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Journal of Virology, November 2001, p. 10319-10325, Vol. 75, No. 21
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.21.10319-10325.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
Interleukin-7 in Plasma Correlates with CD4 T-Cell Depletion
and May Be Associated with Emergence of Syncytium-Inducing
Variants in Human Immunodeficiency Virus Type 1-Positive
Individuals
Anuska
Llano,
Jordi
Barretina,
Arantxa
Gutiérrez,
Julià
Blanco,
Cecilia
Cabrera,
Bonaventura
Clotet, and
José A.
Esté*
Retrovirology Laboratory irsiCaixa, Hospital
Universitari Germans Trias i Pujol, Universitat Autònoma de
Barcelona, 08916 Badalona, Spain
Received 11 January 2001/Accepted 26 July 2001
 |
ABSTRACT |
Human immunodeficiency virus type 1 (HIV-1) primary infection is
characterized by the use of CCR5 as a coreceptor for viral entry, which
is associated with the non-syncytium-inducing (NSI) phenotype in
lymphoid cells. Syncytium-inducing (SI) variants of HIV-1 appear in
advanced stages of HIV-1 infection and are characterized by the use of
CXCR4 as a coreceptor. The emergence of SI variants is accompanied by a
rapid decrease in the number of T cells. However, it is unclear why SI
variants emerge and what factors trigger the evolution of HIV from R5
to X4 variants. Interleukin-7 (IL-7), a cytokine produced by stromal
cells of the thymus and bone marrow and by keratin, is known to play a key role in T-cell development. We evaluated IL-7 levels in plasma of
healthy donors and HIV-positive patients and found significantly higher
levels in HIV-positive patients. There was a negative correlation between circulating IL-7 levels and CD4+ T-cell count in
HIV-positive patients (r = 
0.621;
P < 0.001), suggesting that IL-7 may be involved
in HIV-induced T-cell depletion and disease progression. IL-7 levels
were higher in individuals who harbored SI variants and who had
progressed to having CD4 cell counts of lower than 200 cells/µl than
in individuals with NSI variants at a similar stage of disease. IL-7
induced T-cell proliferation and up-regulated CXCR4 expression in
peripheral blood mononuclear cells in vitro. Taken together, our
results suggest a role for IL-7 in the maintenance of T-cell
regeneration and depletion by HIV in infected individuals and a
possible relationship between IL-7 levels and the emergence of SI variants.
| |
INTRODUCTION |
Human immunodeficiency virus type 1 (HIV-1) primary infection is characterized by the presence of
non-syncytium-inducing (NSI) variants with low replication kinetics,
capable of infecting macrophages and CD4+ memory
T cells, that use the receptor CCR5 as a coreceptor for viral entry
(21). Later, as the disease progresses, the
syncytium-inducing (SI) variants emerge (2). SI variants
are characterized by high replication kinetics in vitro and the
capacity to infect naive CD4+ T cells by using
CXCR4 as a coreceptor (4, 26). The emergence of SI
variants is accompanied by an accelerated decrease of
CD4+ cell count, rapid disease progression, and
the establishment of AIDS (10, 13). However, it remains
unclear why SI variants emerge and how this relates to CXCR4 expression
in vivo. It is probable that multiple host factors affect HIV-1
coreceptor levels or function; interleukin-4 (IL-4) has been shown to
decrease the expression of CCR5 and increase CXCR4 expression, favoring
the propagation of X4 strains (42). Other factors that may
induce overexpression of CXCR4 or block the replication of R5-NSI
variants may favor the selection of X4-SI HIV variants and could
determine when SI variants will arise.
During clinical latency, HIV-1 replicates, inducing the destruction of
CD4+ T cells and immature cells in the bone
marrow, thymus, and lymph nodes, where T cells are produced
(25). The immune system responds by inducing the
proliferation of T cells, and hence the CD4+
T-cell number is maintained relatively constant during this stage of
the infection (11, 20, 23, 43). The development of AIDS
was thought to be caused by exhaustion of the immune system. That is,
at a certain point, the immune system cannot maintain the high rate of
T-cell production necessary to compensate for HIV-induced T-cell
depletion (27). Nevertheless, HIV-1 infection destroys
T-cell supplies in the periphery by direct infection and killing of
cells and through hyperactivation of the immune system
(15), suggesting that it may be not exhaustion but rather homeostatic inability, along with gradual wasting of T-cell supplies, that leads to T-lymphocyte depletion in HIV-1 infection (16, 17).
It is known that cytokines play an important role in HIV-1 infection.
However, determination of their function in viral dynamics, replication, and disease progression is very complex, because different
cytokines have opposite effects on viral replication (19, 24, 32,
34, 42). IL-7 is a cytokine produced by stromal cells of the
thymus and the bone marrow and by keratinocytes (18, 38, 39,
45). IL-7 has recognized functions in B-cell lymphopoiesis
(30) and has been shown to take part in the
differentiation of thymocytes into mature T cells that will leave the
thymus and move to the periphery (7, 29). Similarly, IL-7
contributes to the development, proliferation, and homeostatic
maintenance of T cells (12, 14, 33, 35, 40). IL-7 is known
to enhance viral replication (6, 41) and may induce CXCR4
expression on resting CD4+ memory T cells in
vitro (22). IL-7 production by human stromal cells is
induced by IL-1 and by tumor necrosis factor alpha (44), which have been found to also enhance HIV production in vitro (32).
The role of IL-7 as a marker of disease progression has not been well
established. Napolitano et al. (31) have shown that increased circulating levels of IL-7 are strongly associated with CD4+ T lymphopenia in HIV-1 disease.
Nevertheless, the importance of these results to the understanding of
HIV pathogenesis requires further confirmation. Furthermore, we need to
assess the effect of IL-7 on the evolution of HIV in vivo.
We have evaluated IL-7 levels in plasma of healthy individuals and
HIV-1-infected patients and correlated their expression in HIV-positive
individuals to CD4+ T-cell depletion, disease
progression, and emergence of the SI phenotype.
| |
MATERIALS AND METHODS |
Patient and donor samples.
Blood samples from healthy donors
and from HIV-positive individuals were collected from our hospital
blood blank and from the HIV unit, respectively. Samples were collected
with informed consent and processed immediately after collection.
Briefly, 10 to 20 ml of whole blood was collected in EDTA-Vacutainer
tubes (Becton Dickinson [BD], Madrid, Spain). Plasma was isolated
from each sample after centrifugation of blood samples at 400 × g for 10 min and was immediately cryopreserved and
stored at 80°C until use. Peripheral blood mononuclear cells (PBMC)
were obtained by separation on Ficoll-Hypaque density gradient and
either used immediately in fractional studies or cryopreserved in
liquid nitrogen for further determinations. Some patients were
enrolled in clinical trials with monotherapy (zidovudine [AZT] or
dideoxyinosine [ddI]) or dual therapy (AZT plus dideoxycytosine, AZT
plus ddI, or AZT plus lamivudine [3TC]) and were later included in
triple antiretroviral therapy. These patients usually initiated
treatment at a late stage of disease and the treatment options were not
efficacious, increasing the possibility selecting SI variants.
T-lymphocyte proliferation.
Fresh PBMC
(106) from two healthy donors were cultured with
different antigens as follows: medium control, phytohemagglutinin (PHA)
(4 ng/ml) plus IL-2 (4 ng/ml) as a positive control, PHA plus
IL-2 plus IL-7 (10 ng/ml), and IL-7 alone (1 and 10 ng/ml). The
cultures were maintained at 37°C in a 5% CO2
incubator for 5 days. [3H]thymidine was then
added to each well and incubated overnight. The cells were harvested,
and the amount of incorporated [3H]thymidine
was measured in a liquid scintillation counter (1450 Microbeta; Wallac,
Turku, Finland). The stimulation index was calculated by dividing the
counts per minute of PBMC after specific stimulation by the counts per
minute of PBMC incubated with medium control. A stimulation index of
>5 was considered to be a positive response in this assay.
CXCR4 expression.
Fresh PBMC from healthy donors were
cultured with IL-7 at different concentrations and with stromal
cell-derived factor 1 (SDF-1) (500 ng/ml) or medium alone as controls.
After 5 days of incubation, PBMC were collected and CXCR4 and CD4
expression was analyzed by flow cytometry as described below.
Detection of IL-7 and RANTES levels in plasma.
Plasma IL-7
levels were determined by an ultrasensitive commercial enzyme-linked
immunosorbent assay (ELISA) (Quantikine HS Human IL-7 Immunoassay; R&D
Systems, Minneapolis, Minn.) according to the manufacturer
instructions. RANTES levels were measured by a commercial ELISA
(Endogen, Barcelona, Spain).
Viral isolation and phenotype in MT-2 cells.
PBMC (10 × 106) from HIV-infected individuals were
cocultured with PBMC (5 × 106) from healthy
donors stimulated with 3 µg of PHA per ml and 25 IU of IL-2 per ml.
Viral replication was quantified by evaluation of antigen p24
production in coculture supernatants, using a commercial ELISA
(Innogenetics, Madrid, Spain). Coculture supernatants that were
positive for p24 were collected after centrifugation at 400 × g for 5 min, and the SI or NSI phenotype was
determined in MT-2 cells as was previously described (9).
For simplicity, individuals from whom SI or NSI variants were isolated
are referred to hereafter as SI or NSI individuals, respectively.
Flow cytometry.
CD4+ and
CXCR4+ T-cell subpopulations were determined by
flow cytometry analysis. Aliquots of 50 µl of whole-blood samples
were stained with monoclonal antibodies CD4-PerCP and CXCR4-PE (BD) for
15 min, and then the samples were washed twice in phosphate-buffered saline, resuspended in phosphate-buffered saline containing 1% formaldehyde, and analyzed in a FACScalibur flow cytometer (BD).
Measurement of viral load.
Plasma HIV RNA levels were
determined using a commercial assay (Amplicor VIH-1 Monitor Assay;
Roche Molecular Systems, Somerville, N.J.) according to the
manufacturer's instructions. Undetectable levels of RNA in plasma were
considered equivalent to 200 copies/ml.
Statistical analysis.
Statistical analysis was performed
using parametric and nonparametric tests (Spearman r and
Mann-Whitney U tests). P values of <0.05 were considered to
have statistical significance. Data were analyzed using the SPSS
version 9.0 software package.
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RESULTS |
T-lymphocyte proliferation.
IL-7 has been described as an
indispensable factor for T-cell development (33). As can
be observed in Fig. 1, IL-7 induced the
proliferation of T cells at 10 ng/ml (stimulation index = 11) and
boosted PHA- and IL-2-induced cell proliferation activity in vitro,
confirming a known property of this cytokine. Our data support previous
studies in which IL-7 has been described as an important agent in
T-cell proliferation (14).
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FIG. 1.
Lymphocyte proliferative response to PHA (4 µg/ml)
plus IL-2 (4 ng/ml), PHA plus IL-2 plus IL-7 (10 ng/ml), and IL-7 alone
(1 or 10 ng/ml). The stimulation index was calculated by dividing the
counts per minute of PBMC in stimulated wells by the counts per minute
of PBMC in medium alone. The results are from a representative
experiment of two performed.
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IL-7 up-regulates CXCR4 expression in vitro
To
determine if IL-7 modulates CXCR4 expression in T cells, we incubated
PBMC of two uninfected donors for 5 days with different concentrations
of this cytokine. IL-7 up-regulated the expression of the CXCR4
receptor in a dose-dependent manner, whereas SDF-1, the natural ligand
of CXCR4, down-regulated CXCR4 expression (Fig. 2A). Although IL-7 caused the greatest
up-regulation of CXCR4 expression at 100 ng/ml (Fig. 2B), 0.1 ng/ml was
sufficient to up-regulate CXCR4 expression in vitro. However, CD4
expression was not modified by IL-7 (Fig. 2B). This finding suggests a
possible role of IL-7 in selection of SI variants in HIV-positive
patients with high IL-7 levels in plasma through up-regulation of
CXCR4.
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FIG. 2.
(A) Effect of IL-7 and SDF-1 on expression of CXCR4 in
PBMC. IL-7 was evaluated at concentrations of 100, 10, 1, and 0.1 ng/ml. SDF-1 was evaluated at 500 ng/ml. CXCR4 expression is
represented as mean fluorescence intensity (MFI). (B) Comparison of
CXCR4 and CD4 expression in PBMC from a healthy donor, either
stimulated with 100 ng of IL-7 per ml (thick lines) or without
stimulation (thin lines). The results are from a representative
experiment of two performed.
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IL-7 levels in HIV-1-infected patients and healthy donors.
IL-7 levels in 49 plasma samples from healthy volunteers and in 131 plasma samples from HIV-positive patients were analyzed in a
cross-sectional study. The HIV-positive group had significantly (P < 0.001) higher levels of IL-7 than the healthy
donor group (Fig. 3). The IL-7 levels
measured in plasma were 3.6 ± 3.05 and 9.4 ± 5.7 pg/ml
(means and standard deviations [SD]) for the healthy donor and
HIV-positive groups, respectively. Other immunological and virological
characteristics were evaluated for HIV-positive patients, with the
findings that the means and SD of CD4 and CD8 T-cell counts and the
log10 viral load were 243 ± 221 cells/µl, 796 ± 586 cells/µl, and 5.26 ± 5.5 copies/ml,
respectively. RANTES levels were evaluated for healthy donors
(12.7 ± 16.1 ng/ml) and HIV-positive patients (27.7 ± 21.2 ng/ml); the differences between the groups were significant
(P < 0.001), as previously described (1).
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FIG. 3.
Expression of IL-7 levels in plasma of healthy donors
and HIV-positive patients. Results are depicted in box plot diagrams,
where the box represents the 25th and 75th quartiles and the line
represents the median value. Bars indicate 5th and 95th percentiles,
and circles indicate atypical values. The means ± SD of IL-7
levels in plasma for the healthy donor group and the HIV-positive
patient group were 3.6 ± 3.05 and 9.4 ± 5.7 pg/ml,
respectively.
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IL-7 as a marker of disease progression.
It has been recently
shown that increased production of IL-7 accompanies HIV-1-mediated
T-cell depletion (31) Similarly, we have found a clear
negative correlation between IL-7 levels in plasma and absolute
CD4+ T-cell counts in HIV-positive individuals
(r = 0.621; P < 0.001) (Fig.
4A). A similar but weaker correlation was
found between IL-7 levels and CD8+ T-cell levels
(r = 0.406; P < 0.001) (Fig. 4B).
When we grouped HIV-positive individuals according to their
immunological status (that is, stratifying HIV-positive patients
according to their CD4+ T-cell count) (Fig. 4C),
the subset with <200 CD4 cells/µl had significantly
(P < 0.001) higher levels of IL-7 in plasma
(12.26 ± 5.86 pg/ml) than the subsets with CD4 cell counts of
between 200 and 500 and above 500 cells/µl (6.67 ± 4.10 and
5.69 ± 2.75 pg/ml, respectively). These data suggest that
CD4+ T-cell depletion, caused by HIV-1
replication, may alter IL-7 levels in plasma as a means to regenerate
T-cell numbers.
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FIG. 4.
(A and B) Correlation between IL-7 levels and CD4 T-cell
count (r = 0.621) (A) and between IL-7 levels and
CD8 T-cell count (r = 0.406) (B) in HIV-positive
patients. (C) Levels of IL-7 in plasma of HIV-positive patients
stratified according to CD4 T-cell count in three subsets, i.e., <200,
200 to 500, and >500 CD4 cells/µl. The means ± SD of IL-7
levels in plasma for the three subsets were 12.26 ± 5.9, 6.67 ± 4.1, and 5.69 ± 2.7 pg/ml, respectively. Subsets are
depicted in box plots as described for Fig. 3.
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IL-7 as a marker for the emergence of the SI phenotype.
PBMC
from HIV-positive individuals were cocultured with PBMC from healthy
donors to isolate virus. HIV-1 p24 antigen-containing supernatant from
each coculture was then used for evaluation of the SI phenotype in MT-2
cells. Fifty-six samples tested as SI, and 75 samples tested as NSI.
When we analyzed IL-7 levels in the HIV-positive group separated into
groups that harbored SI and NSI viruses, we found significantly
(P < 0.001) higher levels of IL-7 in the SI group
(13 ± 6 pg/ml) than in the NSI group (7 ± 4 pg/ml) (Table
1; Fig.
5A). Significant differences were also found between the SI group and the NSI group in
CD4+ T-cell count, CD8+
T-cell count, and viral load, suggesting a more advanced stage of
disease in the SI group than in the NSI group. There were no significant differences in RANTES levels between the groups.
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FIG. 5.
(A) IL-7 levels in plasma in HIV-positive patients
separated according to the viral phenotype (SI or NSI). IL-7 levels are
depicted in a box plot as described for Fig. 3. (B and C) Linear
regression between IL-7 levels and CD4 T-cell counts in patients of the
SI group (r = 0.522) (B) and the NSI group
(r = 0.293) (C). (D) Levels of IL-7 in plasma of
HIV-positive individuals of the SI and NSI groups stratified according
to CD4 T-cell count in three subsets as described for Fig. 4C.
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We correlated CD4
+ T-cell counts with IL-7 levels
separately in the SI and NSI groups, finding a higher correlation
between
the two parameters in the SI group (
r =
0.522;
P < 0.001) than
in the NSI group
(
r =
0.293;
P = 0.014) (Fig.
5B and
C).
Since HIV disease may progress in the absence of the SI phenotype, it
was important to compare IL-7 levels between individuals
in the NSI or
SI group in a similar stage of disease. Thus, we
stratified the
individuals of both groups according to their CD4
T-cell count (Fig.
5D). The NSI group showed no significant differences
in IL-7 levels in
the three subsets of CD4 levels (7.3 ± 3.2,
6.3 ± 4, and
5.7 ± 2.9 pg/ml). In contrast, in the SI group, we
found
significantly (
P < 0.001) higher levels of IL-7
(14.6 ±
5.4 pg/ml) in the subset with the lower CD4 cell count
(<200 cells/µl)
than in the two other subsets (7.8 ± 4.5 and
5.6 ± pg/ml, respectively).
It is interesting that the SI subset
with a CD4 cell level of
<200 cells/µl showed significantly
(
P < 0.001) higher levels of
IL-7 than the NSI subset
with a similar CD4 cell count, whereas
there were no significant
differences in IL-7 levels between the
NSI and the SI groups when the
CD4 cell count was above 200 cells/µl.
High IL-7 levels are associated with SI variants.
To
characterize the IL-7 level in plasma as a marker of the emergence of
the SI phenotype, we stratified patients according to the IL-7 level in
plasma (Fig. 6) The results showed that
89% of individuals with more than 13 pg of IL-7 per ml belonged to the
SI group and that this decreased to 32 and 22% when IL-7 levels were
below 13 and 2 pg/ml, respectively. The 78% of the individuals with
IL-7 levels below 2 pg/ml belonged to the NSI group. As the IL-7 level
increased (2 to 13 pg/ml and >13 pg/ml), the proportion of NSI
individuals was lower (68 and 11%, respectively). Thus, the IL-7 level
in plasma may be a marker for the emergence of the SI phenotype.
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FIG. 6.
Percentages of individuals belonging to the SI and NSI
groups, stratified according to the levels of IL-7 in plasma in three
subsets (<2, 2 to 13, and >13 pg/ml.
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Longitudinal study.
A longitudinal study was designed to
evaluate changes in IL-7 levels with respect to standard virological
and immunological markers of HIV-1 disease (viral load and CD4
cell count) and to better characterize IL-7 as a marker of disease
progression. Frozen plasma samples that were collected from five
HIV-positive individuals for a period of 2 to 7 years were used to
evaluate IL-7 levels in plasma. Patients were selected on the basis of
availability of plasma samples taken at least every 3 months for the
period of the study, in which IL-7 levels and viral load could be
evaluated. All patients had received antiretroviral therapy during the
course of the disease; therefore, the CD4+ T-cell
count, viral load, and IL-7 levels in plasma were expected to be
influenced by drug treatment. In Fig. 7,
we show IL-7, CD4+ T-cell count, and viral load
trends for two patients as a representative sample of the longitudinal
study. In patient A, a decrease in IL-7 level corresponded to an
increase in CD4 T-cell count and to a decrease in viral load,
indicating an effective response to the treatment with
indinavir. The data for patient B revealed biphasic trends in the
measured parameters; that is, this patient did not respond
satisfactorily to the first treatment with double therapy (AZT plus
3TC), which caused a initial increase in IL-7 level and in viral load
and a decrease in CD4 T-cell count. After 2 years the patient began
receiving triple antiretroviral therapy, which caused a decrease in
viral load and in IL-7 levels and an increase in CD4 T-cell count.
Taken together, these data suggest that the plasma IL-7 level may be an
effective marker of disease progression in HIV-positive patients.
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FIG. 7.
IL-7 levels, CD4 T-cell counts, and log10
viral load in two patients along the course of the longitudinal study.
In patient A, time zero corresponds to the initiation of treatment (AZT
plus ddI plus 3TC plus indinavir). In patient B, time zero corresponds
to the initiation of the first treatment (AZT plus 3TC plus d4T), which
was continued for 2 years; the second treatment (AZT plus 3TC plus d4T
plus indinavir) (time of initiation is shown by the arrowhead) covers
the following 2 years. The lines represent the trends calculated by
linear regression.
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DISCUSSION |
In our cross-sectional study, we have found a significant
difference in plasma IL-7 levels between HIV-negative donors and HIV-positive patients. Confirming recently published results (12, 31), we have found a negative correlation between IL-7 levels in
plasma and CD4+ T-cell counts in HIV-positive
patients (r = 0.621), suggesting that HIV infection
may mask the proliferative effect of IL-7 (Fig. 1) (31).
In addition, a longitudinal study with HIV-positive patients showed
that variations in CD4+ T-cell counts caused by
the response to treatment were accompanied by similar variations in
plasma IL-7 levels. These data support the idea of IL-7 as an indicator
of CD4+ T-cell depletion and consequently as a
marker of disease progression.
There is controversy about the origin of the T-cell renewal that
compensates for T-cell depletion in HIV infection. Some evidence points
to a persistent immune activation induced by viral replication that
causes proliferation of existing naive CD4+ T
cells in the periphery (16). Other evidence points to
thymic output of new naive T cells (8, 29) caused by a
homeostatic response to T-cell depletion. Previous observations have
associated abundant thymic tissue in HIV-positive individuals with
increased numbers of naive T cells (8, 36). Since IL-7 is
produced by stromal cells of the thymus and is implicated in thymocyte maturation, our data may indicate a homeostatic response that is
mediated by IL-7. Alternatively, IL-7 produced by extrathymic tissue or
induced by other factors (e.g., tumor necrosis factor alpha) could
explain the observations made here. The fact that some individuals with
<200 CD4 cells/µl have low IL-7 levels in plasma may support
the latter hypothesis.
Our results suggest a relationship between IL-7 levels in plasma and
HIV phenotype, since HIV-positive patients with high IL-7 levels had a
high probability (0.89) of having the SI phenotype. It is unclear why
individuals with low CD4 cell counts of the NSI phenotype have
significantly lower IL-7 levels than those individuals with SI
variants. If IL-7 increases in response to CD4 cell depletion, NSI
individuals with CD4 cell counts of <200/µl should have plasma IL-7
levels similar to those of SI individuals in the same immunological
status. One possible explanation is that NSI and SI variants may have
different tropisms for cell subpopulations that produce IL-7 (3,
5, 37). In addition, HIV-1 may induce a collapse of the
regulatory signals that control CD4 cell number, allowing for IL-7
production without a concomitant effect on CD4 proliferation. Our data
indicate that, unlike CD4 cell counts, IL-7 levels could discriminate
between those individuals with the NSI phenotype and those with the SI
phenotype in that subset of individuals with advanced disease progression.
IL-7 may be considered a causal factor for the emergence of the SI
variants, together with other factors such as SDF-1. We have shown that
individuals with high levels of SDF-1 were at a lower risk of
developing HIV variants of the SI phenotype (28).
The immune system may respond to CD4 T-cell depletion caused by HIV
replication by inducing the proliferation of circulating naive CD4 T
cells and by producing homeostatic signals (such as IL-7) that induce
production of new naive CD4 T cells. However, at a certain time during
infection, the immune system may not be able to respond to the signals
induced by decreased CD4 T-cell number, which in turn act on existing
CD4 cells. Consequently, higher IL-7 levels may induce the
overexpression of CXCR4 (Fig. 2A), allowing SI variants to grow. High
SDF-1 levels could maintain lower expression of CXCR4 and keep SI
variants at bay, and at the same time, high SDF-1 levels could block
the effect of IL-7 and/or other factors that affect CXCR4 expression.
This hypothesis could help to explain the correlation between the
emergence of SI variants and the rapid CD4 T-cell decline and why SI
variants appear late after infection. The effect of IL-7 on CXCR4
expression could be masked by the same principle governing IL-7 and CD4
cell count: it is possible that during HIV-1 infection, increased IL-7 could lead to the selective destruction of CXCR4-expressing cells. The
regulation of CXCR4 expression appears to be governed by multiple factors that may be active at any given time and that require further study.
In conclusion, our observations on the increased production of IL-7 in
HIV-positive individuals and its correlation to T-cell depletion
suggest that IL-7 may have an important role in the maintenance of
T-cell homeostasis in HIV infection. Intrapatient IL-7 production may
be an effective marker of the disease progression and a causal factor
for the emergence of SI HIV variants.
| |
ACKNOWLEDGMENTS |
This work was supported in part by Fundación para la
Investigación y la Prevención del SIDA en España
(FIPSE) project 3111/00, Ministerio de Ciencia y Tecnología
project BFM2000-1382, and the Fundació irsiCaixa. J. Blanco is an
FIS researcher from the Fundació para la Recerca Biomédica
Hospital Germans Trias i Pujol. A. Llano and J. Barretina hold
predoctoral scholarships from FIS.
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FOOTNOTES |
*
Corresponding author. Mailing address: Fundació
irsiCaixa, Retrovirology Laboratory, Hospital Universitari Germans
Trias i Pujol, 08916 Badalona, Spain. Phone: 34-934656374. Fax:
34-934653968. E-mail: jaeste{at}ns.hugtip.scs.es.
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Journal of Virology, November 2001, p. 10319-10325, Vol. 75, No. 21
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.21.10319-10325.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.
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Top
Abstract
Introduction
