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Secretion by Activated T Cells in HIV-1 Infection Associated with Viral Suppression and a Lack of Disease Progression1
*
Wistar Institute, Philadelphia, PA 19104;
Philadelphia Field Initiating Group for HIV Trials, Philadelphia, PA 19107; and
Johns Hopkins School of Public Health, Baltimore, MD 21205
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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were analyzed in progressive HIV-1
disease. Both cytokines exert positive effects on Ag presentation and
inhibit HIV-1 infection of macrophages.
Anti-CD3/anti-CD28-activated PBMC from HIV-1-infected individuals
(n = 74) compared with uninfected subjects
(n = 30) secreted significantly less IL-13 (median,
0.64 ng/ml vs 2.07 ng/ml; p < 0.001) and IFN-
(median, 40.96 ng/ml vs 129.5 ng/ml; p < 0.005).
Decreased IL-13 and IFN- secretion in HIV infection was present in
sorted CD4+ and CD8+ T cell subsets, and
additional analysis determined concurrent deficiency at the protein and
transcriptional level. Longitudinal analysis showed that cytokine
secretion levels correlated positively with CD4 count and negatively
with plasma HIV-1 viral load. Patients changing to suppressive
antiretroviral therapy during the study showed increases in IL-13 and
IFN- secretion. Overall, results show a decline in IL-13 and IFN-
secretion in progressive HIV-1 infection and suggest a role for both
cytokines as part of T cell adaptive responses associated with a lack
of disease progression. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, IL-2, IL-4, IL-10, and IL-12
(4, 5, 6, 7, 8, 9, 10, 11). Decreased secretion of type 1 cytokines such as IL-2 and
IFN- following mitogen stimulation of T cells in progressive HIV
infection is associated with a higher susceptibility to opportunistic
infections (4, 9, 12, 13, 14, 15, 16, 17). In contrast, the role of T cell-derived type
2 cytokines remains uncertain in spite of their clinical use in
combination with antiretroviral therapy as immunotherapy targeted
against chronic viral-induced activation and AIDS-associated Kaposi’s
sarcoma (18, 19, 20).
IL-13, originally described as an IL-4-like type 2 cytokine (21, 22),
has received limited attention in studies of HIV-1 pathogenesis in
spite of its potential importance to immunotherapy as a cytokine with
properties different than those of IL-4 (22, 23). 1) Receptors for
IL-13 and IL-4 are differentially expressed on human T cells, B cells,
and monocytes. Whereas IL-13 has IL-4-like effects on monocytes and B
cells, IL-13 does not regulate T cell function due to a proposed lack
of IL-13 receptor expression on T cells (22, 24). By contrast, IL-4
regulates T cell function by differentiating type 2 T cells (25). 2)
IL-13 is secreted by Th0, Th1, and Th2 cells, in contrast to the
secretion of IL-4 by only Th2 cells (24, 26, 27). 3) Whereas IL-4 and
IL-13 are secreted by CD4+ and CD8+ T cell
memory (CD45RO+) subsets, IL-13 is also secreted by the T
cell-naive subset (CD45RA+) (26, 28). 4)
Calcineurin/calmodulin pathways leading to nuclear translocation of
NF-AT-1 are required for IL-4 induction, whereas IL-13 induction is
independent of this pathway (28, 29). Therefore, we have focused our
analysis on IL-13, as compared with IFN-, based on the lack of IL-13
protein secretion information in HIV-1 pathogenesis and its potential
significance to adjunct immunotherapy. Specifically, IL-13 enhances Ag
presentation in HIV-1-infected PBMC (21, 30, 31), inhibits macrophage
HIV-1 expression (32, 33, 34, 35), and primes macrophages for IL-12 secretion
(31, 36). To our knowledge, only one cross-sectional analysis has
focused on IL-13 mRNA expression as compared with IL-4 mRNA in
HIV-1-infected individuals, which indicated increased IL-13 mRNA
expression in unstimulated PBMC and lymph node tissue (37). It is
important to expand our understanding of IL-13 from message to protein
secretion by activated T cells in HIV-1 pathogenesis to indirectly
assess its potential as immunotherapy relative to its secretion in
disease progression.
A predominance of cytokine secretion studies in HIV-1-infected PBMC
utilizing polyclonal cell stimulation via mitogen or chemical induction
has limited interpretation of cytokine responses following more
physiological stimulation of T cells. Ag-specific T cell activation
depends on stimuli provided by APC MHC/B-7 interactions with CD3 and
CD28 on T cells (38). In HIV infection, multiple steps in this
interaction have been described to affect the degree of T cell
Ag-specific activation such as decreased concentrations of CD4 T cells
(1), dysfunctional CD3 complex signal transduction (39), higher
susceptibility for APC-mediated apoptosis (3), and predominant
decreases in CD28 expression on CD8 T cells (40, 41, 42, 43). Although up to
3-fold decreases in CD28 expression are found on CD8 cells of
HIV-1-infected individuals at end stage disease, CD28 remains expressed
on 68–92% of CD4 T cells, representing a large potentially responsive
T cell pool to stimuli provided by APC (40, 43, 44, 45). We studied
cytokine secretion by T cells from HIV-infected individuals at various
stages of disease and viremia levels following stimulation via CD3 and
CD28, as a model system of functional cytokine secretion by the pool of
T cells able to be activated by this pathway. We compared IL-13 to
IFN- secretion due to decreased secretion of IFN- in progressive
HIV infection (9, 12, 16, 17, 46) and to test for differential
secretion. These investigations also evaluated cytokine secretion
before and after highly active antiretroviral therapy
(HAART)3 to directly test the
association between IL-13 and IFN- secretion and viral suppression.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Venous peripheral blood samples were obtained in citrate-coated
tubes following informed consent by The Wistar Institute’s phlebotomy
unit (30 HIV- donors) and by the Philadelphia Field
Initiating Group for HIV Trials (74 HIV-1+ donors), and
PBMC isolated by Ficoll-Hypaque (Pharmacia, Piscataway, NJ) density
gradient centrifugation. Ficoll-isolated cells were cultured in RPMI
1640 (Life Technologies, Grand Island, NY) supplemented with
penicillin/streptomycin (100 U/ml and 100 µg/ml, respectively) and
10% heat-inactivated male AB+ human sera (Sigma Chemical,
St. Louis, MO). A subset of 52 HIV-1+ donors were
repeatedly sampled for an average of 3.2 times during a period of 39
wk. Participating patients represented early and late stages of HIV-1
infection as measured by CD4 T cell/µl (Fig. 1
) and receiving different regimens of
antiviral therapy (Table III). Antiretroviral therapy of subjects shown
on Figs. 3, 4, and 5 and Table I are summarized by showing the number
of reverse transcriptase inhibitors over the number of protease
inhibitors (PI) (i.e., "2/1" representing two reverse transcriptase
inhibitors and one PI therapy regimen). All HIV-1+ patient
clinical information was obtained from chart evaluation by study
nurses.
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PBMC (106 cells/ml) or sorted cells (5 x
105 cell/ml), obtained as described below, were stimulated
by anti-CD3/anti-CD28 by using plates previously coated
overnight at 4°C with anti-CD3 OKT3 (IgG2a) at 5 µg/ml in 0.1 M
sodium carbonate buffer (pH 9.5). At the time of stimulation, wells
were rinsed with PBS, and cells were resuspended in medium containing
1% (v/v) anti-CD28 ascites CK-248 (IgM) (47, 48). Preliminary
experiments indicated that soluble IgM anti-CD28 was twice as
effective in stimulating IL-13 and IFN- as plate-bound IgG2a
anti-CD28 (clone 9.3) when used together with plate-bound OKT3.
Supernatants were collected from unactivated and activated cultures at
4 days poststimulation based on preliminary time course analyses on
infected and healthy controls demonstrating peak concentration for both
cytokines at this time point.
Quantitation of cytokines
IL-13, IFN-, and IL-5 concentrations were determined by ELISA
according to the manufacturer’s recommendations (Biosource
International, Camarillo, TX) or by in-house RIA (IFN-) performed as
described (49) (mAbs: coating, B133.1; detection, B133.5) with
commercial IFN- (Genzyme, Cambridge, MA) standards. All cytokine
measurements were based on the average of duplicate samples. The
sensitivity of IFN- RIA was 2.5 ng/ml, and those of commercial
IL-13, IL-5, and IFN- ELISA were 12, 6, and 4 pg/ml,
respectively.
RNase protection assays
Cellular RNA was isolated by Trizol extraction (Life
Technologies), quantitated by spectrophotometer and assessed for
degradation by ethidium bromide staining in denaturing gels. RNA
samples (10 µg) were analyzed by RNase protection assay (RiboQuant,
Pharmingen, San Diego, CA). In brief, RNA samples were hybridized with
32P-labeled riboprobes for IL-13, IFN-, and GAPDH and
digested with RNases; protected regions were separated in denaturing
polyacrylamide gels, dried, and quantitated on a Phosphoimager
(Molecular Dynamics, Sunnyvale, CA).
Flow cytometry analysis
PBMC from uninfected and HIV-1+ donors were stained with 1) biotinylated anti-CD4 Q4120, followed by streptavidin-Red 670 (Sigma), 2) anti-CD8-FITC (Sigma), and 3) anti-CD45RO-PE (Sigma). Stained cells were separated into CD4+, CD8+, CD4+/RO+, and CD8+/RO+ T cell subsets by sorting on an Epics ELITE flow cytometer (Coulter Immunology, Hialeah, FL). Sorting gates were based on typical lymphocyte light scatter and isotype control fluorescence for the cell populations of interest. Sorted cell subsets were reanalyzed for purity, checked for viability by dye exclusion, and plated at 5 x 105 viable cells/ml in 96-well plates for stimulation and analysis as described above.
Statistical analysis
Data sets were tested for normal distributions by the
Kolmogorov-Smirnov test. Nonnormally distributed groups were analyzed
by the Mann-Whitney U test and Spearman’s ranked order
correlation analysis. Assumptions for all statistical tests shown are
fulfilled. Significant two-tailed differences were defined at an 
level of 0.05 (p < 0.05). Statistical analysis
was conducted with StatMost (DataMost, Salt Lake City, UT) and
SigmaStat (Jandel, San Francisco, CA) software.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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declines with HIV disease
progression
Secretion of IL-13 and IFN- was measured in 30 uninfected
controls and 74 HIV-1-infected donors following PBMC stimulation with
anti-CD3/anti-CD28. Results demonstrated a significant decrease
of IL-13 and IFN- secretion in HIV-1-infected patients with <500 T
cells/µl as compared with uninfected donors (Fig. 1
). However,
cytokine secretion from enriched CD4+ T cell subsets from
infected patients indicated that decreased secretion was not
exclusively due to a decrease in CD4+ cell number
(demonstrated below). Although median IFN- secretion was higher in
patient samples above 500 T cells/µl, this group of responses was not
significantly different from those of the uninfected control. IL-13 and
IFN- secretion were significantly correlated (r =
0.54, p < 0.001) at all stages of disease, suggesting
that both cytokine secretions are equally affected. To rule out the
presence of a nonspecific reductions in cytokine responses from
activated HIV-1-infected PBMC, we measured IL-5 secretion in parallel
with IL-13 and IFN- in a subset of six anti-CD3/anti-CD28
stimulated HIV-1-infected PBMC as compared with three uninfected PBMC.
Results showed a lack of reduction for IL-5 in supernatants from
HIV-1-infected patient samples in spite of decreased IL-13 and IFN-
(data not shown). Taken together, these data indicate a decreased
secretion of IL-13 and IFN- following anti-CD3/anti-CD28
stimulation with progressive HIV disease.
Both CD4 and CD8 T cell subsets from HIV-1-infected individuals
secrete less IL-13 and IFN-
We determined the level of IL-13 and IFN- secretion in enriched
CD4+, CD8+, CD4+RO+,
and CD8+RO+ T cell subsets after flow
cytometric sorting from freshly isolated uninfected (n
= 3) and HIV-1-infected (n = 3) PBMC (Fig. 2, Table I). Enriched CD4+ T cell
subsets following sorting from both uninfected (2 of 3) and HIV-1 (2 of
3) donors showed the greatest increase in IL-13 secretion as compared
with their corresponding intact PBMC responses (Fig. 2, A
and B). As expected, in uninfected donors, IL-13 secretion
was shown to be a product of both CD4 and CD8 subsets, although
primarily secreted from CD4+ and
CD4+/CD45RO+ T cell subsets. Interestingly, in
spite of an increased IL-13 secretion by HIV-1-infected
CD4+ T cell subsets in 2 of 3 donors tested, total
secretion levels still remained decreased by 84% in comparison with
the same T cell subsets from uninfected donors (Fig. 2C).
These data indicate that both total and memory subsets of CD4 and CD8 T
cells from HIV-1-infected individuals with <455 CD4 T cells/µl
(highest CD4 count tested) are intrinsically impaired in their ability
to secrete IL-13 following cell enrichment and stimulation. In contrast
to IL-13, IFN- secretion was not increased in enriched uninfected
donor T cell subsets (data not shown), suggesting a difference between
cytokines on the factors (e.g., IL-12) contributing to PBMC-stimulated
cytokine secretion. In spite of the decrease in IFN- secretion
following sorting, all HIV-1-infected subsets secreted lower
concentrations of IFN- relative to control uninfected donor subsets.
Taken together, these results suggest that decreased secretion of IL-13
and IFN- in progressive HIV-1-infected PBMC can be attributed in
part to a decreased capacity for secretion by CD4 and CD8 T cell
subsets in addition to a decrease in total CD4 T cell number.
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at transcriptional level
To determine the relationship between decreased protein secretion
and mRNA induction following T cell activation, IL-13 and IFN- mRNA
levels were compared between healthy and HIV-1-infected donors at
various stages of disease by RNase protection assay (n
= 20). Protein secretion for both cytokines was also measured in
parallel. Unactivated and anti-CD3/anti-CD28-activated PBMC
mRNA were collected at 36 h poststimulation based on peak message
levels for IL-13 and IFN- by time course analysis of activated
uninfected samples (data not shown). RNase protection analysis was also
performed on fresh unstimulated PBMC from 8 HIV-1 donors to determine
general baseline levels of cytokine message present at the time of PBMC
isolation and stimulation. Results showed a lack of message for either
cytokine in HIV-1-infected PBMC tested at the time of isolation (Fig. 3) whereas samples following activation
showed impaired IL-13 and IFN- message induction and protein
secretion (Fig. 4). We did observe a
greater sensitivity for IFN- message vs protein detection in 2 of 20
patients as represented in Fig. 4 by patient 97-476 who induced IFN-
message in the absence of protein detection by RIA. Longitudinal mRNA
and protein secretion from 6 patients supported an association between
mRNA induction and protein secretion by showing parallel changes for
both measures in sequential samples (data not shown). Overall, these
results suggest that HIV-1 infection is associated with a decrease in
transcriptional activation of IL-13 and IFN- in activated T cells
which results in lower protein secretion.
Increased secretion of IL-13 and IFN- associated with reduction
of viral load
To test the stability of T cell cytokine secretion over time and
the association between viral load and cytokine secretion, we measured
IL-13 and IFN- secretion in longitudinal samples from a subgroup of
52 from the 74 patients in the study. These patients were repeatedly
sampled for an average of 3.2 times during a 39-wk period. Results
showed individual cytokine secretion responses were stable in patients
showing no changes in CD4 T cell count or plasma viremia. Patient
profile 25 in Fig. 5 is representative of
a stable response profile showing reproducible IL-13 secretion levels
during a 13-wk period. Stable deficiency profiles for both IL-13 and
IFN- were also observed in association with elevated viral load
measurements during the period of study (data not shown). A significant
negative correlation between either IFN- or IL-13 and viral load was
observed on analysis of all cytokine samples associated with viral load
measurements in the study (Table II).
However, the presence of a positive association between cytokine
secretion and CD4 count in this same cross-sectional subgroup could not
establish independent effects between viral load and CD4 count in
accounting for levels of cytokine secretion.
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secretion was suggested by analysis of patient data according
to the amount of therapy they were taking and by the analysis of
patients starting de novo suppressive HAART regimens. First,
classification of patients by amount of antiretroviral therapy showed
an increase in median secretion for both cytokines in patients
receiving three or more antiretrovirals with CD4 counts above 200 T
cells/µl (Table III). Second, as shown
in patient profile 10 in Fig. 5B, reduced cytokine secretion
in the absence of therapy at wk 0 (145 CD4 T cells/µl) which
continues during a brief nonsuppressive HAART regimen (wk 11) is
followed by an increase in IL-13 and IFN- secretion within a 7-wk
period following the start of a novel suppressive HAART regimen (wk
35). A similar response to suppressive HAART is shown with patient 19
in Fig. 5C, who represents one of an additional group of
three patients who started on a suppressive HAART regimen within 1–2
wk before our first sample. Indeed, longitudinal samples from eight of
nine patients who started HAART therapy following a baseline sample
showing decreased IL-13 and IFN- secretion support a role for viral
load in affecting cytokine secretion levels. Following the start of
HAART, these patients showed increased IL-13 and IFN- secretion
above the lower uninfected limit threshold (1 SD below the mean
uninfected secretion level) in periods of 3–8 wk in spite of baseline
CD4 counts as low as 145 T cells/µl.
Increased cytokine secretion was not restricted to de novo suppressive
HAART because patients changing HAART regimens due to noncompliance
also showed increases in cytokine secretion. Patient 17 in Fig. 5D illustrates these latter patients by showing a change of
HAART regimen (wk 3) resulting in better suppression of viremia and an
increase in IL-13 and IFN- secretion. Taken together, results showed
that T cell cytokine secretion of IL-13 and IFN- is a stable
functional parameter of T cell function in the absence of clinical
progression.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and
IL-12 are proposed to contribute to disease progression, our data
directly addressed secretion of IL-13 based on the lack of any data on
its secretion during HIV-1 pathogenesis in spite of its clear potential
as an immunotherapeutic (e.g., enhanced Ag presentation (21, 31),
inhibition of HIV-1 in vitro infection (32, 33, 34, 35, 50, 51),
antiinflammatory effects (22), and priming for IL-12 secretion (31, 36)).
In general, a significant decrease of IL-13 and IFN- secretion was
observed in stimulated PBMC from HIV-1-infected individuals whose CD4
count was <500 CD4 T cells/µl (Fig. 1). However, individual examples
of decreased cytokine secretion with higher than 500 CD4 T cells/µl
were observed as shown in Fig. 4. In support of a decrease in cytokine
secretion due to T cell-specific factors rather than a decrease in
total CD4 number alone, IL-13 and IFN- remained deficient following
activation of enriched CD4, CD8, or respective CD45RO memory subsets as
compared with uninfected controls (Table I, Fig. 2). We interpret these
results to indicate that in addition to decreasing CD4 T cell number,
an inherent deficiency in secretion of IL-13 and IFN- from CD4 and
CD8 T cell subsets is present in progressive HIV-1 infection. Potential
mechanisms acting to contribute to decrease cytokine expression may
include HIV-1 gp-120/CD4-mediated alteration of the protein tyrosine
kinase fyn and lck pathways involved in
CD3-mediated signal transduction (39, 52), alteration of the CD3/TCR
complex (39), and total CD28 expression (39, 53, 54). In contrast to
defects associated with the T cell CD3 complex, CD28 signaling has been
suggested to remain functional in HIV infection (55). However, CD28
expression by CD8 T cells subsets in progressive HIV infection has
been shown to be preferentially decreased, which may provide a
potential mechanism to account for the increased deficiency of IL-13
secretion between activated CD8 vs CD4 T cells subsets from the same
HIV-1-infected patient (Fig. 2) (40, 41, 42, 43). The presence of multiple
viral and host factors determining total levels of T cell activation
and cytokine expression is consistent with the variability of cytokine
secretion profiles observed between otherwise comparably HIV
disease-staged donors. Therefore, as a T cell product from activated
CD4 or CD8 type 1 and type 2 T cells (24, 26, 27), the decrease of
IL-13 secretion would suggest this cytokine is not expressed at normal
levels during immune activation of T cells following interaction with
MHC-II and B-7 on APC.
The presence of viral-induced mechanisms affecting the activation of
cytokine genes at a step before transcription is consistent with the
observation of decreased IL-13 and IFN- mRNA in association with
decreased protein secretion in HIV-1-infected PBMC (Fig. 4). Of
interest was our inability to reproduce a previous report of increased
message for IL-13 in unstimulated PBMC from eight HIV-1-infected donors
(Fig. 3) (37). Although the reasons for difference in results remain
uncertain (i.e., sensitivity between gene expression assays, the
variability of IL-13 expression by CD4 count or antiretroviral therapy
as shown in this study, and sample processing), our study conclusively
shows a decrease of IL-13 gene expression and protein secretion
following CD3/CD28 T cell activation in progressive HIV infection.
T cell cytokine secretion of IL-13 and IFN- appear to be a stable
functional parameter in the absence of clinical changes in disease
progression (Fig. 5A). By contrast, patients starting or
modifying HAART regimens showed changes in cytokine secretion
consistent with a negative association between viral load and either
IL-13 or IFN- secretion (exemplified in Fig. 4, B–D). Increases in IL-13 and IFN- secretion
in patients who responded to therapy by decreasing their viral load are
in concert with previous demonstrations of increased redistribution of
circulating CD4 memory cells (CD45RO), recovery of PHA proliferative
responses at 1–2 wk (56, 57), and an increase in CD28+
expression as early as 1 wk after initiation of therapy (56) (42).
Therefore, increased IL-13 and IFN- secretion in these patients may
reflect the summation of: 1) functional capacity of redistributed
memory (CD45RO+) CD4+ T cells able to secrete
both cytokines (26); 2) an increase in expression of CD28; and 3) the
absence of viral-induced disturbances to the CD3 signal transduction
complex (39, 53, 54). Although we interpret increases in cytokine
secretion to be associated with immune reconstitution as a result of
viral suppression, we cannot rule out independent effects by HAART on T
cell function and cytokine secretion. Interestingly, no significant
decrease or increase in IL-13 or IFN- secretion from HIV-1-infected
PBMC over uninfected sample levels was observed at the onset of
suppressive antiviral therapy, indicating a reconstitution of cytokine
levels comparable with those measured in uninfected controls.
Contrary to showing IL-13 as a T cell product that is selectively
overexpressed in association with HIV-1 disease progression as would be
expected according to recent hypotheses on HIV-1 pathogenesis (37, 58),
our data would indicate an impairment in the development of T
cell-mediated type 2 responses based on the recently described
dependent contribution of IL-13 to these responses (59). On the other
hand, the role of IL-13 in early immune responses or type 1 immunity
remains largely undefined, althought it is a secreted product from
CD45RA, Th0, and Th1 T cells (24, 26, 28). Overall, we interpret a
decrease of IL-13 and IFN- secretion from activated T cells in HIV
infection to be consistent with the presence of a general state of T
cell immunodeficiency following APC-mediated activation affecting both
type 1 and type 2 responses. Although our cross-sectional and
longitudinal analyses show that T cell secretion of IL-13 and IFN-
is not associated with immune responses from patients who are viremic
or at late stages of HIV-1 disease, additional longitudinal studies
would be needed to determine whether changes in cytokine secretion
signal a change in disease progression.
The demonstrated effects of both IL-13 and IFN- to have direct
antiviral effects on HIV-1 macrophage infections (32, 33, 34, 35, 50, 51), to
enhance Ag presenting function (21, 31), and to be associated with
improved disease status (increased CD4 or decreased HIV viral load)
suggest a contribution by these cytokines in maintaining immune
function following HIV-1 infection. It remains to be tested whether
IL-13 or IFN- may be beneficial as adjunct immunotherapy with
antiviral chemotherapy due to their association with a lack of disease
progression and their proposed effects on viral and immune regulation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Luis J. Montaner, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. E-mail address:
3 Abbreviations used in this paper: HAART, highly active antiretroviral therapy; PI, protease inhibitors.
Received for publication November 4, 1998. Accepted for publication March 25, 1999.
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L. Azzoni, E. Papasavvas, J. Chehimi, J. R. Kostman, K. Mounzer, J. Ondercin, B. Perussia, and L. J. Montaner Sustained Impairment of IFN-{gamma} Secretion in Suppressed HIV-Infected Patients Despite Mature NK Cell Recovery: Evidence for a Defective Reconstitution of Innate Immunity J. Immunol., June 1, 2002; 168(11): 5764 - 5770. [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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M. L. Garba, C. D. Pilcher, A. L. Bingham, J. Eron, and J. A. Frelinger HIV Antigens Can Induce TGF-{beta}1-Producing Immunoregulatory CD8+ T Cells J. Immunol., March 1, 2002; 168(5): 2247 - 2254. [Abstract] [Full Text] [PDF]
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T. L.-Y. Chang, A. Mosoian, R. Pine, M. E. Klotman, and J. P. Moore A Soluble Factor(s) Secreted from CD8+ T Lymphocytes Inhibits Human Immunodeficiency Virus Type 1 Replication through STAT1 Activation J. Virol., January 15, 2002; 76(2): 569 - 581. [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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 X. Ma and L. J. Montaner Proinflammatory response and IL-12 expression in HIV-1 infection J. Leukoc. Biol., September 1, 2000; 68(3): 383 - 390. [Abstract] [Full Text] [PDF]
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is introduced in the
x-axis to signify a change in therapy with the new
therapy listed in bold underneath. Secretion values for IL-13 (solid
bars) are according to the left axis, and IFN-