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,§
,§,§
Divisions of
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Hematology/Oncology,
Human Cancer Genetics, and
Infectious Disease, Department of Internal Medicine, and
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Department of Medical Microbiology and Immunology and the Comprehensive Cancer Center, Ohio State University, Columbus, OH 43210;
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Division of Infectious Disease, Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; and
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Department of Medicine, Roswell Park Cancer Institute, Buffalo, NY 14263
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-
) and the chemokine macrophage inflammatory protein
(MIP)-1 following stimulation with the combination of two monokines,
IL-15 plus IL-12. The C-C chemokines MIP-1, MIP-1ß, and RANTES
have been identified as the major soluble macrophage-tropic
HIV-1-suppressive factors produced by CD8+ T cells, which
exert their action at the level of viral entry. Here, we demonstrate
that monokine-activated NK cells, isolated from both normal and
HIV-1+ donors, produce similar amounts of MIP-1,
MIP-1ß, and RANTES protein, in vitro. Further, supernatants of
monokine-activated NK cells obtained from both normal donors and AIDS
patients showed potent (routinely 
90%) suppressive activity against
HIV-1 replication in vitro, compared with unstimulated control
supernatants. NK cell supernatants inhibited both macrophage-tropic
HIV-1NFN-SX and T cell-tropic HIV-1NL4–3
replication in vitro, but not dual-tropic HIV-189.6.
Importantly, the C-C chemokines MIP-1, MIP-1ß, and RANTES were
responsible only for a fraction of the HIV-1-suppressive activity
exhibited by NK cell supernatants against macrophage-tropic HIV-1.
Collectively these data indicate that NK cells from normal and
HIV-1+ donors produce C-C chemokines and other unidentified
factors that can inhibit both macrophage- and T cell-tropic HIV-1
replication in vitro. Since NK cells can be expanded in patients with
HIV-1, AIDS, and AIDS malignancy in vivo, this cell type may have an
important role in the in vivo regulation of HIV-1
infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, TNF-, as well as the C-C chemokine macrophage inflammatory
protein (MIP)3-1, production by human NK cells
(7, 8, 9).
HIV-1 isolates are categorized as macrophage-tropic (M-tropic), T
cell-tropic (T-tropic), or dual-tropic, based upon their ability to
replicate in monocyte-derived macrophages and/or T cell lines (10).
Soluble factors derived from the culture supernatants of activated
CD8+ T cells have been shown to suppress the replication of
HIV-1 in vitro (11, 12). The C-C chemokines MIP-1, MIP-1ß,
and RANTES have been identified as major CD8+ T
cell-derived M-tropic HIV-1-suppressive factors (13) and act by
competitive binding to CCR5 or by down-regulation of surface CCR5, the
primary coreceptor for M-tropic HIV-1 entry into target cells (14, 15).
Wagner et al. have recently shown that the C-C chemokines are
released from the CD8+ T cell cytolytic granules complexed
to proteoglycans and, in this form, exert greater inhibition of HIV-1
replication (16). Similarly, CXCR4 has been identified as the
coreceptor for T-tropic HIV-1 entry (17) and is inhibited by its
natural CXC chemokine ligand, SDF-1 (18, 19). Based upon this
correlation between cellular tropism and coreceptor usage, it has been
proposed to refer to M-tropic HIV-1 strains that utilize coreceptor
CCR5 as R5 viruses, to T-tropic strains that use coreceptor CXCR4 as X4
viruses, and to dual-tropic strains utilizing both coreceptors as R5X4
viruses (20).
Exogenous, s.c. administration of ultra-low dose IL-2 has been shown to
selectively expand human NK cells in vivo (21, 22, 23). We have observed a
significant, selective expansion of this subset of innate immune
effector cells in both phase I (21) and phase II (23) studies of
ultra-low dose IL-2 therapy given to patients with AIDS and
AIDS-associated malignancies, when CD4+ T cells are often
below 100/mm3. Additionally, we have shown that ultra-low
dose IL-2 therapy can increase endogenous IFN- gene expression in
these patients in vivo, as well as enhance IFN- protein production
by LPS- and Toxoplasma gondii-stimulated PBMC in vitro
(24). Thus, the human NK cell represents an expandable reservoir of
cytokine producing cells in HIV-1-infected patients.
In the current study, we investigated whether NK cells derived from HIV-1-infected patients produce C-C chemokines, and whether monokine-activated NK cells from such patients could inhibit HIV-1 infection in vitro.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Purified recombinant human (rh) IL-15 was provided by Immunex
Corporation (Seattle, WA). Purified rhIL-12 (sp. act., 4.5 x
106 U/mg) was obtained from Genetics Institute (Cambridge,
MA). Purified rhIL-2 (spec. act., 18 x 106 IU/mg) was
obtained from Chiron (Emeryville, CA). All cytokines were reconstituted
in sterile PBS with 0.1% human albumin (Armour Pharmaceutical,
Kankakee, IL). Neutralizing goat anti-human MIP-1, MIP-1ß, and
RANTES polyclonal Abs were purchased from R&D Systems (Minneapolis,
MN). Normal goat Ig was used as a control (R&D Systems). PE-conjugated
anti-human CD56 mAb was purchased from Coulter Immunology (Hialeah,
FL), and PE-isotype control mAb were purchased from Becton Dickinson
(San Jose, CA).
Patients
Studies were performed on blood obtained after informed consent from seven HIV+ patients receiving highly active antiretroviral therapy (HAART), with HIV-1 RNA < 200 copies/ml of plasma by PCR. Blood was also obtained after informed consent from two patients with AIDS receiving ultra-low dose IL-2 therapy, as described (23).
Isolation of human NK cells
PBMC were obtained from patients with HIV-1 infection or AIDS,
or from normal donor fresh leukopacs (American Red Cross, Columbus, OH)
using Ficoll-Hypaque (Sigma, St. Louis, MO) density gradient
centrifugation. Red blood cells were lysed, after which PBMC were
washed twice in RPMI 1640 supplemented with 10% human AB serum (HAB,
C-six Diagnostics, Mequon, WI), antibiotics, and anti-PPLO (Life
Technologies, Grand Island, NY) (10% HAB), and cultured for 2 h
in plastic tissue culture dishes to remove adherent monocytes. T cells,
B cells, and remaining monocytes were depleted using goat
anti-mouse immunomagnetic beads (PerSeptive Biosystems, Framingham,
MA) and a combination of murine mAb reactive against CD3, CD20, and
HLA-DR, as described (25). Nondepleted cells were then stained with
CD56-PE mAb, washed in 10% HAB, and isolated by FACS for
CD56+ NK cells on a Coulter ELITE flow cytometer (Coulter
Immunology). Sorted CD56+ NK cells were routinely 97%
pure by flow cytometric analysis.
Preparation of human NK cell-conditioned supernatants
Sorted CD56+ NK cells were cultured in 10% HAB at a density of 1 x 106 cells/ml, in sterile 96-well U-bottom plates. NK cells were then stimulated with IL-15 (10 ng/ml), IL-12 (10 U/ml), IL-15 plus IL-12, or no stimulus (medium alone control). After a 72-h incubation at 37°C in 5% CO2, culture supernatants were harvested, centrifuged to remove cells and debris, and stored at -80°C. In some experiments, sorted CD56+ NK cells were cultured as described above, but at a density of 5 x 104/ml.
Measurement of NK cell cytokine production
NK cell production of MIP-1, MIP-1ß, and RANTES was
measured from cell-free culture supernatants utilizing commercial ELISA
kits, following the manufacturer’s instructions (R&D Systems). RANTES
levels were corrected for any background obtained from the culture
medium (10% HAB, 
250 pg/ml). Results represent the mean of duplicate
wells ± SD.
Preparation of primary PBL targets
PBMC from normal donors were prepared as described above and cultured in 100-mm tissue culture dishes at a density of 15 x 106/ml in 10% HAB. After 2 h, nonadherent cells were removed, centrifuged, and resuspended in RPMI 1640 supplemented with 10% FCS and antibiotics (10% FCS), and incubated with phytohemagglutinin (PHA, 5 µg/ml; Sigma) for 2–3 days. PBL were next washed twice in RPMI 1640, resuspended in 10% FCS supplemented with 10 U/ml IL-2, and seeded (2 x 105 cells/well) into 96-well flat-bottom plates for infection assays. PBL were then used as targets for infection assays 0–2 days following IL-2 stimulation (3–5 days postisolation).
HIV-1 infection assays
PBL prepared as described above were preincubated in 100% (v/v)
NK cell-conditioned supernatants or controls, supplemented with 10 U/ml
IL-2, for 1 h before infection. A molecularly cloned virus,
HIV-1NFN-SX (26), encoding the envelope of the M-tropic
isolate HIV-1JR-FL (27), was then added to the wells at a
final input of 0.5 ng/ml p24 in a total volume of 100 µl, and
incubated for 4 h at 37°C. Other viruses utilized included
dual-tropic HIV-189.6 (28) (1 ng/ml p24) and T-tropic
HIV-1NL4–3 (29) (5 ng/ml p24). Target cells were then
washed twice with RPMI 1640 to remove excess unbound virus, and the NK
cell-conditioned supernatants (100% v/v) or controls in 10% HAB were
replaced. PBL were then cultured for 14 days at 37°C. On days 6, 8,
and 10 postinfection, half of the culture supernatant (50 µl) was
harvested for p24 assessment and replaced with 10% HAB supplemented
with 10 U/ml IL-2. Target cells were monitored for viability during the
course of the infection assays by vital dye exclusion. To examine the
effects of the C-C chemokines, some NK cell supernatants were
precleared of these chemokines with polyclonal neutralizing Abs (R&D
Systems). Supernatants were first incubated with anti-human
chemokine-neutralizing Abs (anti-MIP-1, anti-MIP-1ß, and
anti-RANTES, each at 2–50 µg/ml, concentrations able to
neutralize 95% of their activity as determined by the manufacturer)
or an equivalent amount of normal goat Ig (6–150 µg/ml) for 1 h
at 4°C with gentle agitation. Protein G-Sepharose (Bio-Rad, Hercules,
CA) was then added, and the supernatants were incubated with gentle
agitation for an additional hour. The protein G-Sepharose was then
pelleted by centrifugation, and the chemokine-cleared supernatants were
transferred to another microfuge tube without disturbing the Sepharose
pellet. This clearing process resulted in monokine-stimulated NK cell
supernatants with undetectable MIP-1, MIP-1ß, RANTES, and goat Ig
protein by ELISA (data not shown). Target cells infected and cultured
in fresh 10% HAB supplemented with 10 U/ml IL-2 and uninfected target
cells were additional controls.
Detection of HIV-1 p24 production
Quantitation of HIV-1 p24 protein production in the supernatants of infected targets was performed using a commercial p24 Ag capture ELISA kit (AIDS Vaccine Program, Frederick, MD), following the manufacturer’s instructions.
Statistical analysis
Statistics were determined by using the Student t test, with p < 0.05 considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Human NK cells produce MIP-1 and a variety of cytokines in
response to stimulation with the monokine combination IL-15 plus IL-12
(7, 9). We therefore assayed NK cells from normal donors and
HIV+ patients for production of the known HIV-1-suppressive
C-C chemokines MIP-1, MIP-1ß, and RANTES (13). Fig. 1
shows the levels of these C-C
chemokines in NK cell culture supernatants obtained from normal
(n = 8) and HIV-1+ (n = 7)
donors (5 x 104 cells/ml). NK cells from
HIV-1+ patients produced equivalent amounts of MIP-1,
MIP-1ß, and RANTES in response to IL-15 plus IL-12, when compared
with normal donors. Supernatants from NK cells activated with the
combination of IL-15 plus IL-12 showed the greatest and most
significant increase in MIP-1 (p < 0.0008)
and MIP-1ß (p < 0.0003), when compared with
supernatants from NK cells cultured in medium alone. RANTES was
measurable but not significantly different under any culture condition
in NK supernatants from normal or HIV-1+ individuals (data
not shown).
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We next investigated the ability of supernatants from
monokine-stimulated NK cells to inhibit HIV-1 replication in vitro. We
used the M-tropic HIV-1NFN-SX (26), which utilizes CCR5 as
a coreceptor. The effect of normal donor NK cell supernatants on viral
replication was assessed by comparing unstimulated (medium only) to
monokine-stimulated NK cell supernatants. Supernatants from
unstimulated and IL-15-stimulated NK cells produced high amounts of
HIV-1 p24 by day 6 postinfection of target PBL (Fig. 2). Supernatants from IL-12-stimulated NK
cells reduced HIV-1 p24 levels by approximately 50%
(p < 0.03), compared with medium controls.
However, PBL targets infected and cultured in supernatants from NK
cells stimulated with IL-15 plus IL-12 demonstrated 95% decrease in
p24 production, compared with medium controls
(p < 0.0005). We also quantitated the levels
of C-C chemokines in the IL-15 plus IL-12-stimulated NK cell
supernatants (cultured at 1 x 106 cells/ml) shown in
Fig. 2, and the mean ± SEM (pg/ml) were 27,442 ± 4,668 for
MIP-1, 29,295 ± 4,887 for MIP-1ß, and 4,576 ± 1,482
for RANTES. To control for the direct effects of any remaining rIL-15
and rIL-12 in the NK cell supernatants, the residual amounts of these
cytokines were quantitated (15–30% of input for rIL-12, 35–50% of
input for rIL-15), and these levels were assayed for any effects on
HIV-1NFN-SX replication. In our infection system, rIL-12
did not change p24 production compared with medium alone, while IL-15
and IL-15 plus IL-12 modestly increased (1.5- to 2-fold) p24 production
(data not shown). Therefore, we concluded that these recombinant
cytokines were not directly involved in the observed inhibition of p24
production by stimulated NK cell supernatants.
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To directly verify that the inhibition by normal donor NK
cell supernatants was also operating in HIV-1+ patients, we
tested the supernatants of monokine-stimulated NK cells isolated from
HIV-1+ patients for the ability to suppress HIV-1
replication in vitro. Extended leukopheresis of HIV-1+
patients for the purpose of this in vitro assay could not be justified
on ethical grounds. Sufficient numbers of human NK cells were therefore
isolated from two AIDS patients that had received s.c. ultra-low dose
IL-2 (1.2 x 106 IU/m2/day) and,
hence, had an expanded NK cell population (23). Supernatants from their
NK cells that were activated by IL-15 plus IL-12 significantly
decreased HIV-1 replication in vitro by 90%, compared with
unstimulated control supernatants (Fig. 3, p < 0.0024).
Likewise, identical supernatants obtained from monokine-activated NK
cells of one HIV-1+ patient on highly active antiretroviral
therapy (HAART) and not receiving IL-2 inhibited HIV-1 replication in
vitro by 90% (data not shown).
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To assess whether the measured C-C chemokines were responsible for
the observed suppression of HIV-1 replication, we utilized neutralizing
Abs to MIP-1, MIP-1ß, and RANTES to block their effects on HIV-1
replication. Fig. 4 shows that the
inhibition of p24 production by stimulated NK cell supernatants could
be only partially abrogated by preclearing with neutralizing Abs
against MIP-1, MIP-1ß, and RANTES, compared with supernatants mock
cleared with an equal amount of nonreactive goat Ig. To insure that
partial abrogation was not a result of insufficient amounts of the
neutralizing Abs, the experiment was repeated using a 25-fold excess of
the concentrations necessary to neutralize the measured amounts of
chemokines present in the supernatants and yielded similar results
(data not shown).
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We also examined the effects of NK cell supernatants on the
replication of two additional HIV-1 strains, the T-tropic
HIV-1NL4–3 that utilizes CXCR4 as a coreceptor for entry
and the dual-tropic HIV-189.6 that can utilize either CCR5
or CXCR4 as a coreceptor, as well as several other potential HIV-1
coreceptors (30). Supernatants from NK cells costimulated with IL-15
plus IL-12 significantly inhibited the replication of
HIV-1NL4–3 by 75%, compared with unstimulated control
supernatants (Fig. 5, p
< 0.0013). However, identical monokine-stimulated NK cell supernatants
were not able to significantly inhibit the replication of
HIV-189.6, compared with controls.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in vitro (7, 9). In this report, we demonstrate that monokine-stimulated NK cells,
isolated from HIV-1+ donors, also produce the C-C
chemokines MIP-1 and MIP-1ß in amounts equivalent to normal
donors. We therefore tested whether such monokine-stimulated NK cell
supernatants were able to inhibit M-tropic HIV-1NFN-SX
replication in vitro. The culture supernatants from normal donor NK
cells stimulated with IL-12 alone inhibited HIV-1NFN-SX
replication by approximately 50%, and NK cells stimulated with the
combination of IL-15 plus IL-12 significantly inhibited HIV-1
production by 95%, compared with medium controls. In addition, IL-15
plus IL-12-stimulated NK cells isolated from HIV-1+
patients, or AIDS patients receiving ultra-low dose IL-2 therapy, also
inhibited HIV-1NFN-SX replication by 90%, compared with
medium controls. Therefore, human NK cells from normal donors and
HIV-1+ patients inhibit HIV-1 infection in vitro.
We next investigated whether the measured C-C chemokines present in the
NK cell supernatants were responsible for the observed suppression of
HIV-1NFN-SX replication in PBL targets. Interestingly,
these known inhibitors of M-tropic HIV-1 replication were only
partially responsible for the HIV-1 suppression from the stimulated NK
cell supernatants. These data suggest that other factor(s) produced by
monokine-stimulated NK cells inhibit M-tropic HIV-1 infection in our
assay system. Possible candidates would include unidentified C-C
chemokines, which may be able to block HIV-1NFN-SX
infection via binding to CCR5, as well as other factors yet to be fully
characterized (31). Since IL-15 plus IL-12-stimulated human NK cells
are potent producers of IFN- and TNF- (7), experiments are
currently underway to evaluate their role in the HIV-1-suppressive
effect of these supernatants. In addition, supernatants from stimulated
NK cells significantly inhibited the replication of T-tropic
HIV-1NL4–3. This observation suggests that factor(s)
produced by NK cells may inhibit the usage of CXCR4 as a coreceptor for
viral entry by T-tropic HIV-1, or that NK cell supernatants also exert
suppressive action at another point in the viral life cycle. To our
knowledge, human NK cells have not yet been shown to produce a C-X-C
chemokine that binds to CXCR4, and experiments are ongoing to identify
such CXCR4 chemokine ligands within monokine-stimulated NK cell
supernatants. One explanation why supernatants from stimulated NK cells
were unable to inhibit dual-tropic HIV-189.6 may involve
its use of many coreceptors for entry, including CXCR4, CCR5, CCR3, and
CCR2b (30). In this scenario, factors within NK cell supernatants may
not be able to block all possible coreceptors for HIV-189.6
fusion. Monocyte-derived macrophages can also be induced to produce C-C
chemokines following LPS-stimulation, and these supernatants have been
shown to inhibit replication of M-tropic HIV-1 strains in both
monocyte-derived macrophages and CD4+ lymphocytes, but not
T-tropic HIV-1 strains (32).
Since the identification of chemokine receptors as coreceptors for HIV-1 entry (14, 15, 17), and ability of chemokine ligands to block entry (13, 18, 19), several studies have examined their importance in the pathogenesis of HIV-1 infection. Studies have demonstrated that individuals homozygous for a 32-bp deletion in the CCR5 gene are resistant to HIV-1 infection, while heterozygous individuals have slower progression to AIDS (33, 34, 35, 36). Additionally, high-risk individuals who are multiply exposed, yet remain uninfected, have been shown to produce high levels of C-C chemokines (37). These studies highlight the importance of CCR5 interaction with its natural ligands and M-tropic HIV-1 in the natural history of HIV-1 infection.
ultra-low dose IL-2 therapy has been shown in phase I and phase II trials to selectively expand CD56+ NK cells in vivo in patients with AIDS and AIDS malignancy (21, 23). Here, we show that NK cells obtained from these patients can be stimulated to suppress HIV-1 replication in vitro. Thus, the IL-2-expanded NK cell may be an endogenous source of C-C chemokines and, through the elaboration of these and possibly other factors, may contribute to defense against HIV-1 infection in patients receiving ultra-low dose IL-2 therapy.
Note Added in Proof. A recent report by Oliva et al. (38) described a similar role for NK cell suppression of HIV-1 infection in vitro.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Michael A. Caligiuri, Ohio State University, 458A Starling-Loving Hall, 320 West 10th Avenue, Columbus, OH 43210. E-mail address:
3 Abbreviations used in this paper: MIP; macrophage inflammatory protein; M-tropic, macrophage-tropic; T-tropic, T cell-tropic; HAB, human AB serum; rh, recombinant human; PE, phycoerythrin.
Received for publication June 29, 1998. Accepted for publication July 29, 1998.
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M. A. Olszewski, G. B. Huffnagle, R. A. McDonald, D. M. Lindell, B. B. Moore, D. N. Cook, and G. B. Toews The Role of Macrophage Inflammatory Protein-1{alpha}/CCL3 in Regulation of T Cell-Mediated Immunity to Cryptococcus neoformans Infection J. Immunol., December 1, 2000; 165(11): 6429 - 6436. [Abstract] [Full Text] [PDF]
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B. Cipriani, G. Borsellino, F. Poccia, R. Placido, D. Tramonti, S. Bach, L. Battistini, and C. F. Brosnan Activation of C-C beta -chemokines in human peripheral blood gamma delta T cells by isopentenyl pyrophosphate and regulation by cytokines Blood, January 1, 2000; 95(1): 39 - 47. [Abstract] [Full Text] [PDF]
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J. Gosselin, A. TomoIu, R. C. Gallo, and L. Flamand Interleukin-15 as an Activator of Natural Killer Cell-Mediated Antiviral Response Blood, December 15, 1999; 94(12): 4210 - 4219. [Abstract] [Full Text] [PDF]
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T. A. Fehniger, M. H. Shah, M. J. Turner, J. B. VanDeusen, S. P. Whitman, M. A. Cooper, K. Suzuki, M. Wechser, F. Goodsaid, and M. A. Caligiuri Differential Cytokine and Chemokine Gene Expression by Human NK Cells Following Activation with IL-18 or IL-15 in Combination with IL-12: Implications for the Innate Immune Response J. Immunol., April 15, 1999; 162(8): 4511 - 4520. [Abstract] [Full Text] [PDF]
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