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*
Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom; and
Veterans Affairs Research Center for AIDS and HIV Infection, University of California at San Diego, La Jolla, CA 92093
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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The establishment of a stable memory T cell pool suggests there is tight control of the mechanisms leading to cell death to maintain a balance among cell proliferation, survival, and apoptosis. In mammals, apoptosis is conducted through two main pathways. One involves the engagement of death receptors such as Fas (also referred to as CD95) through interactions with ligands (e.g., Fas ligand) and has been referred to as the extrinsic pathway or "death by design" (13, 14). The second pathway, referred to as the intrinsic pathway or "death by neglect," is governed by the Bcl-2 family, which includes both proapoptotic (e.g., Bax, Bik) and antiapoptotic (e.g., Bcl-2, Bcl-xL) members, promoting or preventing death signals from diverse cytotoxic stimuli (e.g., cytokine deprivation, DNA, or mitochondrial damage) (13, 15). In lymphocytic choriomeningitis virus infection, memory CD8+ T cells express an increased level of Bcl-2, protecting them from apoptosis and possibly contributing to their maintenance in vivo (16). In acute EBV infection in humans, the high rates of apoptosis in the initial EBV-specific CD8+ T cell population are related to down-regulation of Bcl-2 (17).
In this study, we present the first detailed examination of the dynamics of CD8+ T cells responding to a human infection, HIV-1, looking at their activation and differentiation states between acute and chronic phases of infection in relation to Ag-specific CD4+ T cell numbers. The recent use of tetrameric peptide-bound HLA class I molecule complexes to identify Ag-specific CD8+ T cells has enabled new advances in the study of the interplay between viruses and CTLs (18, 19, 20). We have used these reagents to follow HIV-specific CD8+ T cell populations through the different stages of HIV-1 infection, and to examine their activation status (looking at CD38 and Ki67 expression), susceptibility to apoptosis (Bcl-2 and Fas expression), and differentiation state (using CD28, CD27, CD45RA, and perforin expression). We have found that during acute infection, in contrast to chronic infection, HIV-specific CD8+ T cells are highly activated and prone to apoptosis. There is then a rapid differentiation of cells from early differentiated to an intermediate maturation state. This maturation occurs regardless of the presence or absence of detectable HIV-specific CD4+ T cells. These data have general implications for our understanding of the definition of memory and effector cells in humans.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Samples were taken from a well-characterized cohort of volunteers with acute HIV-1 infection in San Diego, CA. The local Institutional Review Boards and Ethical Committees approved this study. PBMCs were separated from heparinized blood and cryopreserved for subsequent studies. HLA typing was conducted by amplification refractory mutation system-PCR using sequence-specific primers, as previously described (21).
Fourteen patients were selected for the study of CD8+ T cells, on the basis of their having an HLA type for which we had relevant tetramers, and following the detection of HIV-specific CD8+ T cell populations using these tetramers. Patients were classified in two groups: 1) those individuals who were diagnosed before or at the time of HIV-1 seroconversion (referred to as preseroconversion acute HIV, n = 7), defined by symptomatic disease, recent high risk exposure, high plasma HIV-1 RNA (ranging from 3 x 105 to 3 x 106 copies/ml (mean 8.3 x 105 copies/ml)) and either a negative HIV-1 ELISA or a negative/indeterminate HIV-1 Western blot; and 2) those individuals diagnosed after HIV-1 seroconversion, but within 180 days of primary HIV-1 infection (postseroconversion primary HIV, n = 7) (with viral load ranging from 1.2 x 104 to 6.4 x 105 copies/ml (mean 2 x 105 copies/ml)). Upon diagnosis of acute HIV-1 infection, the majority of the subjects were treated with antiretroviral therapy (ART).3 Samples from group 1 were analyzed at multiple time points when possible, and the first time points were taken before the start of ART.
For comparison, another group of individuals with chronic HIV-1 infection was studied: individuals with low viral load (ranging from 3 x 102 to 1.6 x 105 copies/ml (mean 5.6 x 104 copies/ml)) for at least 3 years with or without treatment.
Ags and Abs
Peptides were synthesized by F-moc chemistry and corresponded to previously defined and optimized CTL epitopes. Anti-CD8 (PerCP), anti-CD27 (FITC or allophycocyanin), anti-CD28 (FITC or allophycocyanin), anti-CD38 (allophycocyanin), anti-CD45RA (FITC), anti-Fas (FITC), anti-Bcl-2 (FITC), anti-Ki67 (FITC), and anti-perforin (FITC) Abs were purchased from BD Biosciences (Mountain View, CA) or BD PharMingen (San Diego, CA).
Preparation of HLA-peptide tetrameric complexes
The HLA molecule H chain cDNAs were modified by substitution of
the transmembrane and cytosolic regions with a sequence encoding the
BirA biotinylation enzyme recognition site, as previously described
(18). These modified HLA H chains and
2-microglobulin were synthesized in a
prokaryotic expression system (R&D Systems, Minneapolis, MN), purified
from bacterial inclusion bodies, and allowed to refold with the
relevant peptide by dilution. Refolded monomeric complexes were
purified by FPLC and biotinylated using BirA (Avidity, Denver,
CO), then combined with PE-labeled streptavidin (Sigma-Aldrich,
St. Louis, MO) at a 4:1 molar ratio to form tetrameric HLA/peptide
complexes (tetramers). The tetramers used in these studies were as
follows: HLA-A*0201-SLYNTVATL (A2 gag p17), A*0201-ILKEPVHGV
(A2 pol), B7-IPRRIRQGL (B7 env gp41), B8-FLKEKGGL
(B8 nef), B8-DIYKRWII (B8 gag p24), and
B*2705-KRWIIMGLNK (B27 gag p24), A11-QVPLRPMTYK (A11
nef) complexes.
Cell surface and intracellular staining
Cell surface and intracellular stainings were conducted on thawed cryopreserved PBMCs. Titrated tetramers (PE conjugated) were added for 15 min at 37°C, followed by addition of a panel of titrated Abs (FITC, PerCP, or allophycocyanin conjugated) and incubation for 15 min at room temperature. The lymphocytes were then fixed. Cells were washed in PBS, 0.5 mM EDTA, and 1% BSA, fixed, and permeabilized in FACS permeabilization buffer (BD Biosciences). After washing, intracellular staining was performed for 15 min at room temperature in the dark using titrated concentration of Abs. Cells were then washed and stored in Cell Fix buffer (BD Biosciences) at 4°C until flow cytometry analysis was performed. Samples were analyzed on a BD Biosciences FACSCalibur. The threshold for perforin levels (high or low) was generally set so that 35–50% of CD8+ T cells were perforin high. The quadrants shown are not intended to separate negative and positive populations, but to emphasize distinct differences in levels of expression between populations. In addition to the use of isotype control Abs, thresholds were generally established on the basis of differences observed between acute and chronic infection, as well as previously defined associations between different markers, e.g., proliferating (Ki67+) cells are contained in the activated (CD38+) cell subset.
ELISPOT assays
Ninety-six-well polyvinylidene plates (Millipore, Bedford, MA)
were precoated with 15 µg/ml anti-IFN-
mAb, 1-DIK (Mabtech,
Stockholm, Sweden). For the detection of CD4+ T
cell responses, fresh PBMCs were first depleted of
CD8+ T cells: PBMCs were incubated with an excess
of anti-CD8 magnetic beads (Dynal Biotech, Oslo, Norway) for 30 min
on ice (5:1, beads:PBMC), followed by two washes with RPMI, 2% FCS
(the depletion was efficient at 96–99% by FACS analysis). A total of
105 CD8-depleted PBMCs was then plated out in the
presence of either staphylococcal enterotoxin B (2 µg/ml), CMV lysate
(10 µg/ml; Advanced Biotechnology, Columbia, MA), HIV-1 p24
(10 µg/ml, rHIV-1 IIIB gag p24 produced in the
baculovirus system), HIV-1 gp120 (10 µg/ml, rHIV-1 IIIB
envelope expression gp120 produced in the baculovirus system), HIV-1
tat (10 µg/ml, rHIV-1 IIIB tat produced in the
baculovirus system), or peptide pools of nef (10 µg/ml for
each peptide, HIV-1 LAI, thirteen 15 mers with 5-aa overlap) or HIV-1
p17 (10 µg/ml for each peptide, HIV-1 SF2, twenty 20 mers with 10-aa
overlap). The plates were incubated overnight at 37°C, 5%
CO2, and washed with PBS/0.05% Tween before
addition of the second, biotinylated anti-IFN- mAb, 7-B6-1
biotin (Mabtech) at 1 µg/ml and incubated at room temperature for
3 h. After washing, streptavidin-conjugated alkaline phosphatase
(Mabtech) was added at room temperature for 90 min. Individual
cytokine-producing cells were detected as dark spots after a 20-min
reaction with 5-bromo-4-chloro-3-indolyl phosphate and nitroblue
tetrazolium using an alkaline phosphatase-conjugate substrate (Bio-Rad,
Richmond, CA). The number of specific T cells was calculated by
subtracting the negative control values, and expressed as either the
number of spot-forming units (SFU) per 106 PBMC
(CD8+ responses) or SFU per
106 CD8+-depleted PBMC
(CD4+ responses). To derive the total HIV-1
response, responses toward all the HIV-1 Ags used were added
together.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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High levels of plasma viremia are generated during acute HIV-1
infection, which is immediately associated with the expansion of a
range of HIV-specific CD8+ T cells. The numbers
of virus-specific CD8+ T cells decline as viral
load falls, whether this is due to either immune control or the prompt
institution of ART (Fig. 1
A).
The magnitude of each CD8+ T cell expansion may
vary according to the Ag, with strong responses often seen toward
nef epitopes.5 Using
HIV-specific tetramers, the phenotype of these expanded populations was
monitored from primary infection onward. During acute infection, the
great majority of the virus-specific cells were activated, expressing
high levels of the activation marker CD38 (Fig. 2A). CD38 expression fell
rapidly, closely following the viral load, and was expressed only at
low levels during chronic infection. The activation state of the cells
correlated with the levels of TCR expression, as measured by the
brightness of tetramer staining: activated cells displayed slightly
lower tetramer staining than when resting (Fig. 2B), as
described recently (22, 23). Ki67 is an intracellular
marker of proliferation; expression is restricted to cells in cycle. As
expected, its expression in HIV-specific CD8+ T
cells was mainly detected during the expansion phase of acute
infection, and subsequently decreased (Fig. 1B). In our
group of acute seroconverter patients, the percentage of
tetramer-staining cells in cycle ranged from 11 to 41% (data not
shown).
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C). The level of Bcl-2 expression showed a close
inverse correlation with CD38 expression, and therefore with the degree
of activation of the cells (Fig. 1C). Changes in Fas
expression also occurred. In contrast to naive
CD8+ T cells
(CD27+CD28+CD45RO-),
Ag-experienced CD8+ T cells demonstrate
extracellular Fas expression, which is significantly increased when the
cells are activated (Fig. 2D). Accordingly, HIV-specific
CD8+ T cells expressed a high level of Fas during
acute infection, while this was much lower in resting cells, during the
chronic phase (Fig. 1D). HIV-specific
CD8+ T cells may thus be highly prone to
apoptosis during primary infection, presumably through either of the
main apoptotic pathways, and may be more protected from cell death and
hence more stable during chronic infection. This susceptibility to
apoptosis is closely related to the activation status of the cells, and
therefore also to the Ag load present in the patient. When viral
rebound occurs, HIV-specific CD8+ T cells again
exhibit high CD38 levels (22)6 and also reduced
Bcl-2 expression (data not shown). Our observations of the activation
state of virus-specific cells were not directly influenced by the use
of ART, but more closely followed the viral load, as a similar
phenotype was seen in both treated and untreated patients (Fig. 2, A and C, and data not shown). We were able to use
a panel of tetramers, including A2 p17, A2 pol, B8
nef, B8 p24, B27 p24, and A11 nef for studies in
the acute seroconverters, and no significant differences were observed
between CD8+ populations with different
specificities. Rapid, but incomplete differentiation of HIV-specific CD8+ T cells during the course of HIV infection
Ag stimulation drives the differentiation of naive
CD8+ T cells into Ag-primed cells, which can be
further distinguished, according to cell surface expression of the
costimulatory receptors CD28 and CD27:
CD28+CD27+ cells are seen
as precursors or early differentiated cells, and
CD28-CD27- are fully or
late differentiated cells, which express higher levels of perforin
(24, 25, 26).6
We followed the differentiation of the HIV-specific
CD8+ T cell population from acute to chronic
infection, measuring CD28, CD27, CD45RA, and perforin expression in
these cells. Early during acute infection, high numbers of
CD28+CD27+ cells were
observed, which differentiated rapidly (within 2–4 wk) into
CD28+CD27- intermediately
differentiated cells (Figs. 1E and 2, E and
F). The maturation process was very rapid. As soon as the
cell activation diminished and the expansion phase ended, phenotypes
resembled that observed during chronic infection, with the majority of
the cells displaying CD27, but not CD28. Furthermore, no clear
separation between CD28+ and
CD28- cells could be observed during acute
infection, to suggest ongoing differentiation (Fig. 1E).
Substantial, but low numbers of
CD28-CD27- cells could be
observed later, toward the end of the acute infection. As expected, the
majority of cells were also CD45RA negative, even very early in acute
infection (data not shown). IFN- ELISPOT assays conducted using
specific CTL epitopes suggested that the capacity of the HIV-specific
CD8+ T cells to produce IFN- during acute
infection could vary, ranging from lower levels to ones similar to
those observed during chronic infection (data not shown). In accordance
with the phenotypes previously described, low levels of perforin were
found in these cells at all time points (Fig. 2G).
The CD8+ T cell phenotype appears to be independent of the HIV-specific CD4+ T cell response
HIV-specific CD4+ T cells secreting IFN-
in response to viral Ags are usually found in low numbers in HIV
carriers (27, 28). They are thought to disappear early
during primary infection (29), presumably because as
activated cells homing to areas of viral replication, they are a prime
target for viral infection and destruction. Loss of
CD4+ T cell help may be a cause of impairment of
CTL function, rendering CTL less able to control HIV-1 replication
(30). In this study, Ag-specific
CD4+ T cell responses were measured using IFN-
ELISPOTs conducted on CD8+ T cell-depleted PBMCs.
Fig. 3A shows a comparison
between numbers detected in our cohort of patients undergoing primary
HIV infection before treatment, and numbers detected in a cohort of
patients undergoing chronic infection with and without treatment. In
both groups, most responses were either nonsignificant (<50 SFU per
106 cells) or relatively low (between 50 and 500
SFU per 106 cells). Although there may be a trend
toward higher CD4+ T cell responses during acute
infection, of borderline statistical significance, the difference is
minimal compared with the level of CMV-specific responses in the same
individuals, which were generally much higher (>500 SFU
106 cells).
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B). This suggests that the phenotype
of the HIV-specific CD8+ T cells is independent
of the virus-specific CD4+ T cell response
detected in the periphery, at least as far as IFN- secretion is
concerned. The phenotype of the whole CD8+ T cell populations is altered in both acute and chronic HIV-1 infection
To assess the impact of HIV infection on the whole
CD8+ T cell population, we compared the changes
in activation and differentiation between an individual HIV-specific
CD8+ T cell population and the remaining
CD8+ T cells in that patient. Surprisingly, the
CD8+ T cell activation status as a whole, as
measured by the expression of CD38, Bcl-2, and Ki67, was very similar
to what was observed in the HIV-specific population, in both acute and
chronic infections (Fig. 4A).
A majority (
80%) of CD8+ T cells expressed
CD38 and low levels of Bcl-2, with about one-fifth of the
CD8+ T cells staining positive for Ki67 during
acute infection, similar to the proportions seen for the B8
nef-specific population. Thus, it appears that HIV infection
has an impact on the great majority of the CD8+ T
cell population.
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B). In healthy donors,
CD8+ T cells are mainly found in the naive and
presumably early differentiated Ag-primed cells, both
CD28+CD27+ (as exemplified
in Fig. 4B). During acute HIV infection, similar to the
pattern displayed by HIV-specific CD8+ T cells,
the whole CD8+ T cell population also displayed a
shift toward the
CD28-CD27+ subsets (Fig. 4B). However, during chronic infection, the
CD8+ T cell population as a whole displays a
distribution distinct from that of the HIV-specific
CD8+ T cells, with clear enrichment of
CD28-CD27- cells
(31). While the activation phenotype appears similar
between the two populations, the differentiation phenotype differs.
This implies that HIV is not the only cause of the differentiation
phenotype changes undergone by the whole CD8+ T
cell population. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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illustrates the most common model
depicting the evolution of the HIV-specific cellular immune response:
beginning with a peak of viremia, followed by the appearance of
HIV-specific CD8+ T cells, characterizing the
acute phase, leading to the asymptomatic chronic phase, in which CTL
numbers are reduced and viral load has fallen because of either
immunological control or antiretroviral treatment. Our observations
parallel the pattern of CD8+ T cell responses
described in murine models, in which both effector and memory phases
have been characterized. During the initial (acute or effector) phase,
the virus-specific CD8+ T cells are activated and
expand to a large population that is poised between proliferation and
apoptosis. Then as the antigenic challenge diminishes, the cells stop
proliferating and their numbers are substantially reduced through
apoptosis. As cells enter the resting phase, their susceptibility to
apoptosis is reduced, accompanied by up-regulation of Bcl-2 and
down-regulation of Fas. These characteristics show clear parallels with
the dynamics of CTL responses to SIV in rhesus monkeys
(32). During the second (chronic or memory) phase when
viremia is low, the pool of memory CD8+ T cells
remains apparently stable. These cells might be maintained by the
ongoing transcription of particular HIV genes (notably nef)
that is known to occur in treated chronic infection even when viral
load remains undetectable (33, 34, 35), as we have recently
mentioned (36). However, this may be unlikely, as the
cells are mainly resting, in contrast with cells responding to viral
rebound. Moreover, recent reports have demonstrated that naive
CD8+ T cells undergo programmed differentiation,
following a brief encounter with Ag, to generate ultimately a pool of
memory T cells that can survive and maintain their rapid-response mode
in the absence of Ag (23, 37, 38).
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In recent studies, we and others suggested that a paucity of
IFN--producing CD4+ T cells specific for
HIV-1, in comparison with the levels of CMV-specific help, may be a
cause for incomplete or impaired maturation of the
CD8+ T cells
(40).4
However, our present data show that HIV-specific
CD8+ T cells do not appear to differentiate any
further even in individuals exhibiting unusually high HIV-specific
CD4+ T cell responses in primary infection. This
suggests that CD8+ T cell maturation may be
independent of the numbers of specific CD4+ T
cells, in keeping with recent observations (23, 37). It is
still open to debate whether HIV-specific CD8+ T
cells are functionally deficient or whether the phenotype of the
CD8+ T cells is an appropriate host response for
this particular infection, despite the low perforin levels
(41). In favor of the second hypothesis is the observation
that during primary infection, when virological control appears to be
achieved for a time, the cell phenotype does not differ significantly
from that observed during chronic infection.5 The
numbers of HIV-specific IFN--producing CD4+ T
cells are generally quite low even during primary infection, and their
numbers do not seem dependent on the stage of infection. This may
conceivably be a normal response to HIV-1 infection, but it seems more
likely that these cells are lost very early in virus replication, as
the viral load begins to rise. This raises insurmountable practical
problems in studying the essential features of the acute HIV-1
CD4+ T cell response, as patients would need to
be studied very early following contact with the virus, well before the
development of symptoms.
The last point we address concerns the phenotypic comparison between HIV-specific CD8+ T cells and the CD8+ T cell population as a whole. During acute HIV-1 infection, up to 80–90% of all the CD8+ T cells in whole blood are activated, one-fifth of them showing active proliferation, a similar proportion to that observed in the HIV-specific CD8+ T cell populations. Recent studies in the mouse have shown that bystander activation triggered during viral infection is limited, and that the majority of activated CD8+ T cells are virus specific (8, 9). However, in the case of acute HIV-1 infection, it seems unlikely that 80–90% of the CD8+ T cells are HIV specific (although we have not ruled this out). An important part of the general activation of CD8+ T cells may be a consequence of bystander activation (42), but it is also feasible that this could also be due to immune responses to other pathogens and viruses, either reactivated or appearing in the context of HIV-induced immunosuppression. The differences in the distribution of differentiation subsets between HIV-specific CD8+ T cells and the whole CD8+ T cell population are particularly striking for the CD28-CD27- subset. We know that the majority of CMV-specific CD8+ T cells occur in this subset.5 These are therefore one potential example that could account for the expanded CD28-CD27- subset in the general CD8+ T cell population, but other opportunistic infections could also be activated, particularly in the context of HIV-induced immunosuppression, and thus lead to changes in the phenotypic distribution of the whole CD8+ T cell population.
In this study, we have provided a detailed analysis of the dynamics and phenotype of the CD8+ T cell response during acute and chronic HIV-1 infection and its relationship to the number of specific CD4+ T cells. This is the first such analysis in the context of a human infection, and shows close parallels with the findings previously obtained in mouse models. Our observations have important implications for the understanding of effector and memory responses in human infections in general, and HIV-1 in particular.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Victor Appay, Medical Research Council Human Immunology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DS, U.K. E-mail address: vappay{at}gwmail.jr2.ox.ac.uk
3 Abbreviations used in this paper: ART, antiretroviral therapy; SFU, spot-forming unit.
4 L. Papagno, V. Appay, J. Sutton, T. Rostron, G. M. A. Gillespie, G. S. Ogg, A. King, A. T. Makadzange, A. Waters, C. Balotta, A. Vyakarnam, P. J. Easterbrook, and S. L. Rowland-Jones. Comparison between HIV and CMV specific T cell responses in long term HIV infected donors.
5 C. A. Spina, P. Hansasuta, V. Appay, G. S. Ogg, T. Rostron, S. J. Little, D. D. Richman, and S. L. Rowland-Jones. Predominance of Nef epitope responses in HIV-specific CD8+ T-cells during acute HIV-1 infection and subsequent antiviral therapy: concurrent analysis of cytokine secretion. Submitted for publication.
6 V. Appay, P. R. Dunbar, M. Callan, P. Klenerman, G. M. A. Gillespie, L. Papagno, G. S. Ogg, A. King, F. Lechner, C. A. Spina, S. Little, D. V. Havlir, D. D. Richman, N. Gruenor, G. Pape, A. Waters, P. J. Easterbrook, M. Salio, V. Cerundolo, A. J. McMichael, and S. L. Rowland-Jones. Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Submitted for publication.
Received for publication October 22, 2001. Accepted for publication January 31, 2002.
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A. Y. Kim, G. M. Lauer, K. Ouchi, M. M. Addo, M. Lucas, J. S. z. Wiesch, J. Timm, M. Boczanowski, J. E. Duncan, A. G. Wurcel, et al. The magnitude and breadth of hepatitis C virus-specific CD8+ T cells depend on absolute CD4+ T-cell count in individuals coinfected with HIV-1 Blood, February 1, 2005; 105(3): 1170 - 1178. [Abstract] [Full Text] [PDF]
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J.-M. Doisne, A. Urrutia, C. Lacabaratz-Porret, C. Goujard, L. Meyer, M.-L. Chaix, M. Sinet, and A. Venet CD8+ T Cells Specific for EBV, Cytomegalovirus, and Influenza Virus Are Activated during Primary HIV Infection J. Immunol., August 15, 2004; 173(4): 2410 - 2418. [Abstract] [Full Text] [PDF]
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L. E. Gamadia, E. M. M. van Leeuwen, E. B. M. Remmerswaal, S.-L. Yong, S. Surachno, P. M. E. Wertheim-van Dillen, I. J. M. ten Berge, and R. A. W. van Lier The Size and Phenotype of Virus-Specific T Cell Populations Is Determined by Repetitive Antigenic Stimulation and Environmental Cytokines J. Immunol., May 15, 2004; 172(10): 6107 - 6114. [Abstract] [Full Text] [PDF]
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P. Mooij, I. G. Nieuwenhuis, C. J. Knoop, R. W. Doms, W. M. J. M. Bogers, P. J. F. ten Haaft, H. Niphuis, W. Koornstra, K. Bieler, J. Kostler, et al. Qualitative T-Helper Responses to Multiple Viral Antigens Correlate with Vaccine-Induced Immunity to Simian/Human Immunodeficiency Virus Infection J. Virol., April 1, 2004; 78(7): 3333 - 3342. [Abstract] [Full Text] [PDF]
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P. K. C. Goon, T. Igakura, E. Hanon, A. J. Mosley, A. Barfield, A. L. Barnard, L. Kaftantzi, Y. Tanaka, G. P. Taylor, J. N. Weber, et al. Human T Cell Lymphotropic Virus Type I (HTLV-I)-Specific CD4+ T Cells: Immunodominance Hierarchy and Preferential Infection with HTLV-I J. Immunol., February 1, 2004; 172(3): 1735 - 1743. [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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P. K. C. Goon, T. Igakura, E. Hanon, A. J. Mosley, B. Asquith, K. G. Gould, G. P. Taylor, J. N. Weber, and C. R. M. Bangham High Circulating Frequencies of Tumor Necrosis Factor Alpha- and Interleukin-2-Secreting Human T-Lymphotropic Virus Type 1 (HTLV-1)-Specific CD4+ T Cells in Patients with HTLV-1-Associated Neurological Disease J. Virol., September 1, 2003; 77(17): 9716 - 9722. [Abstract] [Full Text] [PDF]
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L. E. Gamadia, E. B. M. Remmerswaal, J. F. Weel, F. Bemelman, R. A. W. van Lier, and I. J. M. Ten Berge Primary immune responses to human CMV: a critical role for IFN-gamma -producing CD4+ T cells in protection against CMV disease Blood, April 1, 2003; 101(7): 2686 - 2692. [Abstract] [Full Text] [PDF]
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G. H. Learn, D. Muthui, S. J. Brodie, T. Zhu, K. Diem, J. I. Mullins, and L. Corey Virus Population Homogenization following Acute Human Immunodeficiency Virus Type 1 Infection J. Virol., October 25, 2002; 76(23): 11953 - 11959. [Abstract] [Full Text] [PDF]
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acute), and the chronic HIV group (•, chronic).
