|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
IMMUNOBIOLOGY
From the Department of Immunology/Microbiology at
Rush-Presbyterian-St Luke's Medical Center, Rush University,
Chicago, IL.
Although human immunodeficiency virus (HIV)
gag/pol DNA can be detected in naive T cells,
whether naive T cells can be productively infected by HIV is still
questionable. Given that interleukin-7 (IL-7) is a prospective
therapeutic immunomodulator for the treatment of HIV, we
evaluated the effect of IL-7 on promoting naive T-cell infection
of laboratory-adapted (IIIB), M-tropic, and primary isolates of HIV.
Initially, we determined that the 3 cell surface markers widely used to
identify naive T cells (CD45RA+CD45RO CD4+ primed/memory T cells constitute
the main target for productive human immunodeficiency virus (HIV)
infection.1-3 Whether HIV productively infects naive T
cells in vivo is still controversial.4-9 Naive T cells
were shown to harbor replication-competent HIV,7,10 but
are not an active site of HIV replication in the absence of mitogen
stimulation.11 Even in studies demonstrating HIV infection of naive T cells, further analysis of integrated HIV indicated that HIV
DNA did not always integrate into the genome.5,10 Infected
naive T cells, nonetheless, have been identified in HIV-seropositive individuals,7,10 but it is unclear if such in vivo naive T cells were once primed cells that reverted to a naive
phenotype12,13 or are truly naive T cells that are infected
in vivo. In the simian immunodeficiency virus (SIV) model,
SIV RNA was detected by in situ hybridization in naive T cells,
suggesting that these cells may serve as an additional reservoir for
HIV.14 Collectively, the consensus is that naive T cells,
either in vivo or in vitro, do not support HIV productive infection
mainly because these cells exist in a quiescent stage, a concept that
is being challenged. The association between productive HIV replication
and cell turnover is presumably due to the higher level of
deoxyribonucleotides present for reverse transcription15
during cell division or due to the expression, in actively replicating
cells, of certain cellular factors that may allow for the stabilization
of the HIV preintegration complex. However, recent data
indicate that active cell division may not be required for HIV
replication. In particular, ex vivo lymphoid histocultures point to HIV
productive infection of naive T cells.16 These infected
naive T cells were in the G0/G1A phase of the
cell cycle, indicating that HIV may not require active cell replication
for productive infection as was previously thought. A similar finding
is also reported by Kinter et al.17 The mechanisms
involved in the infection of naive CD4 T cells are unclear.
Interleukin-7 (IL-7) is a cytokine produced predominately by bone
marrow and thymus stromal cells and is a critical factor in both B- and
T-cell development.18,19 IL-7 treatment can also induce
IL-2 receptor (CD25) expression on naive T cells, rendering them more
responsive to the IL-2-mediated effects.20 In vivo IL-7
treatment was shown to successfully induce immune reconstitution
following bone marrow transplantation in the mouse model, as measured
by IL-7-mediated enhancement in the proliferation of immature
thymocytes and improved survival after challenge with influenza
virus.18 IL-7 has also been shown to increase a marker of
de novo T-cell synthesis known as T-cell receptor excision circles
(TRECs) in thymic explant models,21 possibly by inducing intrathymic T-cell receptor rearrangement22,23 or by
enhancing the survival of early thymocyte
progenitors.23-25 IL-7 can also enhance the survival of
peripheral T cells by up-regulating the antiapoptosis gene,
Bcl2.24 Given that IL-7 treatment can induce naive T-cell
expansion without antigenic stimulation26,27 or differentiation28,29 and the recent reports that IL-7 is
inversely correlated with CD4 counts in HIV+
patients,30-32 we evaluated the impact of IL-7 treatment
of naive T cells on their susceptibility to HIV infection by both
T-cell-adapted and primary isolates of HIV.
Isolation of peripheral blood mononuclear cells and naive
T-cell subsets
Cytokine treatment of CD45RA+CD45RO Lymphocyte proliferation assay CD45RA+CD45RO cells were cultured in
96-well U-bottom plates at 1 × 106 cells per
milliliter in 200 µL total volume. The cells were then stimulated
with IL-2 (100 U/mL) or IL-7 (1000 U/mL). At 6 days after
stimulation, the cells were pulsed with 1 µCi (.037 MBq) 3[H]-thymidine (NEN Life Science
Products, Boston, MA) for 6 hours, then lysed and harvested
onto nitrocellulose paper by means of a plate harvester. The
amount of radioactivity was measured with a scintillation counter.
Immunostaining and flow cytometric analysis Isolated cell populations were stained immediately or after 6 days in culture for immunophenotypic analysis of T-cell surface markers by means of CD3-conjugated fluorescein isothiocyanate (FITC); CD4-conjugated phycoerythrin (PE), allophycocyanin (APC), or FITC; and CD8-conjugated peridinin chlorophyll protein (PerCP) antibodies. Cells were also stained for naive phenotypic markers for CD45RA-FITC:CD45RO-PE:CD4-PerCP; CD45RA-FITC:CD45RO-PE:CD8-PerCP:CD4-APC; CD45RA-FITC:CD62L-PE:CD4-PerCP; CD27-FITC:CD95-PE:CD45RO-PerCP). CXCR4 and CCR5 cell surface staining were performed by means of the following panel for CD4-FITC: CXCR4-PE:CD8-PerCP; CD4-FITC:CCR5-PE:CD8-PerCP. IL-7 receptor (IL-7R) staining was performed by means of CD45RA-FITC:IL-7R-PE:CD4-PerCP:CD45RO-APC, and CD45RA-FITC:IL-7R-PE:CD8-PerCp:CD45RO-APC antibodies, and the number of IL-7Rs per cell were quantified by means of quantibright beads. All values were normalized to isotope values. In some experiments, intracellular Ki-67 staining was performed by initially fixing the lymphocytes with fluorescence-activated cell sorter (FACS) lyse solution (Becton Dickinson). The fixed cells were then permeabilized by incubation with FACS permeabilization buffer (Becton Dickinson, San Jose, CA), followed by intracellular staining with Ki-67-FITC antibody and cell surface staining with CD45RO-PE and CD4- or CD8-PerCP. All monoclonal antibodies were purchased from Becton Dickinson (San Jose, CA) or PharMingen. Three- and 4-color flow cytometric analysis was performed by means of a FacsCaliber instrument and CELLQuest Software (Becton Dickinson, San Jose, CA).Quantitative polymerase chain reaction-enzyme linked immunosorbent assay for the measurement of TRECs and HIV-1 gag/pol DNA content To evaluate enrichment of naive T-cell populations (CD45RA+CD45RO,
CD45RA+CD62L+,
CD45ROCD27+CD95low) for TRECs,
total DNA from these 3 isolated populations was extracted by means of
DNAzol reagent (GIBCO BRL), as described by the manufacturer. The DNA
was amplified for coding joint TRECs, by means of a previously described quantitative polymerase chain reaction-enzyme linked immunosorbent assay (PCR-ELISA) approach.34 Briefly, 1 and
0.5 µg genomic DNA was amplified in the presence of 200 µM
digoxigenin-uridine (UTP) labeling mix; 2 µM each forward
(5'-CTAATAATAAGATCCTCAAGGGTCGAGACTGTC-3') and reverse
(5'-CCTGTTTGTTAAGGCACATTAGAATCTCTCACTG-3') primer; 1 × PCR buffer;
2.5 mM MgCl2; and 0.02 U/µL Taq polymerase
(Boehringer Mannheim, Indianapolis, IN). The PCR protocol consisted of
DNA denaturation at 95°C for 5 minutes, followed by 25 cycles of
amplification at 90°C for 30 seconds, 60°C for 30 seconds, 72°C
for 30 seconds, and a final extension step at 72°C for 7 minutes.
Cloned coding joint TRECs at various copies (500 000, 50 000, 5000 and 0) were coamplified with each PCR to serve as standards for the
assay. Precautions were taken to avoid PCR contamination.
Quantitation of the coding joint TRECs was performed by means of an
ELISA, following the manufacturer's instructions with few
modifications (Boehringer Mannheim). Briefly, 10 µL each of the
amplified product was denatured in a 96-well plate with 20 µL denaturation solution at room temperature for 10 minutes.
Subsequently, 220 µL hybridization solution containing 7.5 pmol/mL
biotin-labeled internal probe (5'-TCTGTGTCTAGCACGTAGCC-3')
(Fisher-Genosys, Woodlands, TX) was added. This mix was then
transferred to a streptavidin-coated plate and incubated at 55°C for
3 hours. After extensive washing with an ELISA wash buffer, 200 µL
antidigoxigenin peroxidase solution (1:100) was added to each well. The
plate was then incubated at 37°C for 30 minutes with gentle shaking,
washed, and exposed to 2,2-Azino-di- [3-ethylbenzthiaxoline
sulfonate] substrate solution for 30 minutes at 37°C in the
dark. Absorbance was read at 405 and 490 nm, and a standard curve of
optic density (OD) values versus copies of input standard
plasmid was generated by means of a software program (SoftMax Pro,
Molecular Devices, Sunnyvale, CA). For each PCR-ELISA reaction, the
standards were amplified in duplicates, and the mean OD was used to
quantitate the number of copies per microgram of coding joint TREC in
each of the unknown samples.
HIV-1 gag/pol DNA content was measured with a modified PCR-ELISA approach.34 Specifically, genomic DNA was extracted by means of GenomicPrep DNA isolation kit as described by the manufacturer (Amersham Pharmacia Biotech, Piscataway, NJ). The PCR mix consisted of 200 µM digoxigenin-UTP labeling mix; 1 × PCR buffer; 2.5 mM MgCl2; 2 µM each forward (SK38) (5'-ATAATCCACCTATCCCAGTAGGAGAAAT -3') and reverse (SK39) (5'-TTTGGTCCTTGTGTTATGTCCAGAATGC-3') primer (Fisher-Genosys), which recognize conserved sequences in HIV gag/pol genome; 1 or 0.5 µg genomic DNA; and 0.02 U/µL Taq polymerase (Boehringer Mannheim). PCR cycling consisted of DNA denaturation at 95°C for 5 minutes, followed by 30 cycles of amplification at 90°C for 30 seconds, 60°C for 30 seconds, 72°C for 30 seconds, and a final extension step at 72°C for 7 minutes. Specified amounts of HIV-1 gag/pol DNA were generated from the 8E5 cell line, which consists of one proviral copy per cell. The HIV gag/pol standards were used at 25 000, 10 000, 6000, 2000, 1000, 500, and 0 copies and were coamplified with each PCR run. Subsequently, hybridization solution containing 7.5 pmol/mL biotin-labeled internal probe (SK19) (5'-ATCCTGGGATTAAATAAAATAGTAAGAATGTATAGCCCTAC-3') (Fisher-Genosys) was used for ELISA quantitation, as described.34 HIV-1 infection Phytohemagglutinin (PHA)-stimulated PBMCs or purified CD45RA+ CD45RO naive T cells were infected
with HIV IIIB, Bal, and primary isolates (302 056, 302 073,
302 142, 302 144, National Institutes of Health, AIDS
Research and Reference Reagent program, Bethesda, MD) at 2 ng HIV p24
per 1 × 106 cells for 2 hours at 37°C. Subsequently,
HIV-exposed cultures or mock-infected cultures were washed twice to
remove unbound virus and cultured in the presence of IL-2 or IL-7. HIV
primary isolates were determined to use CCR5 and not CXCR4 by
genetically engineered cell line (ghost cell)
analysis.35 HIV infection was performed either at
day 0 of culture or 6 days after IL-2 or IL-7 treatment. HIV-1
infection was monitored by quantitation of p24 antigen in culture
supernatants, by means of an HIV-1 p24 ELISA (AIDS Vaccine Program,
Frederick, MD), or by measurement of HIV gag/pol DNA content
with the PCR-ELISA approach described earlier.
CD45RA+CD45RO ,
CD45RA+CD62L+, and
CD45ROCD27+CD95low, yet there is
no clear understanding of which phenotype best represents naive T
cells. Prior to studies to evaluate the impact of IL-7 on
naive T-cell susceptibility to HIV infection, we conducted comparative
analysis of these 3 phenotypes to evaluate which phenotype is enriched
for recent thymic emigrants; to this end, we used the TREC assay, which
measures a byproduct of T-cell receptor rearrangements to generate
episomal DNA deletion circles known as TRECs. These TRECs are
diluted with each round of cell division and serve as markers of de
novo T-cell synthesis, when cell turnover is normalized, or as
markers of the replicative history of the cells (reviewed in Steffens
et al36). We hypothesized that the phenotype that is best
enriched in TRECs will be closely associated with the naive phenotype.
CD45RA+CD45RO were isolated by means of
multiple immunoselection steps to purify these populations (Figure
1A). The cells were evaluated for TREC DNA content by means of a quantitative PCR-ELISA
approach.34 TREC content was equivalent in these 3 phenotypes (P = .67; Figure 1B). Furthermore, flow
cytometric studies indicated that enrichment for the
CD45RA+CD45RO phenotype simultaneously
enriched for the CD45RA+CD62L+ and
CD45ROCD27highCD95low populations
(Figure 1C; P = .09). These comparative data
provided a rationale for the use of
CD45RA+CD45RO phenotype in all subsequent
studies, given that the 3 populations are equivalent in TREC content
and that CD45RA+CD45ROcells were the simplest
to purify.
Impact of IL-7 treatment on naive cell proliferation and maintenance of the naive phenotype IL-7 has been reported to stimulate the proliferation of naive T cells without acquiring the primed (CD45RO) phenotype.26 We have also confirmed this finding in our IL-7-treated naive T-cell cultures. Specifically, highly purified adult naive (CD45RA+CD45RO) T cells were
treated with IL-2 (100 U/mL), IL-7 (1000 U/mL), or PHA (4 µg/mL) or
left untreated, and CD45RA+CD45RO expression
was evaluated by flow cytometry on days 0, 3, and 6. IL-7 treatment,
like IL-2-treated cells, did not significantly alter the expression of
the naive CD45RA+CD45RO phenotype, while PHA,
as expected, decreased the level of unprimed T cells
(CD45RA+CD45RO) by 53% after 6 days in
culture (Figure 2A). To confirm that CD45RA+CD45RO naive cells were proliferating
in response to treatment with IL-7 without the acquisition of the
primed (CD45RO) phenotype, we evaluated cellular proliferation using
both a lymphocyte proliferation assay (LPA) and intracellular staining
for Ki67, a nuclear antigen associated with cells in G1, S,
M, or G2 phases of cell cycle but not in G0. At
6 days after IL-7 treatment, the naive T cells exhibited an
approximately 7-fold increase in 3[H]-thymidine
incorporation over unstimulated controls (Figure 2B). While the LPA
response to PHA was diverse, with some donors exhibiting a higher level
of thymidine incorporation than others, IL-7-treated naive T cells
were more uniform in their response to IL-7-mediated cell
proliferation. Intracellular Ki67 staining of IL-7-treated naive T
cells, in contrast to IL-2-treated cultures, demonstrated a greater
degree of proliferation of naive T cells, without the acquisition of
the primed (CD45RO) phenotype (Figure 3).
However, only a small subset of IL-7-treated naive T cells were
proliferating. Specifically, 8% of the total lymphocytes treated with
IL-7 were Ki67+ and CD45RO (Figure 3Ai), and
none of these proliferating (Ki67+) cells had switched to
CD45RO+ phenotype after 6 days in culture (Figure
3Aiv-Avi). Of these IL-7-treated naive T cells, the majority of the
proliferating cells were CD8+ cells (Figure 3Aiii) rather
than CD4+ T cells (Figure 3Aii), albeit CD4+
cells were also proliferating in response to IL-7 treatment. In
contrast, all PHA-treated cells switched to the CD45RO phenotype (Figure 3Aiv-Aix), but the majority were Ki67 (Figure
3Avii-Aix), which may be due to the fact that the expression of Ki67 is
degraded after the cells have completed the cell cycle and that by 6 days of PHA stimulation, the majority of the cells have already
divided.
IL-7 promotes both T-tropic and M-tropic HIV replication in naive T cells We evaluated the susceptibility of IL-2- and IL-7-treated naive T cells to HIV infection by T-tropic (IIIB) and primary isolates (strain 302 144 and 302 142). Receptor usage of the primary isolates was confirmed by ghost cell analysis. CD45RA+CD45RO cells were then isolated and
exposed to DNase-treated T-tropic or primary HIV strains; after
extensive washing, the cells were propagated in the presence of IL-2 or
IL-7. At 6 days after infection, HIV p24 was measured by means of a
standard ELISA. Both untreated, IL-2-treated, and IL-7-treated
cultures were not productively infected, as indicated by undetectable
p24 (data not shown). To investigate whether HIV may be rescued from
naive T cells after cytokine treatment,
CD45RA+CD45RO naive cells were infected as
described above, cultured for 3 days with or without cytokine (IL-7 or
IL-2) stimulation, and then cocultured with PHA-stimulated PBMCs
depleted of CD8+ T cells. HIV productive infection still
could not be rescued from naive T cells. This finding is in support of
a study by Roederer et al,11 which demonstrated that HIV
may not be rescued from naive T cells even after stimulation
(anti-CD3/anti-CD28).
Given that IL-7 induces the proliferation of some of the naive cells,
which may be a prerequisite for productive HIV infection, we evaluated
the impact of IL-7 pretreatment of naive T cells to induce their
susceptibility to productive HIV infection.
CD45RA+ CD45RO
We also evaluated HIV gag/pol DNA content from representative IL-7-pretreated and infected cultures (Figure 4B). HIV gag/pol DNA content of HIV IIIB from IL-7-pretreated, infected cells (41 000 copies per microgram) was considerably more than that of primary isolates (16 000 and 4000 copies per microgram), yet the p24 values from primary isolate-infected cultures (5000 and 2500 pg/mL) was much higher than the T-tropic-infected cultures (1000 pg/mL). These data suggest that most of the DNA in IL-7-treated T-tropic-infected cultures may be unintegrated and thus account for the lower p24 measured, whereas the majority of primary isolates may be integrated. IL-2 pretreatment, on the other hand, did not promote HIV replication (Figure 4A) and did not increase HIV entry since HIV gag/pol content remained relatively the same with or without IL-2 pretreatment (Figure 4B). Finally, the virions released from IL-7-pretreated naive T cells were also infectious as the supernatants from IL-7-pretreated/HIV IIIB-infected cells productively infected PHA-stimulated PBMCs (Figure 4C). It is important to note that while the ability of IL-7 to mediate HIV
productive infection of naive T cells was observed in 4 healthy donors,
2 healthy donors did not respond to this IL-7 effect. To examine
whether IL-7R levels differed between donors that responded to
IL-7 (n = 4) and those that did not (n = 2), we measured IL-7R
levels from all donors and determined that IL-7R levels were comparable
in the 2 groups as evaluated on CD4+ and CD8+
naive T cells (Figure 5), and no
correlation was found between nonresponders and IL-7R levels.
Specifically, median IL-7R levels on CD4+ naive T cells
from responders was at 723 molecules per cell versus 838.5 molecules
per cell on nonresponders. These data suggest that the block to IL-7
responsiveness in a few donors is downstream of IL-7R expression and
may be due to the lack of another factor (or factors) that contributed
to their lack of permissiveness to IL-7-mediated HIV replication in
naive T cells.
Impact of IL-7 treatment on CXCR4 and CCR5 expression on
CD45RA+CD45RO naive
T cells were cultured in the presence or absence of IL-7 or IL-2
stimulation, and the kinetics of CXCR4 and CCR5 expression was
monitored for 6 days in culture. IL-7 mediated the up-regulation of
CXCR4, which was evident at day 2 after stimulation and gradually increased thereafter (Figure 6). In
IL-7-treated naive T cells, the level of up-regulation of CXCR4 was
greater on CD8+ T cells than CD4+ T cells
(Figure 6Aii-Aiii). IL-2, on the other hand, did not seem to
significantly alter CXCR4 expression on naive T cells, as the level of
CXCR4 on IL-2-treated naive T cells was similar to untreated cultures
(Figure 6Ai-Aiii). The level of CCR5 expression on untreated naive T
cells was below the detection limits of flow cytometry and was not
augmented by IL-7 or IL-2 treatments (Figure 6Biv-Bvi). This observed
impact of IL-7 treatment on CXCR4 and CCR5 expression on naive T cells
was consistent in all donors examined, regardless of their
infection outcome.
In advanced stage of HIV disease, it is still unclear which cell
type or types contribute to the propagation of HIV when
CD4+ T cells are at their lowest numbers and the viral load
is at its highest values. Naive T cells are not classically associated with potent virion release. At best, HIV may latently infect naive T
cells, but a secondary signal such as mitogen stimulation is required
to induce HIV replication in naive T cells. We evaluated the
susceptibility of naive T cells to HIV infection. Initially, we
validated the phenotype of naive T cells using the TREC assay. Three
phenotypes (CD45RA+CD45RO Others have reported that IL-7 mediates the expansion of
CD4+ T cells without T-cell receptor engagement or the
acquisition of the primed (CD45RO) phenotype.26-28,42 We
validated this observation using flow cytometric analysis, LPA assay,
and Ki67 staining. We have shown that IL-7, unlike IL-2 or PHA
treatment of naive T cells, induces the expansion of the naive T cells
while maintaining their naive phenotype
(CD45RA+CD45RO Although IL-7 up-regulated CXCR4, we believe that the IL-7-mediated
productive infection of HIV may not be strictly at the level of
enhanced entry. Alternative/additional mechanism(s) may be involved for
the following reasons: (1) IL-7 did not up-regulate CCR5, yet M-tropic
HIV replicated well in IL-7-pretreated
CD45RA+CD45RO Recent studies have suggested that IL-7 may contribute to the restoration of homeostasis following T-cell depletion,30-32 as IL-7 induces the proliferation of immature thymocytes, protects developing cells from apoptosis by up-regulation of bcl-2,24 and can act as a mobilizer of T-cell precursors.42 IL-7 has also been shown to play an important role in the restoration of lymphopenia after bone marrow transplantation47 and other T-cell-depleted conditions.48 Interestingly, recent reports have correlated increased serum IL-7 levels with HIV-mediated T-cell depletion and increased viral load,30-32 associating augmented levels of IL-7 with both viral replication and T-cell reconstitution. Collectively, these studies point to an important role for IL-7 in the response to and progression of HIV disease. Our finding that IL-7 can induce productive HIV infection of naive T cells in some donors suggests that it may also play a role in T-cell depletion and contribute to the observed inverse relationship between viral load and CD4 counts.30-32 A high level of provirus in CD4+CD45RA+ cells from neonates is associated with rapid disease progression in infants.9 IL-7 may play an in vivo role in promoting the susceptibility of naive T cells from adults or neonates to HIV productive infection. Studies examining the mechanism(s) of refractoriness to the IL-7-mediated effect, despite normal levels of IL-7R in some donors, will be critical in identifying key cellular or genetic factors that may play a role in the outcome of the response. Future use of IL-7 as an immune modulator to promote immune reconstitution of HIV-infected patients should take into consideration that IL-7 can promote the susceptibility of naive T cells from some donors to HIV productive infection.
We thank Dr Richardson Fleuridor for assistance with statistical analysis. C.M.S. and E.Z.M. are PhD candidates at Rush University (Chicago, IL), and this work is submitted in partial fulfillment of the requirement for the PhD.
Submitted September 26, 2001; accepted December 19, 2001.
Supported by American Foundation for AIDS Research (amFAR 02634-26-RGI and 02682-28-RGI) and Elizabeth Glaser Pediatric AIDS Foundation (PG-51112).
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: Lena Al-Harthi, Rush-Presbyterian-St Luke's Medical Center, Department of Immunology/Microbiology, 1653 W Congress Pkwy, Rm 1577 JSC, Chicago, IL 60612; e-mail: lalharth{at}rush.edu.
1. Chun TW, Carruth L, Finzi D, et al. Quantification of latent tissue reservoirs and total body viral load in HIV-1 infection. Nature. 1997;387:183-188[CrossRef][Medline] [Order article via Infotrieve].
2.
Schnittman SM, Lane HC, Greenhouse J, Justement JS, Baseler M, Fauci AS.
Preferential infection of CD4+ memory T cells by human immunodeficiency virus type 1: evidence for a role in the selective T-cell functional defects observed in infected individuals.
Proc Natl Acad Sci U S A.
1990;87:6058-6062 3. Cayota A, Vuillier F, Scott-Algara D, Feuillie V, Dighiero G. Differential requirements for HIV-1 replication in naive and memory CD4 T cells from asymptomatic HIV-1 seropositive carriers and AIDS patients. Clin Exp Immunol. 1993;91:241-248[Medline] [Order article via Infotrieve]. 4. Helbert MR, Walter J, L'Age J, Beverley PC. HIV infection of CD45RA+ and CD45RO+ CD4+ T cells. Clin Exp Immunol. 1997;107:300-305[CrossRef][Medline] [Order article via Infotrieve].
5.
Woods TC, Roberts BD, Butera ST, Folks TM.
Loss of inducible virus in CD45RA naive cells after human immunodeficiency virus-1 entry accounts for preferential viral replication in CD45RO memory cells.
Blood.
1997;89:1635-1641
6.
Riley JL, Levine BL, Craighead N, et al.
Naive and memory CD4 T cells differ in their susceptibilities to human immunodeficiency virus type 1 infection following CD28 costimulation: implications for transmission and pathogenesis.
J Virol.
1998;72:8273-8280
7.
Blaak H, van't Wout AB, Brouwer M, Hooibrink B, Hovenkamp E, Schuitemaker H.
In vivo HIV-1 infection of CD45RA(+)CD4(+) T cells is established primarily by syncytium-inducing variants and correlates with the rate of CD4(+) T cell decline.
Proc Natl Acad Sci U S A.
2000;97:1269-1274
8.
Chou CS, Ramilo O, Vitetta ES.
Highly purified CD25-resting T cells cannot be infected de novo with HIV-1.
Proc Natl Acad Sci U S A.
1997;94:1361-1365 9. Sleasman JW, Aleixo LF, Morton A, Skoda-Smith S, Goodenow MM. CD4+ memory T cells are the predominant population of HIV-1-infected lymphocytes in neonates and children. AIDS. 1996;10:1477-1484[Medline] [Order article via Infotrieve].
10.
Ostrowski MA, Chun TW, Justement SJ, et al.
Both memory and CD45RA+/CD62L+ naive CD4(+) T cells are infected in human immunodeficiency virus type 1-infected individuals.
J Virol.
1999;73:6430-6435 11. Roederer M, Raju PA, Mitra DK, Herzenberg LA. HIV does not replicate in naive CD4 T cells stimulated with CD3/CD28. J Clin Invest. 1997;99:1555-1564[Medline] [Order article via Infotrieve]. 12. Michie CA, McLean A, Alcock C, Beverley PC. Lifespan of human lymphocyte subsets defined by CD45 isoforms. Nature. 1992;360:264-265[CrossRef][Medline] [Order article via Infotrieve].
13.
Pilling D, Akbar AN, Bacon PA, Salmon M.
CD4+ CD45RA+ T cells from adults respond to recall antigens after CD28 ligation.
Int Immunol.
1996;8:1737-1742
14.
Zhang Z, Schuler T, Zupancic M, et al.
Sexual transmission and propagation of SIV and HIV in resting and activated CD4+ T cells.
Science.
1999;286:1353-1357 15. Stevenson M. Highlights of the 8th conference on retroviruses and opportunistic infections, part 1. Top HIV Med. 2001;9:7. 16. Eckstein DA, Penn ML, Korin YD, et al. HIV-1 actively replicates in naive CD4(+) T cells residing within human lymphoid tissues. Immunity. 2001;15:671-682[CrossRef][Medline] [Order article via Infotrieve]. 17. Kinter A, Moorthy A, T-W C, Horn J, Jackson R, Fauci A. Productive HIV infection of resting CD4+ T cells: the role of lymphoid tissue microenvironment [abstract]. J Hum Virol. 2001;abstract 35. 18. Abdul-Hai A, Or R, Slavin S, et al. Stimulation of immune reconstitution by interleukin-7 after syngeneic bone marrow transplantation in mice [published correction appears in Exp Hematol. 1996;24:1540]. Exp Hematol. 1996;24:1416-1422[Medline] [Order article via Infotrieve].
19.
Bolotin E, Smogorzewska M, Smith S, Widmer M, Weinberg K.
Enhancement of thymopoiesis after bone marrow transplant by in vivo interleukin-7.
Blood.
1996;88:1887-1894 20. Fukui T, Katamura K, Abe N, et al. IL-7 induces proliferation, variable cytokine-producing ability and IL-2 responsiveness in naive CD4+ T-cells from human cord blood. Immunol Lett. 1997;59:21-28[CrossRef][Medline] [Order article via Infotrieve]. 21. Okomato Y, Douek DC, McFarland RD, Koup RA. Increasing thymic output with exogenous IL-7 [abstract]. In: Program and Abstracts of the 7th Conference on Retroviruses and Opportunistic Infections. January 30-February 2, 2000. Chicago, IL. Abstract 326.
22.
Durum SK, Candeias S, Nakajima H, et al.
Interleukin 7 receptor control of T cell receptor gamma gene rearrangement: role of receptor-associated chains and locus accessibility.
J Exp Med.
1998;188:2233-2241
23.
Di Santo JP, Aifantis I, Rosmaraki E, et al.
The common cytokine receptor gamma chain and the pre-T cell receptor provide independent but critically overlapping signals in early alpha/beta T cell development.
J Exp Med.
1999;189:563-574 24. Akashi K, Kondo M, von Freeden-Jeffry U, Murray R, Weissman IL. Bcl-2 rescues T lymphopoiesis in interleukin-7 receptor-deficient mice. Cell. 1997;89:1033-1041[CrossRef][Medline] [Order article via Infotrieve]. 25. Pallard C, Stegmann AP, van Kleffens T, Smart F, Venkitaraman A, Spits H. Distinct roles of the phosphatidylinositol 3-kinase and STAT5 pathways in IL-7-mediated development of human thymocyte precursors. Immunity. 1999;10:525-535[CrossRef][Medline] [Order article via Infotrieve].
26.
Soares MV, Borthwick NJ, Maini MK, Janossy G, Salmon M, Akbar AN.
IL-7-dependent extrathymic expansion of CD45RA+ T cells enables preservation of a naive repertoire.
J Immunol.
1998;161:5909-5917 27. Webb LM, Foxwell BM, Feldmann M. Putative role for interleukin-7 in the maintenance of the recirculating naive CD4+ T-cell pool. Immunology. 1999;98:400-405[CrossRef][Medline] [Order article via Infotrieve]. 28. Hassan J, Reen DJ. IL-7 promotes the survival and maturation but not differentiation of human post-thymic CD4+ T cells. Eur J Immunol. 1998;28:3057-3065[CrossRef][Medline] [Order article via Infotrieve].
29.
Boise LH, Minn AJ, June CH, Lindsten T, Thompson CB.
Growth factors can enhance lymphocyte survival without committing the cell to undergo cell division.
Proc Natl Acad Sci U S A.
1995;92:5491-5495 30. Napolitano LA, Grant RM, Deeks SG, et al. Increased production of IL-7 accompanies HIV1-mediated T-cell depletion: implications for T-cell homeostasis. Nat Med. 2001;7:73-79[CrossRef][Medline] [Order article via Infotrieve].
31.
Clerici M, Saresella M, Colombo F, et al.
T-lymphocyte maturation abnormalities in uninfected newborns and children with vertical exposure to HIV.
Blood.
2000;96:3866-3871
32.
Fry TJ, Connick E, Falloon J, et al.
A potential role for interleukin-7 in T-cell homeostasis.
Blood.
2001;97:2983-2990 33. Coligan J, Kruisbeek A, Margulis D, Shevach E, Strober W, Coico R. Current Protocols in Immunology. New York, NY: John Wiley & Sons; 1994. 34. Al-Harthi L, Marchetti G, Steffens CM, Poulin J, Sekaly R, Landay A. Detection of T cell receptor circles (TRECs) as biomarkers for de novo T cell synthesis using a quantitative polymerase chain reaction-enzyme linked immunosorbent assay (PCR-ELISA). J Immunol Methods. 2000;237:187-197[CrossRef][Medline] [Order article via Infotrieve].
35.
Cecilia D, KewalRamani VN, O'Leary J, et al.
Neutralization profiles of primary human immunodeficiency virus type 1 isolates in the context of coreceptor usage.
J Virol.
1998;72:6988-6996 36. Steffens CM, Smith KY, Landay A, et al. T cell receptor excision circle (TREC) content following maximum HIV suppression is equivalent in HIV-infected and HIV-uninfected individuals. AIDS. 2001;15:1757-1764[CrossRef][Medline] [Order article via Infotrieve]. 37. Webb LM, Foxwell BM, Feldmann M. Interleukin-7 activates human naive CD4+ cells and primes for interleukin-4 production. Eur J Immunol. 1997;27:633-640[Medline] [Order article via Infotrieve]. 38. Bell EB, Sparshott SM. Interconversion of CD45R subsets of CD4 T cells in vivo [comment appears in Nature. 1991;352:28]. Nature. 1990;348:163-166[CrossRef][Medline] [Order article via Infotrieve]. 39. LaSalle JM, Hafler DA. The coexpression of CD45RA and CD45RO isoforms on T cells during the S/G2/M stages of cell cycle. Cell Immunol. 1991;138:197-206[CrossRef][Medline] [Order article via Infotrieve].
40.
Hamann D, Baars PA, Hooibrink B, van Lier RW.
Heterogeneity of the human CD4+ T-cell population: two distinct CD4+ T-cell subsets characterized by coexpression of CD45RA and CD45RO isoforms.
Blood.
1996;88:3513-3521 41. Summers KL, O'Donnell JL, Hart DN. Co-expression of the CD45RA and CD45RO antigens on T lymphocytes in chronic arthritis. Clin Exp Immunol. 1994;97:39-44[Medline] [Order article via Infotrieve]. 42. Komschlies KL, Grzegorzewski KJ, Wiltrout RH. Diverse immunological and hematological effects of interleukin 7: implications for clinical application. J Leukoc Biol. 1995;58:623-633[Abstract].
43.
Gringhuis SI, de Leij LF, Verschuren EW, Borger P, Vellenga E.
Interleukin-7 upregulates the interleukin-2-gene expression in activated human T lymphocytes at the transcriptional level by enhancing the DNA binding activities of both nuclear factor of activated T cells and activator protein-1.
Blood.
1997;90:2690-2700 44. Al-Harthi L, Roebuck KA. Human immunodeficiency virus type-1 transcription: role of the 5'-untranslated leader region (review). Int J Mol Med. 1998;1:875-881[Medline] [Order article via Infotrieve].
45.
Chene L, Nugeyre MT, Guillemard E, Moulian N, Barre-Sinoussi F, Israel N.
Thymocyte-thymic epithelial cell interaction leads to high-level replication of human immunodeficiency virus exclusively in mature CD4(+) CD8( 46. Smithgall MD, Wong JG, Critchett KE, Haffar OK. IL-7 up-regulates HIV-1 replication in naturally infected peripheral blood mononuclear cells. J Immunol. 1996;156:2324-2330[Abstract]. 47. Bolotin E, Annett G, Parkman R, Weinberg K. Serum levels of IL-7 in bone marrow transplant recipients: relationship to clinical characteristics and lymphocyte count. Bone Marrow Transplant. 1999;23:783-788[CrossRef][Medline] [Order article via Infotrieve].
48.
Fry TJ, Christensen BL, Komschlies KL, Gress RE, Mackall CL.
Interleukin-7 restores immunity in athymic T-cell-depleted hosts.
Blood.
2001;97:1525-1533
© 2002 by The American Society of Hematology.
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
|
 |
|
  V. Ostiguy, E.-L. Allard, M. Marquis, J. Leignadier, and N. Labrecque IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade J. Leukoc. Biol., September 1, 2007; 82(3): 645 - 656. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 L. Swainson, S. Kinet, C. Mongellaz, M. Sourisseau, T. Henriques, and N. Taylor IL-7-induced proliferation of recent thymic emigrants requires activation of the PI3K pathway Blood, February 1, 2007; 109(3): 1034 - 1042. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. Oswald-Richter, V. J. Torres, M. S. Sundrud, S. E. VanCompernolle, T. L. Cover, and D. Unutmaz Helicobacter pylori VacA Toxin Inhibits Human Immunodeficiency Virus Infection of Primary Human T Cells J. Virol., December 1, 2006; 80(23): 11767 - 11775. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. J. Zaunders, S. Ip, M. L. Munier, D. E. Kaufmann, K. Suzuki, C. Brereton, S. C. Sasson, N. Seddiki, K. Koelsch, A. Landay, et al. Infection of CD127+ (Interleukin-7 Receptor+) CD4+ Cells and Overexpression of CTLA-4 Are Linked to Loss of Antigen-Specific CD4 T Cells during Primary Human Immunodeficiency Virus Type 1 Infection. J. Virol., October 1, 2006; 80(20): 10162 - 10172. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Zhang, J. Drenkow, C. S. R. Lankford, D. M. Frucht, R. L. Rabin, T. R. Gingeras, C. Venkateshan, F. Schwartzkopff, K. A. Clouse, and A. I. Dayton HIV regulation of the IL-7R: a viral mechanism for enhancing HIV-1 replication in human macrophages in vitro J. Leukoc. Biol., June 1, 2006; 79(6): 1328 - 1338. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Swainson, E. Verhoeyen, F.-L. Cosset, and N. Taylor IL-7R{alpha} Gene Expression Is Inversely Correlated with Cell Cycle Progression in IL-7-Stimulated T Lymphocytes. J. Immunol., June 1, 2006; 176(11): 6702 - 6708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
F. Gondois-Rey, A. Biancotto, M. A. Fernandez, L. Bettendroffer, J. Blazkova, K. Trejbalova, M. Pion, and I. Hirsch R5 Variants of Human Immunodeficiency Virus Type 1 Preferentially Infect CD62L- CD4+ T Cells and Are Potentially Resistant to Nucleoside Reverse Transcriptase Inhibitors J. Virol., January 15, 2006; 80(2): 854 - 865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Carroll-Anzinger and L. Al-Harthi Gamma Interferon Primes Productive Human Immunodeficiency Virus Infection in Astrocytes J. Virol., January 1, 2006; 80(1): 541 - 544. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Audige, E. Schlaepfer, H. Joller, and R. F. Speck Uncoupled Anti-HIV and Immune-Enhancing Effects when Combining IFN-{alpha} and IL-7 J. Immunol., September 15, 2005; 175(6): 3724 - 3736. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-D. Lelievre, F. Petit, D. Arnoult, J.-C. Ameisen, and J. Estaquier Interleukin 7 Increases Human Immunodeficiency Virus Type 1 LAI-Mediated Fas-Induced T-Cell Death J. Virol., March 1, 2005; 79(5): 3195 - 3199. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Bahbouhi, A. Landay, and L. Al-Harthi Dynamics of cytokine expression in HIV productively infected primary CD4+ T cells Blood, June 15, 2004; 103(12): 4581 - 4587. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M.-T. Nugeyre, V. Monceaux, S. Beq, M.-C. Cumont, R. H. T. Fang, L. Chene, M. Morre, F. Barre-Sinoussi, B. Hurtrel, and N. Israel IL-7 Stimulates T Cell Renewal Without Increasing Viral Replication in Simian Immunodeficiency Virus-Infected Macaques J. Immunol., October 15, 2003; 171(8): 4447 - 4453. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. de la Rosa and M. Leal Thymic involvement in recovery of immunity among HIV-infected adults on highly active antiretroviral therapy J. Antimicrob. Chemother., August 1, 2003; 52(2): 155 - 158. [Full Text] [PDF]
|
|
|
|
|
|
L. A. Napolitano, C. A. Stoddart, M. B. Hanley, E. Wieder, and J. M. McCune Effects of IL-7 on Early Human Thymocyte Progenitor Cells In Vitro and in SCID-hu Thy/Liv Mice J. Immunol., July 15, 2003; 171(2): 645 - 654. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Cavalieri, S. Cazzaniga, M. Geuna, Z. Magnani, C. Bordignon, L. Naldini, and C. Bonini Human T lymphocytes transduced by lentiviral vectors in the absence of TCR activation maintain an intact immune competence Blood, July 15, 2003; 102(2): 497 - 505. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Jaleco, L. Swainson, V. Dardalhon, M. Burjanadze, S. Kinet, and N. Taylor Homeostasis of Naive and Memory CD4+ T Cells: IL-2 and IL-7 Differentially Regulate the Balance Between Proliferation and Fas-Mediated Apoptosis J. Immunol., July 1, 2003; 171(1): 61 - 68. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Llano, J. Barretina, A. Gutierrez, B. Clotet, and J. A. Este Interleukin-7-Dependent Production of RANTES That Correlates with Human Immunodeficiency Virus Disease Progression J. Virol., April 1, 2003; 77(7): 4389 - 4395. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Verhoeyen, V. Dardalhon, O. Ducrey-Rundquist, D. Trono, N. Taylor, and F.-L. Cosset IL-7 surface-engineered lentiviral vectors promote survival and efficient gene transfer in resting primary T lymphocytes Blood, March 15, 2003; 101(6): 2167 - 2174. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Jaleco, S. Kinet, J. Hassan, V. Dardalhon, L. Swainson, D. Reen, N. Taylor, and L. Al-Harthi IL-7 and CD4+ T-cell proliferation Blood, December 15, 2002; 100(13): 4676 - 4677. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
Top
Abstract
Introduction
B but acts in synergy with tumor necrosis factor
(TNF)-
to induce NF-
chain but that only IL-7 induced
productive HIV replication in naive T cells, it is suggested that
IL-7-mediated induction of HIV may rely on other factors in addition
to the signaling that occurs through the common 
) CD3(+) thymocytes: a critical role for tumor necrosis factor and interleukin-7.
J Virol.
1999;73:7533-7542