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IMMUNOBIOLOGY
From the Division of Viral Products, Center for
Biologics Evaluation and Research, Food and Drug Administration,
Bethesda, MD.
The effect of interferon Macrophages and CD4+ T cells are the
major targets of infection with the human immunodeficiency virus type 1 (HIV-1). Most primary viral isolates can infect both cell
types.1,2 However, cytotropism of the predominant viral
isolates varies during disease progression. Macrophage (M)-tropic
CCR5-utilizing (R5) viruses have been shown to establish the primary
infection during vertical and sexual transmission.3,4
These viruses are usually isolated during clinical latency, are slow to
replicate, do not form syncytia, and do not infect CD4+
T-cell lines. The development of acquired immunodeficiency syndrome (AIDS) is frequently associated with the emergence of fast-replicating viral strains that form syncytia and can infect both primary
CD4+ T cells and CD4+ T-cell lines (T-tropic).
The mechanisms underlying the emergence of T-tropic viral strains
during disease progression are of major interest in HIV research.
HIV infection and replication are also affected by the cytokine
network. Importantly, cytokines may exert multiple effects on viral
entry and reverse transcription as well as on proviral reactivation.5 In addition to tumor necrosis factor In persons infected with HIV-1, the progressive decline of
cell-mediated immunity results in a higher susceptibility to
opportunistic infections (OIs). Visceral leishmaniasis (VL) and
tuberculosis (TB) are among the most common opportunistic infections in
individuals with AIDS.14,15 Epidemiological data
demonstrated that infection with TB or VL facilitates HIV disease
progression in HIV-1-infected patients.16,17 Infections
with either Leishmania or Mycobacterium tuberculosis are associated with an enhanced production of
proinflammatory cytokines (IFN- The chemokine receptors CCR5 and CXCR4 are the principal cell surface
molecules that together with CD4 allow target cell entry by M-tropic
(R5) and T-tropic (X4) HIV strains, respectively. CCR5 is expressed at
high levels by differentiated macrophages21-23 and is a
critical factor for HIV pathogenesis, because individuals deficient in
CCR5 show high levels of resistance to HIV-1
infection.24,25 The role of CXCR4 in the infection of
macrophages with T-tropic strains is controversial. Low levels of CXCR4
were detected on differentiated macrophages,21,26,27 and
CXCR4 was shown to support infection of macrophages with primary
isolates27,28 but not with syncytia-inducing T-cell
line-adapted viral strains.27,29,30 Other studies
demonstrated that T-cell line-adapted viral strains can enter
macrophages using CXCR4, but viral replication was restricted at a
postentry level.31,32 A recent study33 from
our laboratory demonstrated differences in the biochemical properties
of CXCR4 molecules on monocytes and macrophages that correlated with
the reduced ability of macrophages to form syncytia with X4
envelope-expressing cells compared with monocytes.
Macrophages play a crucial role in the establishment of primary HIV
infection and serve as a reservoir of HIV during opportunistic infections.34 The cytokine milieu created during the onset
of an OI or as a result of local inflammation may affect HIV infection of macrophages by providing a more favorable environment for emerging T-tropic viruses. Therefore, we studied the effect of IFN- Generation of monocyte-derived macrophages and cytokine
treatment
Six-day MDMs were incubated with IFN- In some experiments, a mixture of anti-macrophage inflammatory protein
(MIP)-1 In some experiments, cycloheximide (Cx; 5 ng/mL) and
1-(5-isoquinolinesulfonyl)-2-methyl-piperazine (H7; 100 µmol/L; both from Sigma, St. Louis, MO) were added to the
cultures of MDMs 1 hour prior to addition of the cytokines.
Infection of MDMs with X4 and
R5 HIV-1
Infection of MDMs and polymerase chain reaction (PCR) analysis were done as described.33 In brief, for the PCR assay, 1 million 6-day MDMs untreated or pretreated with cytokines were infected with the following strains (multiplicity of infection [MOI]): NL4-3 (0.1), LAI (0.4), Ba-L (0.02), and ADA (0.01). After 48 hours, cells were harvested and counted. DNA lysates (the equivalent of 1 × 104 cells) were amplified by PCR with gag-specific primers (SK 38/39), and the products were hybridized to a 32P end-labeled SK19 probe.38 The signals on the autoradiographs were compared with those from simultaneously amplified DNA from serially diluted ACH-2 T cells, which contain one provirus per cell. Video images of the film were taken with the GDS 5000 system (UVP Inc, San Gabriel, CA), and densitometry was performed with NIH Image software. To test for productive HIV-1 infection, MDMs, untreated or treated with cytokines, were plated at 200 × 103 cells/mL in triplicate in a 48-well plate. MDMs were infected with LAI or with Ba-L at the same MOI as for PCR for 4 hours. In some experiments, macrophages were infected with the following X4 primary viral isolates: 2166, 2314, 1954, and 1650 (all obtained from the NIH AIDS Research and Reference Program). Infections with primary isolates were performed at an MOI of 0.1 TCID50. Unbound virus was removed after 18 hours of incubation by washes with phosphate-buffered saline. HIV-1 infection was assessed by measuring the amount of soluble p24 in the supernatant. Flow cytometry MDMs were incubated with 20% "pooled" human serum for 30 minutes to block Fc receptors. The following monoclonal antibodies were used: biotinylated 12G5 (anti-CXCR4), FITC-conjugated 2D7 (anti-CCR5; both from Pharmingen, San Diego, CA), FITC-conjugated anti-CD4 (Becton Dickinson, San Jose, CA), and streptavidin-conjugated TRI-color reagent (TC, Caltag Laboratories, South San Francisco, CA). The biotinylated mouse immunoglobulin G2a (IgG2a) and FITC-conjugated mouse IgG2a isotype controls were purchased from Pharmingen. Flow cytometry was performed on FACScan (Becton Dickinson) and analyzed with the use of Cell Quest Software. Data are presented as the delta mean fluorescent channel ( MFC) and were calculated by subtracting the control MFC
values from the experimental values.
Ca++ flux measurements MDMs (107 cells) were loaded with 2 µmol FURA2/AM (Molecular Probes, Eugene, OR) in 1 mL of phosphate-buffered saline for 30 to 60 minutes at 37°C and washed twice in HBSS (BioWhittaker, Walkersville, MD). SDF-1 (100 nmol; PeproTech, Rocky Hill, NJ) was added at the indicated times to 106 cells in 2 mL of HBSS in a continuously stirred cuvette at 37°C in an MS-III fluorometer (Photon Technology, Inc, South Brunswick, NJ). The relative ratio of fluorescence emitted at 510 nm following sequential excitation at 340 and 380 nm was recorded every 200 milliseconds.38CC chemokine enzyme-linked immunosorbent assay CM from 6-day MDMs either untreated or treated with cytokines was collected and analyzed with the use of MIP-1 , MIP-1 , and RANTES ELISA (enzyme-linked immunosorbent assay) kits according to the
manufacturer's instructions (Endogen, Inc, Woburn, MA).
HIV Env-dependent cell fusion assay CD4 12E1 cells were infected with recombinant
vaccinia viruses encoding envelope from JR-FL (M-tropic) strain at 10 plaque-forming units/cell. Macrophages were mixed with TF228 cells
expressing IIIB/BH8 envelope39 or with 12E1 cells
expressing JR-FL envelope at a 1:1 ratio (105 cells each)
and cocultured (in duplicates) for 18 hours. Cell-fusion activity was
quantified by counting syncytia. Where indicated, SDF-1, RANTES (1 µg/mL), or synthetic peptide T22 (2 µmol),40 generously provided by Dr Sam Hwang, were added to macrophage cultures
for 1 hour at 37°C before the addition of Env-expressing cells.
In some experiments, CM from the cultures of untreated or
cytokine-treated MDMs were collected and incubated with a mixture of
anti-MIP-1 Statistical analysis Analysis was performed with the use of JMP statistical software (ver.3.2.2, SAS Institute Inc, Cary, NC). Underlying distributions of syncytia counts andMFC values for CXCR4, CCR5, and CD4 were examined, and cytokine treatment groups were then compared by analysis
of variance. Syncytia counts showed a log normal distribution so that
log transformation was used.
IFN-  , TNF-, IL-6, and IL-10) previously shown
to regulate viral replication43 and mixed with cells
expressing a prototypic T-tropic IIIB envelope (data not shown).
Because only IFN- and IL-6 demonstrated reproducible enhancement in
syncytia numbers, further studies were performed using these cytokines.
MDMs were generated from elutriated monocytes of healthy donors,
incubated with IFN- or IL-6, and subsequently mixed (1:1 ratio) with
X4 envelope-expressing target cells. Syncytia numbers were quantified
in these cultures and analyzed using t tests of
log-transformed counts. Low syncytia numbers were scored in the
cultures of untreated macrophages (mean count 7; Figure 1). In contrast, IFN- and IL-6 induced
an increase in the fusion of MDMs with cells expressing IIIB envelope;
mean syncytia counts were 35 and 67, respectively. Although there was
high variability in the amount of fusion of primary macrophages derived
from healthy individuals, the statistical analysis of data from 30 separate experiments demonstrated that the increase in fusion of
macrophages with IIIB envelope-expressing cells induced by IFN- or
by IL-6 was highly significant (P < .0001;
Figure 1).
Infection of MDMs with X4
HIV-1 is enhanced by IFN- , washed to remove cytokines, and were infected with
HIV-1NL4-3. When DNA was extracted from macrophages
immediately after infection (time zero), no signal was detected,
demonstrating that no residual viral DNA was present in the virus stock
preparations (data not shown). In parallel, DNA from serially diluted
ACH-2 cells was PCR amplified (Figure 2B) and used to generate a
standard curve. Low levels of viral complimentary DNA were detected in
NL4-3-infected macrophages in the absence of cytokines (Figure 2A). In
contrast, treatment of macrophages with IL-6 or with IFN- induced
76-fold and 198-fold increases in the number of cells containing NL4-3 viral DNA, respectively (Figure 2A). Similar data were obtained when
macrophages were infected with HIV-1LAI (data not
shown).
To determine whether an increase in the early production of viral DNA
in cytokine-treated MDMs results in an increased viral replication,
6-day MDMs were incubated with cytokines as described above, washed to
remove cytokines, and were infected with HIV-1LAI (Figure
3). Infection of untreated macrophages
with HIV-1LAI led to a low-level production of p24. In
contrast, production of p24 by macrophages treated with IFN-
Role of CXCR4 in IFN- , or in the absence or in the presence of CXCR4 antagonist,
synthetic peptide, T2240 (Table
1). Low numbers of syncytia were scored
in the cultures of untreated macrophages, and the addition of IFN-
or IL-6 directly to the fusion assay did not increase fusion (data not
shown). Pretreatment of MDMs with IFN- induced an 8-fold and a
4-fold increase of fusion in 2 separate experiments. Similarly,
pretreatment of MDMs with IL-6 induced a 12-fold to 25-fold increase of
fusion with X4-tropic envelopes in 4 independent experiments. In both
cases, the observed fusion with T-tropic envelope-expressing cells was
completely blocked by SDF-1 or by T22 but not by RANTES or the
control peptide (data not shown). These data demonstrate the
involvement of CXCR4 in the enhanced macrophage fusion with X4-tropic
envelopes (Table 1).
To determine whether there was a correlation between enhanced fusion of
cytokine-treated MDMs with X4-tropic envelopes and CXCR4 surface
expression, flow cytometry was performed on the MDMs that were used in
the fusion assays (Figure 4). Statistical analysis of data derived from 12 separate experiments confirmed that
the differences in the numbers of syncytia formed by untreated and
IFN-
SDF-1-induced Ca++ flux in cytokine-treated macrophages Because both IFN- and IL-6 induced an increase in the fusion of
MDMs with X4-tropic envelopes in the absence of an increase in CXCR4
expression, it was of interest to determine whether IFN- or IL-6
induced conformational changes in CXCR4 in macrophages that resulted in
an improved ligand binding. As was reported in our previous study, MDMs
mobilized Ca++ in response to SDF-1.33
However, no differences in the magnitude of Ca++
mobilization in response to SDF-1 were observed between untreated and
IFN-- or IL-6-treated MDMs (Figure
5). These findings suggest that these
cytokines do not affect the ability of CXCR4 to bind to its
ligand.
Effect of Cx and of H7 on the IFN- include
activation of Stat1/3 proteins.44,45 It was
important to determine whether the IFN-- and IL-6-mediated fusion
of MDMs with X4-tropic envelopes is associated with Stat1/3 activation. To test this hypothesis, MDMs were pretreated with an inhibitor of
Stat1/3 activation, the serine-threonine kinase inhibitor, H7,46-48 prior to and during cytokine treatment; these
cells were then mixed with IIIB envelope-expressing cells (Table
2). Addition of IL-6 or IFN- induced
an increase in mean syncytia counts of MDMs from 7 ± 4 to 72 ± 9
and from 14 ± 1 to 61 ± 13, respectively. However, when
macrophages were incubated with H7, the cytokine-induced increase in
IIIB envelope fusion was inhibited (Table 2). In addition, Cx, a
protein synthesis inhibitor, was also an effective inhibitor of the
cytokine-induced fusion of MDMs with T-tropic envelopes (Table 2).
Neither Cx nor H7 had any effect on the fusion of MDMs in the absence
of cytokine treatment. These data suggest that the mechanisms
(including the initial signal transduction steps) by which IFN- and
IL-6 increase the X4 fusion potential of MDM may involve
serine-threonine phosphorylation and protein synthesis.
IFN- and IL-6 augmented X4-tropic viral entry and
replication MDMs, it was of interest to determine the effect of the
same cytokines on infection of MDMs with R5-tropic strains. MDMs were
infected with HIV-1Ba-L and with HIV-1ADA, and
cell lysates were subjected to HIV-1 DNA PCR after 48 hours. IFN- induced a 3-fold and a 14-fold decrease in the number of macrophages containing Ba-L and ADA proviral DNA, respectively (Figure
6). To confirm that the reduced viral
entry correlated with a reduction in viral production,
HIV-1Ba-L-infected MDMs were cultured in the absence or in
the presence of IFN-, and aliquots of the culture medium were
assayed for p24 (Figure 6C). In agreement with the observed reduction
in HIV-1Ba-L viral DNA, an inhibition of virus replication
was observed in MDM cultures in the presence of IFN- (Figure 6C). No
effects were seen in IL-6-treated MDM cultures (data not
shown).
IFN- could be
mediated in part by down-modulation of CD48 and/or CCR5
expression. To investigate these possibilities, the fusion assay was
performed in parallel with surface staining. MDMs formed high numbers
of syncytia with 12E1 cells infected with recombinant vaccinia virus
expressing the JR-FL envelope (Figure
7A). A reduction in fusion with the JR-FL
envelope was observed in MDM cultures pretreated with IFN-. Similar
results were observed when other R5-tropic envelopes (ADA, Ba-L) were used (data not shown). Staining with the CCR5-specific 2D7 monoclonal antibody revealed a considerable degree of variability in the CCR5
expression among macrophages derived from 11 individuals. Treatment of
MDMs with IFN- resulted in a modest reduction of surface CCR5
(Figure 7A-B). Analysis of data from 11 separate experiments revealed
that inhibition of fusion of MDMs with M-tropic envelopes induced by
IFN- was highly significant (P = .0006), whereas the
reduction in surface CCR5 levels was moderate but statistically
significant (P = .022; Figure 7B).
Effect of IL-6-treatment on the infection of macrophages with X4 primary viral isolates To determine whether cytokines can alter susceptibility of macrophages to primary viral isolates, 4 X4 primary isolates were used for the infection of MDMs that were untreated or treated with IL-6 (Figure 8). The p24 production by untreated MDMs was low, ranging from 0.1 ± 0.05 to 0.4 ± 0.1 ng/mL, depending on the virus. Addition of IL-6 to the macrophage cultures induced a 2-fold to a 12-fold increase in p24 production by macrophages infected with X4 primary isolates (Figure 8). These data suggest that proinflammatory cytokines can increase the susceptibility of macrophages to the infection with multiple primary X4 viruses.
Cytokine-treated MDMs secrete -chemokines in
the macrophage-conditioned medium. Production of MIP-1 and MIP-1
was significantly increased in IFN--treated MDMs and to a lesser
degree in IL-6-treated MDMs (Table 3).
No RANTES was detected in the cultures of cytokine-treated MDMs (data
not shown).
To determine whether
In this study, we demonstrated that the proinflammatory cytokines
IFN- The ability of differentiated macrophages to support infection with
T-tropic HIV-1 has been a subject of intensive research over recent
years. Earlier data demonstrated that MDMs are resistant to infection
with T-cell line-tropic viruses. However, studies2,28 reported that, under certain culture conditions, some primary syncytia-inducing viral isolates could infect MDMs. It is possible that
different cell isolation and culture conditions for growing MDMs can
affect the level of macrophage maturation, which was shown to determine
their susceptibility to HIV-1 infection.49 Low
levels of HIV-1NL4-3 entry and of HIV-1LAI
entry (data not shown) into MDMs in the absence of cytokines were
detected in our system in agreement with other reports.32
IFN- The observed increase in MDM fusion with T-tropic envelopes was
specifically inhibited by the CXCR4 agonist, SDF-1 In previous studies,9,24,33,39,41 we and others provided
evidence that CD4, the primary receptor for HIV-1, has a natural affinity for coreceptors CCR5 and CXCR4 as demonstrated by
coimmunoprecipitation of CD4 and coreceptors in monocytes and
macrophages. We recently demonstrated that coexpression of CCR5 and
CXCR4 in A2.01 T-cell line resulted in a significant inhibition of both
fusion with X4 envelope-expressing cells and infection with X4 virus.
This inhibition was reversed by antibodies against CCR5.51
Thus, the susceptibility of cells with limited CD4 to infection with viral strains of different tropism may be influenced by competition between coreceptors for association with CD4. Because The inhibitory effect of IFN- TB and other OIs have been shown to contribute to the pathogenicity of HIV and to accelerate the course of HIV disease.16,17,55,56 The role of macrophages in accelerating the course of HIV disease was established by demonstrating in situ the presence of integrated T-tropic HIV-1 DNA as well as p24 production in macrophages of OI-positive but not OI-negative HIV-1-infected individuals.34 It has been also demonstrated that macrophages become susceptible to T-tropic HIV infection after exposure to the components of the bacterial cell wall.57 In agreement with these reports, our data support the model in which common opportunistic pathogens alter susceptibility of macrophages to HIV by triggering production of cytokines that may be favorable for the entry and replication of more pathogenic T-tropic viral strains. This model is supported by the high levels of proinflammatory cytokines detected in patients with OI.17-19,58 Importantly, although OIs often occur following a decline in peripheral CD4 cell counts to below 200,59 some infections (Leishmania, herpes simplex virus, M tuberculosis, Candida, etc.) can occur early in the course of the disease before the onset of AIDS.60 It is conceivable that proinflammatory cytokines secreted during these infections at the latent stage of the disease may increase susceptibility of MDMs to infection with T-tropic HIV, thus "opening the gates" for the emerging T-tropic viruses. In addition, proinflammatory cytokines were detected in samples obtained by cervicovaginal lavage from women with infections of the genital tract in the absence of HIV infection.61,62 Increased levels of proinflammatory cytokines were observed in cervicovaginal lavage samples obtained from HIV-1-infected women.61,62 Our data support the notion that sexually transmitted diseases may affect local replication of X4 viruses and may partially explain the higher risk of HIV disease acceleration observed in women with these underlying conditions.
We thank the staff of the Department of Transfusion Medicine at NIH for providing elutriated monocytes; Dr Keith Peden for viral stocks; Dr Lee Tiffany for technical assistance; and Dr Philip Murphy, Dr Keith Peden, and Dr Basil Golding for reviewing the manuscript.
Submitted December 21, 1999; accepted July 6, 2000.
Partially supported by a grant from the Office of Women's Health, Food and Drug Administration, and by a grant from the National Institutes of Health Intramural AIDS Targeted Antiviral Program.
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: Marina Zaitseva, Division of Viral Products, Center for Biologics Evaluation and Research, Food and Drug Administration, Bldg 29B, Rm 3G21, 8800 Rockville Pike, Bethesda, MD 20892; e-mail zaitseva{at}cber.fda.gov.
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| Copyright © 2000 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
and interleukin 6 modulate the susceptibility of
macrophages to human immunodeficiency virus type 1 infection
Top
Abstract
Introduction
, 
) or in the
presence of IFN-
) (A) or IL-6 (
) (B) were infected with
HIVLAI. Infected MDMs were cultured in the presence of
cytokines. Viral replication was monitored by p24 measurements. Control
cultures included uninfected MDMs (
). Data represent 3 experiments
performed with macrophages derived from different individuals.
) or treated with IFN-
) were infected with Ba-L for 48 hours. Infected MDMs were washed
and cultured in the presence of IFN-
