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IMMUNOBIOLOGY
From the Center for Blood Research, Harvard Medical
School, and the New England Medical Center, Tufts University School of
Medicine, Boston, MA.
The functional status of circulating human immunodeficiency
(HIV)-specific CD8 T cells in chronically infected subjects was evaluated. By flow cytometry, only 5 of 7 subjects had detectable CD8 T
cells that produced IFN- Several studies suggest that CD8 T cells play a
critical role in the control of virus replication in human
immunodeficiency virus (HIV) infection. Compelling evidence for their
protective role comes from the temporal association of the
viral-specific cytotoxic T lymphocyte (CTL) response with the
decline in plasma viremia in acute HIV infection and from the presence
of a vigorous CTL response to HIV in long-term
nonprogressors.1-6 Direct evidence for the protective role
of CD8 T cells was recently provided in the closely related simian
immunodeficiency virus model in Rhesus macaques, in which elimination
of CD8 T cells resulted in a dramatic increase in viral
load.7,8 However, despite the presence of HIV-specific
CTL, viral production continues at a high level in most untreated
infected subjects and inevitably leads to profound immunodeficiency and
death in the absence of continued antiretroviral therapy. It is unclear
why CD8 T cells provide only partial protection and are ultimately
unable to prevent progression to AIDS. The ineffectiveness of the CTL
response may at least partly be a consequence of viral evasion
strategies, including viral-sequence mutation or nef-mediated
down-modulation of major histocompatibility complex (MHC)
class I cell surface expression.9-17 Targeting of
essential helper CD4 T cells by HIV may be another important cause for
the progressive loss of CD8 T-cell function. Emerging data in the murine lymphocytic choriomeningitis virus (LCMV) model suggest that in
the absence of adequate CD4 help, antiviral CD8 T cells persist
indefinitely in a functionally anergic state.18 Loss of
CD8 T-cell-mediated control of infection in the absence of CD4 T cells
has also been demonstrated in mice infected with a gamma-herpes
virus.19 We recently found that freshly isolated CD8 T
lymphocytes from seropositive subjects are impaired in their ability to
lyse HIV-presenting targets. Our studies suggest that the molecular
basis for this loss of function of CD8 T cells may be linked to the
down-modulation of CD3 Most in vitro techniques for evaluating the functional status of
antigen-specific CD8+ T cells necessitate the use of
repeated antigenic challenge in an artificially enriched cytokine
milieu. In vitro culture may introduce quantitative and qualitative
biases that preclude assessment of the true extent of functional
impairment of specific CD8 T cells in vivo. Further, repeated antigenic
stimulation may result in the outgrowth of clones that are not truly
representative of the circulating repertoire. More direct quantitation
and functional characterization of circulating antigen-specific CD8 T
cells have been greatly facilitated by the development of powerful new
techniques, including highly sensitive tetramer staining and
intracellular cytokine analysis of interferon (IFN)- We used 2 approaches to look for possible functional impairment of
HIV-specific CD8 T cells. One approach was to evaluate IFN- Study population
Production of phycoerythrin-coupled tetrameric A2-HIV-gag and
A2-HIV-RT peptide complexes
Flow cytometry For external staining, PBMC from A2-expressing seropositive subjects were resuspended in 500 µL FACS buffer and stained with 0.5 µg/mL streptavidin-PE-conjugated tetramer for 40 minutes at 4°C. The cells were washed and resuspended in FACS buffer, and aliquots of the suspension were stained with 2 µL of the following fluorescein isothiocyanate (FITC)-conjugated mAbs: CD27, CD28, CD57, CD38, CD62L, HLA-DR, CD45RA, CD45RO, and Cy5-conjugated CD8 mAb or IgG-FITC and PE and Cy5 isotype-matched controls (Immunotech, Westbrook, ME). After incubation for 30 minutes at 4°C, cells were washed and resuspended in FACS buffer with 1% formaldehyde for analysis. For internal staining with bcl-2 (DAKO, Carpenteria, CA) and granzyme A-reactive mAb CB9,20 aliquots of tetramer-stained cells were resuspended in 50 µL Hanks balanced salt solution and permeabilized using the Caltag Laboratories (Burlingame, CA) Fix and Perm kit according to the manufacturer's protocol. Fixed cells were incubated for 15 minutes at room temperature with 2 µL of the respective antibodies conjugated to FITC, washed, and resuspended in 50 µL FACS buffer. The cells were then stained with CD8-Cy5 for 15 minutes and fixed in FACS buffer with 1% formaldehyde for flow cytometric analysis. All samples were analyzed on a FACScalibur with Cell Quest software (Becton Dickinson, Franklin Lakes, NJ) on a lymphocyte-gated population.Immunomagnetic enrichment of tetramer-positive population PBMC, stained with PE-labeled HLA-A2 tetramers in sterile PBS with 2% fetal calf serum (FCS) for 40 minutes in the cold, were washed and incubated with -PE Miltenyi beads (Miltenyi Biotec, Auburn, CA)
for another 15 minutes. The tetramer-PE cells that bound the beads were
immunomagnetically selected on a Miltenyi column according to the
manufacturer's instructions. An aliquot of the selected cells was
costained with -CD8 mAb conjugated to Cy5 to ascertain the levels of
enrichment. Usually, more than 100-fold enrichment of the
tetramer-positive population could be obtained by this method.
Intracellular cytokine staining To enumerate the number of IFN- -producing cells within the
tetramer population, 2 × 106 PBMC were stimulated with
the relevant gag or pol peptide at a concentration of 5 µg/mL in RPMI
1640 with 10% FCS for 8 hours at 37°C. Immunomagnetically selected
tetramer-binding cells were stimulated with the peptide-pulsed
autologous Epstein-Barr virus (EBV)-transformed B lymphoblastoid cell
line (BLCL). In some experiments PBMC were activated with 1 µg/mL
phorbol-12 myristate 13-acetate (PMA; Sigma, St. Louis, MO) and
0.25 µg/mL ionomycin (Sigma). In the last 4 hours of incubation, 10 µmol/L Brefeldin A (Sigma) was added to the cultures. At the end of
the incubation, cells were washed and resuspended in FACS buffer and
were stained with either gag or pol tetramer-PE on a rotator at 4°C
for 40 minutes. Cells were then washed, fixed, permeabilized, and
stained internally with FITC-conjugated IFN- mAb (R&D Systems,
Minneapolis, MN) followed by CD8-Cy5 mAb as described earlier.
Simultaneously, control cultures without peptide stimulation were
similarly stained. The proportion of tetramer-positive cells
secreting IFN- in response to the cognate peptide was
calculated as ([number of IFN--positive CD8 T cells in cultures
stimulated with peptide  number of IFN--positive CD8 T cells in
control cultures without peptide]/total number of tetramer-positive
CD8 T cells in control cultures without peptide) × 100. Cells
stained with isotype-matched FITC-MsIgG1 (R&D Systems) were used as
negative controls.
HIV-infected primary CD4 T cells To evaluate effector function of HIV-specific CD8 T cells ex vivo, we also used uniformly HIV-infected primary CD4+ T cells, generated as previously described,31 as target cells in cytotoxicity assays and as stimulator cells for IFN-
production. Autologous CD4+ T cells were positively
selected with CD4 Miltenyi beads and activated with
phytohemagglutinin. Two days later, cells were infected with
HIVIIIB virus at a multiplicity of infection of 0.1. Infected cells were selected by the method previously
described,28,31 which is based on the down-modulation of
CD4 on HIV-infected cells. After culture for 4 to 7 days, uninfected
cells, which continue to express CD4, were removed by negative
selection with CD4-Dynal beads per the manufacturer's instructions.
HIV infection levels of the negatively enriched population were
confirmed by flow cytometric analysis of p24 expression as
described.31
Flow cytometric determination of IFN- -FITC as above.
Cytotoxicity assay Log-phase BLCL target cells, produced as described,32 were labeled with 100 µCi of chromium 51 for an hour, washed 3 times in RPMI 1640 medium with 10% FCS, and resuspended at 105/mL as described earlier.33,34 Labeled targets (104) were added to triplicate wells of U-bottom microtiter plates in the presence or absence of relevant HIV-gag and pol peptides. After incubating the target cells with the peptides for 1 hour at 37°C, effector cells suspended at various effector:target (E:T) ratios in 100 µL were added to the wells, and the plates were incubated at 37°C over CO2 for 6 hours. Supernatants (35 µL) were counted on a Top Count (Packard, Meriden, CT) microplate reader, and percentage specific cytotoxicity was calculated from the average cpm as ([average cpm spontaneous release)/(total release spontaneous release]) × 100. The spontaneous release for all experiments was within acceptable limits of less than 20%. Cytotoxicity against 51Cr-labeled uniformly HIV-infected primary CD4 blasts and
uninfected CD4 T-cell blast controls was evaluated as
described.30,31
Frequency of circulating HIV-specific CD8 T cells responding to stimulation with uniformly HIV-infected CD4 T cells Detection of IFN- production after exposure of T cells to viral
antigens has been shown to be an extremely sensitive method to identify
antigen-specific T cells. Because both short-term effector and
long-lived memory cells are thought to secrete IFN- immediately on
antigen stimulation,35,36 this method allows identification of all T cells responding to a specific antigen. Thus,
IFN- secretion in response to stimulation with virus-infected cells
should provide an estimate of the total pool of functional viral-specific CD8 T cells. We used uniformly HIV-infected autologous CD4 T cells as stimulator cells to identify by flow cytometry IFN--producing HIV-specific CD8+ T cells from the PBMC
of 7 HIV-seropositive subjects. In 5 of 7 subjects (subjects 219, 307, 350, 606, 701), HIV-specific IFN--secreting CD8 T cells were
detectable, but in 2 subjects (subjects 216, 237) no IFN--producing
cells could be visualized above the background of 0.01%.
IFN--producing cells in the positive subjects varied from 0.3% to
2.9% of CD8 T cells. We have previously found that brief culture of
cells ex vivo in the presence of IL-2 enhances viral-specific
cytotoxicity in some subjects.20,37 Thus, we tested
whether exogenous IL-2 also enhances IFN- production. In 3 subjects
who were on HAART therapy and had undetectable plasma virus (350, 606, 701), the same frequency of IFN--producing cells was observed in
the presence or absence of exogenous IL-2. In 2 other subjects
(subjects 219, 307) who had detectable plasma viremia, the addition of
IL-2 resulted in a 4- to 5-fold increase in the number of
IFN--producing cells. For the 2 other subjects (subjects 216, 237)
in whom HIV-specific IFN--secreting CD8 T cells were not detected
in the absence of IL-2, the addition of IL-2 resulted in a weak but
detectable IFN- response in one. For all subjects taken together,
there was a 1.7-fold higher level of IFN--producing cells in the
presence of IL-2 (median frequency, 0.4% of CD8 T cells without IL-2
vs 0.7% of CD8 T cells with IL-2). HIV-specific CD69 up-regulation on
CD8 T cells was also more pronounced in the presence of IL-2 (median
frequency, 0.1% of CD8 T cells without IL-2 vs 4.9% of CD8 T cells
with IL-2). Figure 1 depicts the flow
cytometric analysis of CD69 up-regulation and IFN- production in one
representative subject. Cumulative data for all subjects tested are
shown in Figure 2.
IFN- Lysis of primary HIV-infected CD4 T cells by freshly isolated and overnight cultured PBMC We also assessed whether lytic function of HIV-specific CD8 T cells corresponded with their ability to secrete IFN-. Uniformly HIV-infected CD4 targets used as stimulator cells for IFN-
production were also used as targets in 51Cr release
assays. In 2 subjects tested (subjects 606, 307) with 2.9% and 0.4%
IFN--producing cells after exposure to HIV, no detectable
cytotoxicity was seen when PBMC were used directly. However, overnight
culture in medium alone restored a modicum of HIV-specific cytotoxicity
(5%-7%) at an E:T ratio of 100:1, which was substantially enhanced to
12% to 25% by adding exogenous IL-2 (Figure
3).
HIV-specific CD8 T cells can be identified by tetramer staining Although our results using HIV-infected autologous stimulator or target cells suggest that HIV-specific CD8+ T cells may be functionally compromised in vivo, the assay does not identify all antigen-specific T cells, only those that are functionally active. Thus, we used MHC-peptide tetramers to enumerate and characterize HIV epitope-specific CD8 T cells. PBMC from a cohort of 15 HLA-A2-expressing subjects infected with HIV-1 were examined for the frequency of CTL-recognizing epitopes restricted by this allele. The clinical characteristics of the subjects, who were at various stages of the disease, are shown in Table 1. CD8 T cells directed against a well-characterized gag epitope SLYNTVATL38,39 and a novel RT epitope YTAFTIPSI that we recently described30 were directly visualized with HLA-A2 MHC-peptide tetramers. For samples that stained above background, the frequency of tetramer-binding cells ranged from 0.2% to 1.4% and 0.2% to 0.8% of the total CD8 T cells for the A2-restricted gag and pol epitopes, respectively. Nine of 15 (60%) subjects recognized the gag epitope, which is similar to data reported by Ogg et al.40 CD8 T cells directed against the novel RT epitope were identified in 5 of 14 (35%) subjects, which approximately corresponds to the frequency reported for recognition of the RT epitope IV9 (ILKEPVHGV).40 Binding of more than 0.1% to both tetramers was seen in 2 of 14 subjects, and in 2 others neither epitope was recognized. Figure 4 shows representative flow cytometric data for each of the epitopes. No correlation was observed between viral load and tetramer positivity in these subjects. However, the study group consisted of a heterogeneous mix of subjects infected for variable time periods and treated with different antiretroviral regimens, which may have influenced the results (data not shown).
Phenotypic characteristics of tetramer-binding, HIV-specific CD8 T cells Because HIV-1 disease progression is associated with phenotypic changes in peripheral blood CD8 T cells that may be reflective of functional changes within the HIV-specific CD8 T-cell compartment, the phenotypic characteristics of tetramer-binding cells were analyzed by 3-color flow cytometry. Antigen-primed T cells have been shown to segregate into 2 distinct phenotypic subsets: a memory population that expresses the RO isoform of CD45 and is CD27+ and an effector population that expresses the RA isoform of CD45 and is CD27 .41,42 As shown in Table
2, applying these criteria, the
tetramer-binding cells from most of the subjects in this study are of
the memory subtype. The tetramer-positive cells were bcl-2 high, which
is also suggestive of a memory subtype.43 However, the
tetramer-positive cells were CD28 and CD62L
and expressed granzyme A, which are thought to be characteristics of
activated effector cells.42 The acute activation marker
CD38, which has been implicated as an adverse prognostic marker for disease progression, was not expressed on most tetramer-positive cells.44,45 The tetramer-positive cells were heterogeneous with respect to other activation markers such as CD57 and HLA-DR. Taken
together, our data suggest that the tetramer-positive cells showed a
mixed pattern of memory and effector characteristics.
Only a fraction of circulating HIV-specific
CD8 T cells produces IFN- -FITC 8 hours after PBMC were
stimulated with the cognate peptide corresponding to each tetramer.
Representative data from stage A1 subject 350 (CD4 count, 1005/µL) and stage B2 subject 307 (CD4 count, 280/µL) are
shown in Figure 5. The IFN--producing
population was generally tetramer-negative after stimulation with the
cognate peptide, presumably because of TcR down-modulation that
accompanies activation. Only a fraction of tetramer-positive CD8 T
cells produced IFN- after specific stimulation (Figure
6). In 7 of 9 subjects, less than 25% of
the tetramer-stained cells produced IFN- in response to
peptide-specific stimulation. The 2 subjects (subjects 350, 705) with a
high proportion of IFN--producing tetramer-positive cells had no
clinical symptoms and had well-maintained CD4 counts of 1005/µL and
650/µL. Five of 7 subjects with less than 25% IFN--producing
tetramer-positive cells had a history of HIV-related CDC stage B or
C symptoms.
Because the direct measurement of functional activity in uncultured
PBMC can be relatively insensitive, in 2 subjects (subjects 219, 606)
we also immunomagnetically selected the tetramer-binding cells using
anti-PE Miltenyi beads for functional studies. A significant enrichment
in tetramer-positive cells was observed after selection (61% and 42%
of CD8 T cells from a starting population of 0.7% and 0.27% of CD8 T
cells, respectively; data not shown). Because tetramer binding itself
may not be a sufficient stimulus for IFN-
Circulating HIV-specific CD8 T cells are not cytolytic against peptide-pulsed targets To determine the cytolytic ability of in vivo-generated tetramer- staining cells, uncultured PBMC from 8 subjects with detectable tetramer-binding cells (subjects 215, 216, 219, 237, 307, 350, 606, 705) were tested against the relevant gag or RT peptide-pulsed autologous BLCL lines or A2-expressing T2 cells. In all subjects, peptide-specific cytotoxicity at an E:T ratio of 100:1 was well below the 5% background cutoff level with fresh or thawed PBMC (highest level was 1.4%). Overnight incubation of the cells in IL-2 did not result in a substantial increase in peptide-specific lysis in any of the subjects (data not shown).
The persistence of HIV viral replication, despite a strong
viral-specific CD8 T-cell response, suggests a functional deficiency of
these cells in vivo. Most functional studies have used ex vivo expanded
CD8 T cells cultured in the presence of cytokines.46 However, it is unclear whether the results obtained in these in vitro
systems are representative of the in vivo picture. Our goal in this
study was to determine the functional properties of HIV-specific CD8 T
cells directly ex vivo before in vitro culture could modify their
characteristics. To evaluate the functional status of circulating HIV-specific CD8 T cells, we used MHC-peptide tetramer staining and a
novel flow cytometric assay to measure IFN- Multiparametric flow cytometric assays that detect rapid intracellular
accumulation of cytokines after a brief period of in vitro stimulation
are increasingly used to measure in vivo T-cell frequencies for
specific antigens. Kern et al47 have used this assay to
measure peptide-specific CD8 T-cell frequencies in samples from known
HLA types in cytomegalovirus infection. However, studies from
our laboratory and from others38,48,49 suggest that the immunodominant HIV epitopes recognized by seropositive subjects are not
predictable on the basis of HLA haplotypes. Because most of the
conserved HIV epitopes are represented on HIVIIIB-infected CD4 T-cell targets, IFN- The frequencies of IFN- To address directly the issue of the existence of HIV-specific CD8 T cells without effector function, we also performed functional and phenotypic characterization on tetramer-staining, HIV-specific CD8 T cells because this method identifies all CD8 T cells directed toward a specific epitope irrespective of their functional status. As suggested by Spiegel et al,52 the nonfunctional fraction of tetramer-stained cells can be used as an index of the accumulation of virus-specific CD8 T cells without effector function in HIV disease. HLA-A2 tetramers were used to visualize HIV epitope-specific CD8 T cells directed against an HIV-gag epitope, SLYNTVATL, and a novel HIV-RT epitope, YTAFTIPSI.29,30,39 With tetramer staining we found that approximately 65% of HIV-infected subjects had CD8 T cells that recognized the gag epitope SLYNTVATL, which is in agreement with published data.40 CD8 T cells that recognize the novel A2-restricted RT epitope YTAFTIPSI, which we recently found to be well presented on HIV-infected primary CD4 T-cell targets,29 were present in approximately 35% of the subjects, a level similar to the well-studied IV9 RT epitope.40 In most subjects less than 25% of the tetramer-stained cells produced
IFN- The tetramer-staining cells from most subjects in this study were
CD45RA Recent studies18,50 have suggested that the mere existence
of antigen-primed CD8 T cells in vivo does not imply their
functionality. Earlier studies20,37 from our laboratory
have shown that freshly isolated CD8 T cells from HIV-infected subjects
have down-modulated CD3 In conclusion, by using a dual approach of MHC-peptide tetramer
staining and IFN-
We thank M. Davis and D. Wiley for the HLA-A2 and
Submitted February 29, 2000; accepted June 20, 2000.
Supported by grants R01 AI42519 (J.L.), R01 AI45406 (J.L.), R29 AI38819 (P.S.), and R21 AI45306 (P.S.) from the National Institutes of Health.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
Reprints: Premlata Shankar, Center for Blood Research, 800 Huntington Ave, Boston, MA 02115; e-mail: shankar{at}cbr.med.harvard.edu.
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A. Hryniewicz, D. A. Price, M. Moniuszko, A. Boasso, Y. Edghill-Spano, S. M. West, D. Venzon, M. Vaccari, W.-P. Tsai, E. Tryniszewska, et al. Interleukin-15 but Not Interleukin-7 Abrogates Vaccine-Induced Decrease in Virus Level in Simian Immunodeficiency Virusmac251-Infected Macaques J. Immunol., March 15, 2007; 178(6): 3492 - 3504. [Abstract] [Full Text] [PDF]
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Y. Sun, J. E. Schmitz, A. P. Buzby, B. R. Barker, S. S. Rao, L. Xu, Z.-y. Yang, J. R. Mascola, G. J. Nabel, and N. L. Letvin Virus-Specific Cellular Immune Correlates of Survival in Vaccinated Monkeys after Simian Immunodeficiency Virus Challenge J. Virol., November 15, 2006; 80(22): 10950 - 10956. [Abstract] [Full Text] [PDF]
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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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T. M. Allen, M. Altfeld, S. C. Geer, E. T. Kalife, C. Moore, K. M. O'Sullivan, I. DeSouza, M. E. Feeney, R. L. Eldridge, E. L. Maier, et al. Selective Escape from CD8+ T-Cell Responses Represents a Major Driving Force of Human Immunodeficiency Virus Type 1 (HIV-1) Sequence Diversity and Reveals Constraints on HIV-1 Evolution J. Virol., November 1, 2005; 79(21): 13239 - 13249. [Abstract] [Full Text] [PDF]
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V. Lazarevic, D. Nolt, and J. L. Flynn Long-Term Control of Mycobacterium tuberculosis Infection Is Mediated by Dynamic Immune Responses J. Immunol., July 15, 2005; 175(2): 1107 - 1117. [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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S. Sundstrom, S. Ota, L. Y. Dimberg, M. G. Masucci, and A. Bergqvist Hepatitis C Virus Core Protein Induces an Anergic State Characterized by Decreased Interleukin-2 Production and Perturbation of Mitogen-Activated Protein Kinase Responses J. Virol., February 15, 2005; 79(4): 2230 - 2239. [Abstract] [Full Text] [PDF]
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J. L. Mbisa, G. N. Nikolenko, and V. K. Pathak Mutations in the RNase H Primer Grip Domain of Murine Leukemia Virus Reverse Transcriptase Decrease Efficiency and Accuracy of Plus-Strand DNA Transfer J. Virol., January 1, 2005; 79(1): 419 - 427. [Abstract] [Full Text] [PDF]
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A. F. Ochsenbein, S. R. Riddell, M. Brown, L. Corey, G. M. Baerlocher, P. M. Lansdorp, and P. D. Greenberg CD27 Expression Promotes Long-Term Survival of Functional Effector-Memory CD8+ Cytotoxic T Lymphocytes in HIV-infected Patients J. Exp. Med., December 6, 2004; 200(11): 1407 - 1417. [Abstract] [Full Text] [PDF]
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M. Dagarag, T. Evazyan, N. Rao, and R. B. Effros Genetic Manipulation of Telomerase in HIV-Specific CD8+ T Cells: Enhanced Antiviral Functions Accompany the Increased Proliferative Potential and Telomere Length Stabilization J. Immunol., November 15, 2004; 173(10): 6303 - 6311. [Abstract] [Full Text] [PDF]
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M. Lichterfeld, X. G. Yu, M. T. Waring, S. K. Mui, M. N. Johnston, D. Cohen, M. M. Addo, J. Zaunders, G. Alter, E. Pae, et al. HIV-1-specific cytotoxicity is preferentially mediated by a subset of CD8+ T cells producing both interferon-{gamma} and tumor necrosis factor-{alpha} Blood, July 15, 2004; 104(2): 487 - 494. [Abstract] [Full Text] [PDF]
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B. L. Shacklett, C. A. Cox, M. F. Quigley, C. Kreis, N. H. Stollman, M. A. Jacobson, J. Andersson, J. K. Sandberg, and D. F. Nixon Abundant Expression of Granzyme A, but Not Perforin, in Granules of CD8+ T Cells in GALT: Implications for Immune Control of HIV-1 Infection J. Immunol., July 1, 2004; 173(1): 641 - 648. [Abstract] [Full Text] [PDF]
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E. J. Wherry and R. Ahmed Memory CD8 T-Cell Differentiation during Viral Infection J. Virol., June 1, 2004; 78(11): 5535 - 5545. [Full Text] [PDF]
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J. M. Brenchley, B. J. Hill, D. R. Ambrozak, D. A. Price, F. J. Guenaga, J. P. Casazza, J. Kuruppu, J. Yazdani, S. A. Migueles, M. Connors, et al. T-Cell Subsets That Harbor Human Immunodeficiency Virus (HIV) In Vivo: Implications for HIV Pathogenesis J. Virol., February 1, 2004; 78(3): 1160 - 1168. [Abstract] [Full Text] [PDF]
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R. Draenert, C. L. Verrill, Y. Tang, T. M. Allen, A. G. Wurcel, M. Boczanowski, A. Lechner, A. Y. Kim, T. Suscovich, N. V. Brown, et al. Persistent Recognition of Autologous Virus by High-Avidity CD8 T Cells in Chronic, Progressive Human Immunodeficiency Virus Type 1 Infection J. Virol., January 15, 2004; 78(2): 630 - 641. [Abstract] [Full Text] [PDF]
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K. Abel, L. La Franco-Scheuch, T. Rourke, Z.-M. Ma, V. de Silva, B. Fallert, L. Beckett, T. A. Reinhart, and C. J. Miller Gamma Interferon-Mediated Inflammation Is Associated with Lack of Protection from Intravaginal Simian Immunodeficiency Virus SIVmac239 Challenge in Simian-Human Immunodeficiency Virus 89.6-Immunized Rhesus Macaques J. Virol., January 15, 2004; 78(2): 841 - 854. [Abstract] [Full Text] [PDF]
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Y. Tsunetsugu-Yokota, Y. Morikawa, M. Isogai, A. Kawana-Tachikawa, T. Odawara, T. Nakamura, F. Grassi, B. Autran, and A. Iwamoto Yeast-Derived Human Immunodeficiency Virus Type 1 p55gag Virus-Like Particles Activate Dendritic Cells (DCs) and Induce Perforin Expression in Gag-Specific CD8+ T Cells by Cross-Presentation of DCs J. Virol., October 1, 2003; 77(19): 10250 - 10259. [Abstract] [Full Text] [PDF]
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S. A. Migueles, A. C. Laborico, H. Imamichi, W. L. Shupert, C. Royce, M. McLaughlin, L. Ehler, J. Metcalf, S. Liu, C. W. Hallahan, et al. The Differential Ability of HLA B*5701+ Long-Term Nonprogressors and Progressors To Restrict Human Immunodeficiency Virus Replication Is Not Caused by Loss of Recognition of Autologous Viral gag Sequences J. Virol., June 15, 2003; 77(12): 6889 - 6898. [Abstract] [Full Text] [PDF]
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D. Zhang, P. Shankar, Z. Xu, B. Harnisch, G. Chen, C. Lange, S. J. Lee, H. Valdez, M. M. Lederman, and J. Lieberman Most antiviral CD8 T cells during chronic viral infection do not express high levels of perforin and are not directly cytotoxic Blood, January 1, 2003; 101(1): 226 - 235. [Abstract] [Full Text] [PDF]
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F. Buseyne, D. Scott-Algara, F. Porrot, B. Corre, N. Bellal, M. Burgard, C. Rouzioux, S. Blanche, and Y. Riviere Frequencies of Ex Vivo-Activated Human Immunodeficiency Virus Type 1-Specific Gamma-Interferon-Producing CD8+ T Cells in Infected Children Correlate Positively with Plasma Viral Load J. Virol., November 13, 2002; 76(24): 12414 - 12422. [Abstract] [Full Text] [PDF]
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Z. Hel, J. Nacsa, E. Tryniszewska, W.-P. Tsai, R. W. Parks, D. C. Montefiori, B. K. Felber, J. Tartaglia, G. N. Pavlakis, and G. Franchini Containment of Simian Immunodeficiency Virus Infection in Vaccinated Macaques: Correlation with the Magnitude of Virus-Specific Pre- and Postchallenge CD4+ and CD8+ T Cell Responses J. Immunol., November 1, 2002; 169(9): 4778 - 4787. [Abstract] [Full Text] [PDF]
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E. Tryniszewska, J. Nacsa, M. G. Lewis, P. Silvera, D. Montefiori, D. Venzon, Z. Hel, R. W. Parks, M. Moniuszko, J. Tartaglia, et al. Vaccination of Macaques with Long-Standing SIVmac251 Infection Lowers the Viral Set Point After Cessation of Antiretroviral Therapy J. Immunol., November 1, 2002; 169(9): 5347 - 5357. [Abstract] [Full Text] [PDF]
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H. Wedemeyer, X.-S. He, M. Nascimbeni, A. R. Davis, H. B. Greenberg, J. H. Hoofnagle, T. J. Liang, H. Alter, and B. Rehermann Impaired Effector Function of Hepatitis C Virus-Specific CD8+ T Cells in Chronic Hepatitis C Virus Infection J. Immunol., September 15, 2002; 169(6): 3447 - 3458. [Abstract] [Full Text] [PDF]
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M. E. Keir, M. G. Rosenberg, J. K. Sandberg, K. A. Jordan, A. Wiznia, D. F. Nixon, C. A. Stoddart, and J. M. McCune Generation of CD3+CD8low Thymocytes in the HIV Type 1-Infected Thymus J. Immunol., September 1, 2002; 169(5): 2788 - 2796. [Abstract] [Full Text] [PDF]
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S. M. Agwale, M. T. Shata, M. S. Reitz Jr., V. S. Kalyanaraman, R. C. Gallo, M. Popovic, and D. M. Hone A Tat subunit vaccine confers protective immunity against the immune-modulating activity of the human immunodeficiency virus type-1 Tat protein in mice PNAS, July 23, 2002; 99(15): 10037 - 10041. [Abstract] [Full Text] [PDF]
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S. Kostense, K. Vandenberghe, J. Joling, D. Van Baarle, N. Nanlohy, E. Manting, and F. Miedema Persistent numbers of tetramer+ CD8+ T cells, but loss of interferon-gamma + HIV-specific T cells during progression to AIDS Blood, April 1, 2002; 99(7): 2505 - 2511. [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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G. Chen, P. Shankar, C. Lange, H. Valdez, P. R. Skolnik, L. Wu, N. Manjunath, and J. Lieberman CD8 T cells specific for human immunodeficiency virus, Epstein-Barr virus, and cytomegalovirus lack molecules for homing to lymphoid sites of infection Blood, July 1, 2001; 98(1): 156 - 164. [Abstract] [Full Text] [PDF]
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Top
Abstract
Introduction
, the key signaling molecule of the TcR
complex.
2 microglobulin were
synthesized and purified from plasmids (obtained from M. Davis and
D. C. Wiley, respectively) and refolded with the A2-restricted HIV-gag epitope peptide SLYNTVATL or the HIV-RT epitope peptide YTAFTIPSI. The complex was biotinylated using the Bir A enzyme as
described.
) or absence (
) of
IL-2 were stained for IFN-
a unifying concept.
Immunol Today.
1998;19:60-64