] -
Liu, Y., McNevin, J., Cao, J., Zhao, H., Genowati, I., Wong, K., McLaughlin, S., McSweyn, M. D., Diem, K., Stevens, C. E., Maenza, J., He, H., Nickle, D. C., Shriner, D., Holte, S. E., Collier, A. C., Corey, L., McElrath, M. J., Mullins, J. I.
(2006). Selection on the Human Immunodeficiency Virus Type 1 Proteome following Primary Infection. J. Virol.
80: 9519-9529
[Abstract] [Full Text] -
Brenchley, J. M., Ruff, L. E., Casazza, J. P., Koup, R. A., Price, D. A., Douek, D. C.
(2006). Preferential Infection Shortens the Life Span of Human Immunodeficiency Virus-Specific CD4+ T Cells In Vivo. J. Virol.
80: 6801-6809
[Abstract] [Full Text] -
Korthals Altes, H., de Boer, R., Boerlijst, M.
(2006). Role of avidity and breadth of the CD4 T cell response in progression to AIDS. Proc R Soc B
273: 1697-1704
[Abstract] [Full Text] -
Dunham, R., Pagliardini, P., Gordon, S., Sumpter, B., Engram, J., Moanna, A., Paiardini, M., Mandl, J. N., Lawson, B., Garg, S., McClure, H. M., Xu, Y.-X., Ibegbu, C., Easley, K., Katz, N., Pandrea, I., Apetrei, C., Sodora, D. L., Staprans, S. I., Feinberg, M. B., Silvestri, G.
(2006). The AIDS resistance of naturally SIV-infected sooty mangabeys is independent of cellular immunity to the virus. Blood
108: 209-217
[Abstract] [Full Text] -
Betts, M. R., Nason, M. C., West, S. M., De Rosa, S. C., Migueles, S. A., Abraham, J., Lederman, M. M., Benito, J. M., Goepfert, P. A., Connors, M., Roederer, M., Koup, R. A.
(2006). HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood
107: 4781-4789
[Abstract] [Full Text] -
Mattapallil, J. J., Douek, D. C., Buckler-White, A., Montefiori, D., Letvin, N. L., Nabel, G. J., Roederer, M.
(2006). Vaccination preserves CD4 memory T cells during acute simian immunodeficiency virus challenge. JEM
203: 1533-1541
[Abstract] [Full Text] -
Samri, A., Durier, C., Urrutia, A., Sanchez, I., Gahery-Segard, H., Imbart, S., Sinet, M., Tartour, E., Aboulker, J.-P., Autran, B., Venet, A., the ANRS ELISpot Standardization Group,
(2006). Evaluation of the Interlaboratory Concordance in Quantification of Human Immunodeficiency Virus-Specific T Cells with a Gamma Interferon Enzyme-Linked Immunospot Assay. CVI
13: 684-697
[Abstract] [Full Text] -
Kan-Mitchell, J., Bajcz, M., Schaubert, K. L., Price, D. A., Brenchley, J. M., Asher, T. E., Douek, D. C., Ng, H. L., Yang, O. O., Rinaldo, C. R. Jr., Benito, J. M., Bisikirska, B., Hegde, R., Marincola, F. M., Boggiano, C., Wilson, D., Abrams, J., Blondelle, S. E., Wilson, D. B.
(2006). Degeneracy and Repertoire of the Human HIV-1 Gag p1777-85 CTL Response.. J. Immunol.
176: 6690-6701
[Abstract] [Full Text] -
Duvall, M. G., Jaye, A., Dong, T., Brenchley, J. M., Alabi, A. S., Jeffries, D. J., van der Sande, M., Togun, T. O., McConkey, S. J., Douek, D. C., McMichael, A. J., Whittle, H. C., Koup, R. A., Rowland-Jones, S. L.
(2006). Maintenance of HIV-Specific CD4+ T Cell Help Distinguishes HIV-2 from HIV-1 Infection.. J. Immunol.
176: 6973-6981
[Abstract] [Full Text] -
Goonetilleke, N., Moore, S., Dally, L., Winstone, N., Cebere, I., Mahmoud, A., Pinheiro, S., Gillespie, G., Brown, D., Loach, V., Roberts, J., Guimaraes-Walker, A., Hayes, P., Loughran, K., Smith, C., De Bont, J., Verlinde, C., Vooijs, D., Schmidt, C., Boaz, M., Gilmour, J., Fast, P., Dorrell, L., Hanke, T., McMichael, A. J.
(2006). Induction of Multifunctional Human Immunodeficiency Virus Type 1 (HIV-1)-Specific T Cells Capable of Proliferation in Healthy Subjects by Using a Prime-Boost Regimen of DNA- and Modified Vaccinia Virus Ankara-Vectored Vaccines Expressing HIV-1 Gag Coupled to CD8+ T-Cell Epitopes. J. Virol.
80: 4717-4728
[Abstract] [Full Text] -
Zhang, Z., Fu, J., Zhao, Q., He, Y., Jin, L., Zhang, H., Yao, J., Zhang, L., Wang, F.-S.
(2006). Differential Restoration of Myeloid and Plasmacytoid Dendritic Cells in HIV-1-Infected Children after Treatment with Highly Active Antiretroviral Therapy. J. Immunol.
176: 5644-5651
[Abstract] [Full Text] -
Pal, R., Venzon, D., Santra, S., Kalyanaraman, V. S., Montefiori, D. C., Hocker, L., Hudacik, L., Rose, N., Nacsa, J., Edghill-Smith, Y., Moniuszko, M., Hel, Z., Belyakov, I. M., Berzofsky, J. A., Parks, R. W., Markham, P. D., Letvin, N. L., Tartaglia, J., Franchini, G.
(2006). Systemic Immunization with an ALVAC-HIV-1/Protein Boost Vaccine Strategy Protects Rhesus Macaques from CD4+ T-Cell Loss and Reduces both Systemic and Mucosal Simian-Human Immunodeficiency Virus SHIVKU2 RNA Levels. J. Virol.
80: 3732-3742
[Abstract] [Full Text] -
Bergmeier, L.A., Lehner, T.
(2006). Innate and Adaptive Mucosal Immunity in Protection against HIV Infection. ADR
19: 21-28
[Abstract] [Full Text] -
Wang, Z., Metcalf, B., Ribeiro, R. M., McClure, H., Kaur, A.
(2006). Th-1-Type Cytotoxic CD8+ T-Lymphocyte Responses to Simian Immunodeficiency Virus (SIV) Are a Consistent Feature of Natural SIV Infection in Sooty Mangabeys. J. Virol.
80: 2771-2783
[Abstract] [Full Text] -
Zuniga, R., Lucchetti, A., Galvan, P., Sanchez, S., Sanchez, C., Hernandez, A., Sanchez, H., Frahm, N., Linde, C. H., Hewitt, H. S., Hildebrand, W., Altfeld, M., Allen, T. M., Walker, B. D., Korber, B. T., Leitner, T., Sanchez, J., Brander, C.
(2006). Relative Dominance of Gag p24-Specific Cytotoxic T Lymphocytes Is Associated with Human Immunodeficiency Virus Control. J. Virol.
80: 3122-3125
[Abstract] [Full Text] -
Snyder-Cappione, J. E., Divekar, A. A., Maupin, G. M., Jin, X., Demeter, L. M., Mosmann, T. R.
(2006). 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.
176: 2662-2668
[Abstract] [Full Text] -
Burgers, W. A., van Harmelen, J. H., Shephard, E., Adams, C., Mgwebi, T., Bourn, W., Hanke, T., Williamson, A.-L., Williamson, C.
(2006). Design and preclinical evaluation of a multigene human immunodeficiency virus type 1 subtype C DNA vaccine for clinical trial. J. Gen. Virol.
87: 399-410
[Abstract] [Full Text] -
Gorse, G. J., Simionescu, R. E., Patel, G. B.
(2006). Cellular Immune Responses in Asymptomatic Human Immunodeficiency Virus Type 1 (HIV-1) Infection and Effects of Vaccination with Recombinant Envelope Glycoprotein of HIV-1. CVI
13: 26-32
[Abstract] [Full Text] -
Hel, Z., Tsai, W.-P., Tryniszewska, E., Nacsa, J., Markham, P. D., Lewis, M. G., Pavlakis, G. N., Felber, B. K., Tartaglia, J., Franchini, G.
(2006). Improved Vaccine Protection from Simian AIDS by the Addition of Nonstructural Simian Immunodeficiency Virus Genes. J. Immunol.
176: 85-96
[Abstract] [Full Text] -
Emu, B., Sinclair, E., Favre, D., Moretto, W. J., Hsue, P., Hoh, R., Martin, J. N., Nixon, D. F., McCune, J. M., Deeks, S. G.
(2005). Phenotypic, Functional, and Kinetic Parameters Associated with Apparent T-Cell Control of Human Immunodeficiency Virus Replication in Individuals with and without Antiretroviral Treatment. J. Virol.
79: 14169-14178
[Abstract] [Full Text] -
Sheth, P. M., Danesh, A., Shahabi, K., Rebbapragada, A., Kovacs, C., Dimayuga, R., Halpenny, R., MacDonald, K. S., Mazzulli, T., Kelvin, D., Ostrowski, M., Kaul, R.
(2005). HIV-Specific CD8+ Lymphocytes in Semen Are Not Associated with Reduced HIV Shedding. J. Immunol.
175: 4789-4796
[Abstract] [Full Text] -
Sylwester, A. W., Mitchell, B. L., Edgar, J. B., Taormina, C., Pelte, C., Ruchti, F., Sleath, P. R., Grabstein, K. H., Hosken, N. A., Kern, F., Nelson, J. A., Picker, L. J.
(2005). Broadly targeted human cytomegalovirus-specific CD4+ and CD8+ T cells dominate the memory compartments of exposed subjects. JEM
202: 673-685
[Abstract] [Full Text] -
Geels, M. J., Dubey, S. A., Anderson, K., Baan, E., Bakker, M., Pollakis, G., Paxton, W. A., Shiver, J. W., Goudsmit, J.
(2005). Broad Cross-Clade T-Cell Responses to Gag in Individuals Infected with Human Immunodeficiency Virus Type 1 Non-B Clades (A to G): Importance of HLA Anchor Residue Conservation. J. Virol.
79: 11247-11258
[Abstract] [Full Text] -
Zaunders, J. J., Munier, M. L., Kaufmann, D. E., Ip, S., Grey, P., Smith, D., Ramacciotti, T., Quan, D., Finlayson, R., Kaldor, J., Rosenberg, E. S., Walker, B. D., Cooper, D. A., Kelleher, A. D., on behalf of the PHAEDRA Study Team,
(2005). Early proliferation of CCR5+ CD38+++ antigen-specific CD4+ Th1 effector cells during primary HIV-1 infection. Blood
106: 1660-1667
[Abstract] [Full Text] -
Mori, K., Sugimoto, C., Ohgimoto, S., Nakayama, E. E., Shioda, T., Kusagawa, S., Takebe, Y., Kano, M., Matano, T., Yuasa, T., Kitaguchi, D., Miyazawa, M., Takahashi, Y., Yasunami, M., Kimura, A., Yamamoto, N., Suzuki, Y., Nagai, Y.
(2005). Influence of Glycosylation on the Efficacy of an Env-Based Vaccine against Simian Immunodeficiency Virus SIVmac239 in a Macaque AIDS Model. J. Virol.
79: 10386-10396
[Abstract] [Full Text] -
Fraser, D. G., Leib, S. R., Zhang, B. S., Mealey, R. H., Brown, W. C., McGuire, T. C.
(2005). Lymphocyte Proliferation Responses Induced to Broadly Reactive Th Peptides Did Not Protect against Equine Infectious Anemia Virus Challenge. CVI
12: 983-993
[Abstract] [Full Text] -
Joos, B., Trkola, A., Fischer, M., Kuster, H., Rusert, P., Leemann, C., Boni, J., Oxenius, A., Price, D. A., Phillips, R. E., Wong, J. K., Hirschel, B., Weber, R., Gunthard, H. F., the Swiss HIV Cohort Study,
(2005). Low Human Immunodeficiency Virus Envelope Diversity Correlates with Low In Vitro Replication Capacity and Predicts Spontaneous Control of Plasma Viremia after Treatment Interruptions. J. Virol.
79: 9026-9037
[Abstract] [Full Text] -
Koibuchi, T., Allen, T. M., Lichterfeld, M., Mui, S. K., O'Sullivan, K. M., Trocha, A., Kalams, S. A., Johnson, R. P., Walker, B. D.
(2005). Limited Sequence Evolution within Persistently Targeted CD8 Epitopes in Chronic Human Immunodeficiency Virus Type 1 Infection. J. Virol.
79: 8171-8181
[Abstract] [Full Text] -
Lore, K., Smed-Sorensen, A., Vasudevan, J., Mascola, J. R., Koup, R. A.
(2005). Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells. JEM
201: 2023-2033
[Abstract] [Full Text] -
Wille-Reece, U., Wu, C.-y., Flynn, B. J., Kedl, R. M., Seder, R. A.
(2005). Immunization with HIV-1 Gag Protein Conjugated to a TLR7/8 Agonist Results in the Generation of HIV-1 Gag-Specific Th1 and CD8+ T Cell Responses. J. Immunol.
174: 7676-7683
[Abstract] [Full Text] -
Asquith, B., Mosley, A. J., Barfield, A., Marshall, S. E. F., Heaps, A., Goon, P., Hanon, E., Tanaka, Y., Taylor, G. P., Bangham, C. R. M.
(2005). A functional CD8+ cell assay reveals individual variation in CD8+ cell antiviral efficacy and explains differences in human T-lymphotropic virus type 1 proviral load. J. Gen. Virol.
86: 1515-1523
[Abstract] [Full Text] -
Peretz, Y., Alter, G., Boisvert, M.-P., Hatzakis, G., Tsoukas, C. M., Bernard, N. F.
(2005). Human Immunodeficiency Virus (HIV)-Specific Gamma Interferon Secretion Directed against All Expressed HIV Genes: Relationship to Rate of CD4 Decline. J. Virol.
79: 4908-4917
[Abstract] [Full Text] -
Barugahare, B., Baker, C., K'Aluoch, O., Donovan, R., Elrefaei, M., Eggena, M., Jones, N., Mutalya, S., Kityo, C., Mugyenyi, P., Cao, H.
(2005). Human Immunodeficiency Virus-Specific Responses in Adult Ugandans: Patterns of Cross-Clade Recognition. J. Virol.
79: 4132-4139
[Abstract] [Full Text] -
Ibarrondo, F. J., Anton, P. A., Fuerst, M., Ng, H. L., Wong, J. T., Matud, J., Elliott, J., Shih, R., Hausner, M. A., Price, C., Hultin, L. E., Hultin, P. M., Jamieson, B. D., Yang, O. O.
(2005). Parallel Human Immunodeficiency Virus Type 1-Specific CD8+ T-Lymphocyte Responses in Blood and Mucosa during Chronic Infection. J. Virol.
79: 4289-4297
[Abstract] [Full Text] -
Eggena, M. P., Barugahare, B., Jones, N., Okello, M., Mutalya, S., Kityo, C., Mugyenyi, P., Cao, H.
(2005). Depletion of Regulatory T Cells in HIV Infection Is Associated with Immune Activation. J. Immunol.
174: 4407-4414
[Abstract] [Full Text] -
Betts, M. R., Exley, B., Price, D. A., Bansal, A., Camacho, Z. T., Teaberry, V., West, S. M., Ambrozak, D. R., Tomaras, G., Roederer, M., Kilby, J. M., Tartaglia, J., Belshe, R., Gao, F., Douek, D. C., Weinhold, K. J., Koup, R. A., Goepfert, P., Ferrari, G.
(2005). Characterization of functional and phenotypic changes in anti-Gag vaccine-induced T cell responses and their role in protection after HIV-1 infection. Proc. Natl. Acad. Sci. USA
102: 4512-4517
[Abstract] [Full Text] -
Chang, J. J., Wightman, F., Bartholomeusz, A., Ayres, A., Kent, S. J., Sasadeusz, J., Lewin, S. R.
(2005). Reduced Hepatitis B Virus (HBV)-Specific CD4+ T-Cell Responses in Human Immunodeficiency Virus Type 1-HBV-Coinfected Individuals Receiving HBV-Active Antiretroviral Therapy. J. Virol.
79: 3038-3051
[Abstract] [Full Text] -
Yue, F. Y., Kovacs, C. M., Dimayuga, R. C., Gu, X. X. J., Parks, P., Kaul, R., Ostrowski, M. A.
(2005). Preferential Apoptosis of HIV-1-Specific CD4+ T Cells. J. Immunol.
174: 2196-2204
[Abstract] [Full Text] -
Kim, A. Y., Lauer, G. M., Ouchi, K., Addo, M. M., Lucas, M., Wiesch, J. S. z., Timm, J., Boczanowski, M., Duncan, J. E., Wurcel, A. G., Casson, D., Chung, R. T., Draenert, R., Klenerman, P., Walker, B. D.
(2005). 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
105: 1170-1178
[Abstract] [Full Text] -
Yang, O. O., Daar, E. S., Jamieson, B. D., Balamurugan, A., Smith, D. M., Pitt, J. A., Petropoulos, C. J., Richman, D. D., Little, S. J., Brown, A. J. L.
(2005). Human Immunodeficiency Virus Type 1 Clade B Superinfection: Evidence for Differential Immune Containment of Distinct Clade B Strains. J. Virol.
79: 860-868
[Abstract] [Full Text] -
Akahata, W., Yang, Z.-y., Nabel, G. J.
(2005). Comparative Immunogenicity of Human Immunodeficiency Virus Particles and Corresponding Polypeptides in a DNA Vaccine. J. Virol.
79: 626-631
[Abstract] [Full Text]
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