* Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy; and
Viral Oncology UPR 9045, CNRS, Villejuif, France
Correspondence: Sandra Gessani, Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy. E-mail: MACROBUTTON HtmlResAnchor gessani{at}iss.it
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Key Words: macrophage • interferons • receptors • soluble mediators
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, interleukin
(IL)-6, interferon (IFN)-ß] in response to lipopolysaccharide (LPS)
[6
], an increased susceptibility to human
immunodeficiency virus (HIV) infection [8
9
10
11
12
], and an
enhanced response to the biological activity of certain cytokines
(i.e., type I and type II IFNs) as a result of an enhanced expression
of the corresponding receptors at the plasma membrane
[13
, 14
]. Very recently, we demonstrated
that differentiation of monocytes to macrophages also results in the
loss of CCR2 expression and functional response to monocyte
chemoattractant protein-1 (MCP-1) [15
]. Moreover, an
increased secretion of MCP-1 was also detected in 7-day-cultured
macrophages with respect to 1-day-cultured monocytes
[15
]. Interestingly, most of the genes modulated during
the course of the spontaneous differentiation process (CD11/CD18,
ICAM-1, HLA-DR, TNF-, IL-6, IFN-ß, and MCP-1) are involved in
macrophage-mediated immune regulation and share 
B-like sequences in
their promoters [16
]. In this regard, we have shown
previously that macrophage differentiation results in the expression of
active p50/p65 nuclear factor (NF)-B heterodimers with the capacity
to activate target gene expression [17
]. Cultured blood
monocytes have been used largely as models of tissue macrophages for
functional analysis and characterization of the differentiation
process. Tissue macrophages are long-lived cells that usually do not
migrate out of tissues, are hyporesponsive to many stimuli, and are
thought to function mainly as scavenger cells [18
,
19
]. Cultured blood monocytes are similar to alveolar
macrophages and different from freshly isolated monocytes with respect
to immunoregulation of T cell responses to stimuli as well as
expression of some cytokines, such as TNF- and IL-1
[20
21
22
].
 View larger version (17K): [in a new window] |
Figure 1. Phenotypical and functional changes occurring during in
vitro differentiation of peripheral blood monocytes to
macrophages. The scheme reflects the results obtained by our group on
the main changes occurring during monocyte differentiation. Monocytes
isolated from the peripheral blood of healthy donors were cultured in
Iscove’s medium containing 15% fetal calf serum (FCS). We refer to
monocytes as those cells that have been maintained in culture for
24 h and to macrophages as those that have been cultured for 7
days.
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In this article, we review data on the regulation of the chemokine/cytokine network in monocytes/macrophages during the course of macrophage differentiation and HIV-1 infection and provide new experimental evidence on the role of some selected cellular factors in HIV-1 infection in the in vitro model of monocyte-derived macrophages.
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View this table: [in a new window] |
Table 1. Correlation between the Differentiation State of Monocytes and Their
Susceptibility to HIV-1 Infection
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, and MIP-1ß, all binding to CCR5
[44
45
46
]. Furthermore, some clinical or
laboratory-adapted HIV strains, including the dual-tropic strain 89.6,
also use other chemokine receptors (CCR3, CCR2b, or other orphan
chemokine receptors) in addition to CCR5 for entry into primary
lymphocytes and macrophages [42
, 47
,
48
]. The recognition that chemokine receptors can be
modulated during macrophage stimulation and differentiation has raised
the intriguing possibility that differences in the susceptibility of
differentiating monocytes to HIV infection can be determined by
differential levels of expression of these coreceptors
[15
, 49
50
51
]. Some recent studies have shown that monocyte differentiation is associated with a differential expression of some chemokine receptors that may contribute to the specific susceptibility of these cells to HIV entry [15 , 49 50 51 ]. Figure 2 summarizes the results obtained by our group on the expression of CD4 as well as of a panel of chemokine receptors in monocytes cultured for 1 and 7 days. CXCR4, CCR5, and CCR2 receptors were found to be expressed consistently at the plasma membrane of 1-day-cultured monocytes, but their expression, as well as that of CD4, decreased, although to different extents, during the course of differentiation. In keeping with our results, down-modulation of CD4 and CXCR4 receptors has also been shown by other groups [49 50 51 52 53 ]. In contrast to our results [15 ] and those reported by Verani and colleagues [54 ], CCR5 expression was found to be increased in differentiating neonatal macrophages as well as in adult macrophages [26 , 49 50 51 ]. Moreover, an increased expression of CCR5 was detected in monocytes cultured in the presence of monocyte differentiation-promoting factors, such as GM-CSF or M-CSF [50 , 55 56 57 ]. Although these studies suggested a correlation between CCR5 expression and susceptibility to HIV infection, to date no relevant studies have yet shown that, under the same experimental conditions, a specific blocking of CCR5-receptor usage renders cells refractory to HIV infection.
 View larger version (37K): [in a new window] |
Figure 2. Surface expression of HIV receptors and coreceptors in
monocytes at different stages of differentiation. Monocytes were
directly or indirectly stained with specific antibodies and analyzed by
fluorescence-activatedcell sorter (FACS), as previously
described [15]. The percentage of cells positive for the expression
of each surface antigen is calculated by differences between the level
of staining with a specific antibody and the baseline of the control
antibody. The expression of CD71 was monitored as control for monocyte
differentiation. Similar profiles were obtained with three different
donors.
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B/Rel family of transcription factors
[58
, 59
]. High levels of viral gene
expression and replication result in part from the activation of
NF-B family members, which, in addition to driving viral RNA
transcription, orchestrate the host inflammatory response. In fact,
NF-B regulates the expression of a variety of cytokines, chemokines,
growth factors, and immunoregulatory genes, which can exert inhibitory
and/or stimulatory effects on HIV replication. Therefore, activation of
NF-B can affect HIV replication and pathogenesis at many different
levels, rendering the relationships between HIV expression and NF-B
activation very complex.
HIV infection has been shown to induce a constitutive NF-B binding
in chronically infected monocytoid cell lines, concomitantly with an
increased HIV LTR activity and virus production, suggesting that HIV-1
can perpetuate its own replication by inducing NF-B activity
[60
]. Moreover, an increased transcription and
processing of the p105 precursor gives rise to increased intracellular
pools of NF-B p50 in chronically infected U937 cells
[61
]. Induction of p65 binding and transcriptional
activity has also been described in HIV chronically infected
myelomonoblastic PLB cells [62
] as well as in acutely
infected THP-1 cells [63
]. In general, HIV replication
in monocytes appears to require at least partial differentiation
[8
9
10
11
12
] and is enhanced by differentiation-promoting
factors [30
31
32
33
34
]. Some studies have investigated the
expression of NF-kB subunits during the course of primary monocyte
differentiation. In particular, we have shown that the appearance of
the strong transactivating subunit p65 in the nucleus is associated
with the acquisition of a fully differentiated macrophage phenotype.
Moreover, monocyte differentiation is accompanied by a concomitant
increase in the level of IB, which could generate a reservoir of
NF-B complexes available for a prompt activation in response to
inducer-mediated stimuli [17
]. Likewise, Lewin and
colleagues [64
] demonstrated high levels of expression
of transcriptionally inactive p50 homodimers in freshly isolated
monocytes, which decreased with time in culture in favor of the
transcriptionally active p50/p65 and p50/RelB heterodimers. Some
studies have investigated the relationships among monocyte
differentiation, HIV infection, and activity of NF-B family members
in primary monocytes/macrophages [64
65
66
]. In this
regard, we examined the induction of NF-B DNA binding activity and
p65 expression 24 h after infection of 1-day- or 7-day-cultured
monocytes with the monocytotropic strain Ba-L of HIV-1. As shown in
Figure 3A
, HIV infection of both cell types did not result in any change in
the synthesis of the p65 subunit. Similar results were obtained for the
p50 subunit (unpublished results). Similarly, the DNA-binding activity
of NF-B complexes to the HIV-1 LTR enhancer sequence was not
affected by HIV infection in both cell populations (Fig. 3B)
. HIV
infection was found to have a different impact on the expression of
NF-B subunits in monocytes/macrophages when they were cultured in
suspension [64
]. In fact, although HIV infection of
freshly isolated macrophages failed to induce NF-B binding activity,
p50/p65 and p50/RelB heterodimers expression was detected in
Teflon-cultured monocyte-derived macrophages [64
].
 View larger version (9K): [in a new window] |
Figure 3. Effect of HIV-1 infection on the expression of p65 and on NF-B
binding activity. (A) Monocytes were infected with
HIV-1Ba-L [300 tissue culture infectious dose
(TCID)50/106 cells] at 1 and 7 days of
in vitro culture. Whole-cell extracts from control or
HIV-infected cultures were prepared 24 h postinfection, loaded on
10% denaturing polyacrylamide gel, transferred to nylon membrane, and
then probed with a polyclonal antibody to p65 as previously described
[17]. (B) Nuclear extracts from day 1 or day 7 monocytes were
prepared 24 h after infection with HIV-1 and analyzed for
NF-B-binding activity to the enhancer region of the HIV-1 LTR as
described elsewhere [17]. Protein-DNA complexes were then separated
on a 5% native polyacrylamide gel. For competition analysis, a 200
molar excess of unlabeled oligonucleotide was incubated with the
extract before the addition of the labeled probe.
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B family expression/activity of NF-B
transcription factors clearly indicates that, despite the many
practical advantages in using cell lines with respect to primary
monocytes, results obtained with monocytic cell lines cannot be
extrapolated simply to primary cells. Furthermore, culture conditions
(i.e., adherence vs. suspension) may strongly affect the responsiveness
of monocytes/macrophages to HIV infection in terms of NF-B
activation, likely reflecting the in vivo existence of a
different responsiveness among monocyte populations.
The IFN system
IFNs are cytokines endowed with pleiotropic effects, including a
potent antiviral activity against viral infections. Several groups have
shown that type I IFN inhibits HIV-1 replication in human cells
cultured in vitro [reviewed in ref. 67
]. These studies
pointed out the existence of multiple mechanisms by which IFN can
affect the HIV infectious cycle, depending on the target cells and on
the timing of IFN addition and virus infection. Notably, a strong
antiviral activity has been demonstrated after treatment of
HIV-infected T cells and macrophages with IFN-, IFN-ß, and IFN-
[68
]. In light of the anti-HIV activities observed in
certain in vitro systems, some studies have subsequently
documented the efficacy of recombinant IFN- in patients with
early-stage HIV infection or with Kaposi’s sarcoma
[69
]. However, the role of IFN in the pathogenesis of
HIV-1 infection is still a matter of conjecture. Table 2
lists the major experimental and clinical changes in the IFN
system commonly observed during HIV disease. The IFN detected in HIV
chronically infected individuals is a poorly characterized form of IFN,
commonly named acid-labile IFN-, previously described in certain
autoimmune diseases [73
]. IFN- is detected in the
serum for a brief period during acute HIV infection and, as disease
progresses, it is found again in the serum with increasing frequency
and concentration [70
71
72
], although a defect in the
synthesis of IFN- by PBMC from HIV-infected individuals has been
described [74
]. Notably, a marked reduction in the
number of the so-called natural IFN-producing cells has been observed
[77
]. Of interest is that these cells, whose nature had
remained elusive for many years, have been identified recently as type
II dendritic-cell precursors [78
], also defined
as plasmacytoid monocytes [79
], which produce unusually
high amounts of type I IFN after microbial challenge. Finally, the
appearance of IFN-2-resistant HIV-1 variants is low at early stages
of infection but dramatically increases once HIV infection progresses
to AIDS. Thus, a role for the circulating IFN- in promoting
resistance or favoring survival of these variants has been suggested
[80
]. Recent findings have shown that type I IFN and
HIV-1 gp41 surface glycoprotein share a region of sequence homology and
a common immunological epitope [76
]. Interestingly,
increased levels of antibodies against type I IFN were described in
HIV-positive individuals [76
].
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View this table: [in a new window] |
Table 2. Dysregulation of the Endogenous IFN System in HIV-1-Infected
Individuals
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-receptor expression on PBMC during the disease progression to
AIDS has been demonstrated previously [75
]. The reduced
binding of IFN- could be due to a down-modulation of receptor
expression caused by the elevated IFN levels in the sera of patients.
These results suggest that hyperproduction of IFN occurring in the
course of HIV infection may represent a strategy evolved by the virus
to escape the IFN-mediated antiviral activity. However, one alternative
explanation for the apparent paradox of high levels of IFN in late
stages of disease could be that HIV infection itself inhibited the
expression of IFN receptors. To characterize the effect of HIV
infection on the IFN response of monocytes/macrophages, our laboratory
has studied recently the expression of type I IFN receptors on in
vitro-infected monocytes/macrophages. In particular, we have
focused on the effect of HIV infection on the spontaneous up-modulation
of type I IFN receptors occurring during differentiation. As shown in
Figure 4A
, infection of monocytes after 1 or 7 days of culture did not
interfere with the spontaneous up-modulation of type I IFN receptor,
because a comparable binding of iodinated type I IFN was detected in
infected cells with respect to uninfected control cultures. These
results suggested that, despite of the lack of HIV-induced effects on
the expression of type I IFN receptors, the biological response to the
ligand could be affected by the virus. In this regard, it has been
shown recently that HIV-1 Tat protein inhibits the activity of PKR, a
crucial component in the establishment of the IFN-mediated antiviral
state, thus providing a potential mechanism by which HIV could suppress
the activity of the IFN system [81
]. We thus
investigated the capacity of IFN to activate a typical signal
transducer, such as STAT1, in infected monocytes/macrophages. Although
a modest increase in the basal levels of expression of the
unphosphorylated STAT1 form was observed following HIV infection, its
activation by tyrosine phosphorylation in response to IFN treatment
occurred at comparable levels in control and HIV-infected
monocytes/macrophages (Fig. 4B)
. These results suggest that the
down-modulation of IFN receptors observed in AIDS patients cannot be
explained simply by a direct effect of HIV on IFN-receptor expression,
at least in cells of the monocyte/macrophage lineage infected in
vitro. It is conceivable to assume that the dysregulation of the
IFN system observed in AIDS is the sum of multiple alterations of
specific components of this system as well as of indirect effects
related to the general dysfunction of the immune system. Moreover, the
HIV-mediated effects on the IFN system may have a different impact on
different cell types, likely depending on the
differentiation/activation state. Further studies, aimed at
characterizing the molecular mechanisms evolved by HIV to counteract
the antiviral and immunoregulatory activities of the IFN system, would
be helpful to better understand the biological relevance of the
dysregulation of the IFN system in the pathogenesis of AIDS.
 View larger version (27K): [in a new window] |
Figure 4. Effect of HIV infection on the expression of type I IFN receptors and
STAT1 activation. (A) Monocytes cultured for 1 or 7 days were infected
with 300 TCID50/106 cells of
HIV-1Ba-L. After 7 days, cells were examined in
[125I]-IFN-2 equilibrium saturation-binding studies,
as previously described [14]. Cells were incubated with various
amounts of [125I]-IFN-2. After incubation for 2 h
at 4°C, cell pellets were washed extensively, and the radioactivity
was measured in a -counter. Specific binding was defined as the
difference between total binding and nonspecific binding in the
presence of a 150-fold excess of unlabeled IFN-; nonspecific binding
did not exceed 15% of total binding. Each point represents the average
of duplicate measurements. ( ) Control, 1-day-cultured monocytes;
( ) control, 8-day-cultured monocytes; ( ) HIV-infected,
8-day-cultured monocytes; ( ) control, 14-day-cultured monocytes;
(•) HIV-infected, 14-day-cultured monocytes. (B) Monocytes were
infected with HIV-1, as described in A. Seven days postinfection, cells
were stimulated for 45 min with 100 international units (IU)/ml of
IFN-ß. Whole-cell extracts were subjected to 8% sodium dodecyl
sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), transferred to
nitrocellulose membrane, and immunoblotted with an antiphospho
STAT1-Y701 antibody (UBI, Lake Placid, NY; upper panel) or an
anti-STAT1 antibody (Transduction Laboratories, Lexington, KY; lower
panel).
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and subsequently
stimulated with gp120 [13
]. Thus, macrophages responded
more efficiently to the priming effect of IFN- for IL-12 production.
This was consistent with a stronger IFN--mediated antiviral response
against VSV in these cells as well as with a higher expression of type
II IFN receptors with respect to 1-day-cultured monocytes
[13
]. Studies on the mechanism of action of cytokines
have revealed that these molecules can affect a variety of steps of the
viral life cycle [83
]. The recent finding that some
chemotactic cytokines can affect the binding and entry of HIV into
target cells [36
] further supports the general concept
that multiple steps of HIV life cycle are regulated by the
cytokine/chemokine network. In a previous section of this article, we
have described the changes in chemokine receptors expression occurring
during monocytes differentiation. In addition, it is noteworthy that
the expression of at least some chemokines is modulated during the
course of monocyte differentiation. In fact, we have found that the
basal levels of secretion of some ß-chemokines, such as MCP-1 and
MIP-1ß, are increased consistently during monocyte differentiation
[15, and unpublished results]. Concomitantly, an MCP-1-mediated
down-modulation of CCR2 receptors was also observed
[15
]. Likewise, spontaneous secretion of some chemokines
has been shown during the differentiation/maturation process of
dendritic cells [89
]. It has been suggested that the
ligand-induced down-modulation of chemokine receptors may represent a
novel mechanism for the regulation of their surface expression
occurring during the differentiation/maturation process of certain cell
types [15
, 89
]. Thus, autoregulatory
circuits, controlling the expression of some chemokine receptors in
monocytes/macrophages, may represent an additional important aspect for
the control of HIV entry in these cells. The characterization of novel
and/or poorly understood mechanisms in the regulation of chemokine
receptors expression may lead to the development of new antiviral
strategies aimed at suppressing HIV replication in macrophages. |
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However, it should be taken into account that cells of the macrophage lineage are highly heterogeneous with respect to phenotypic and functional features. Thus, it is conceivable that HIV can interact differently in vivo with the various monocyte/macrophage subpopulations, resulting in different patterns of infection and immune responses. In particular, the differentiation stage of macrophages can markedly influence the type of interactions between HIV and target cells. Over the last few years, the research efforts of our group have been focused on the characterization of the differential response of monocytes vs. macrophages to various stimuli, including HIV-1 and its gp120 protein, by using a well-characterized monocyte-differentiation model (Fig. 1) . From these studies, we have understood that the type and the extent of response to a variety of stimuli are profoundly influenced by the differentiation stage of macrophages. In particular, the capacity of monocytes to respond to environmental signals, such as low concentrations of bacterial endotoxin as well as to viral infection, is significantly changed after their maturation to macrophages. For example, the differentiation process results in an enhanced responsiveness to the biological effect of some cytokines, such as the type I and type II IFNs. The spectrum of spontaneously secreted cytokines/chemokines can also contribute to some of the differential functional activities. For instance, we have noticed recently that the spontaneous production of some chemokines, such as MCP-1 and MIP-1ß, is markedly enhanced during macrophage differentiation. Under some circumstances, the enhanced chemokine production may result in down-modulation of the corresponding receptors on the cell surface, as in the case of CCR2/MCP-1 interaction [15 ].
A considerable part of our studies on macrophage-cytokines interactions has been focused on the IFN system. Macrophages are early producers of type I IFN in response to virus infection, and IFNs can dramatically suppress HIV replication in macrophages [68 ]. However, it is still unclear what the role of the so-called acid labile IFN is and its interaction with macrophages in the pathogenesis of AIDS. Recent studies from our group indicate that in vitro HIV-infected monocytes/macrophages are as responsive to type I IFN as uninfected cells (Fig. 4) . However, further studies aimed at understanding the significance of the dysregulation of the IFN system in cells of the monocyte/macrophage lineage as well as in natural IFN-producing cells would be extremely important.
Macrophage differentiation implies not only changes in the pattern of
the cytokine/chemokine network but also a differential expression of
important transcription factors, such as NF-B (Fig. 3)
. In this
regard, we found qualitative differences in the expression of NF-B
subunits during the course of monocyte differentiation but not after
HIV infection. On the whole, the results on the effect of
differentiation as well as HIV infection on the expression/activity of
NF-B family members clearly indicate that results obtained with
monocytic cell lines are not predictive of those that can be obtained
with primary monocytes/macrophages. Furthermore, the responsiveness of
monocytes/macrophages to HIV infection in terms of NF-B activation
can be strongly affected by the culture conditions (i.e., adherence vs.
suspension), likely reflecting the in vivo existence of a
different responsiveness among monocyte populations. We emphasize that,
when in vitro experiments aimed at investigating functional
responses of monocytes/macrophages in physiological and pathological
conditions are performed, special care should be given to the
standardization of isolation and culture protocols, because variable
results can be obtained depending on the phenotype of the cells
obtained under different experimental conditions. Standardization of
the experimental work using monocytes/macrophages as a cell model would
allow evaluation and interpretation of the apparently contradictory
results from different groups and may lead to a better understanding of
the complex spectrum of responses of this heterogeneous cell population
to HIV-1 infection.
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component of the human type I interferon receptor during differentiation of peripheral blood monocytes: role in the biological response to type I interferon Eur. J. Immunol. 27,1075-1081[Medline]B in the immune system Annu. Rev. Immunol. 12,141-179[Medline]B subunit expression during differentiation of human peripheral blood monocytes to macrophages Cell Growth Differ 8,435-442[Abstract], MIP-1ß receptor as a fusion cofactor for macrophage-tropic HIV-1 Science (Wash., D.C.) 272,1955-1958[Abstract]-chemokine receptors CKR-5, CKR-3, and CKR-2b as fusion cofactors Cell 85,1149-1158[Medline] functional activity during differentiation of human monocytes and macrophages J. Leukoc. Biol. 66,135-143[Abstract]B during monocyte differentiation by HIV type 1 infection J. Immunol. 146,377-383[Abstract] but not receptor expression in vivo in the acquired immunodeficiency syndrome J. Clin. Invest. 82,1415-1421 and IFN-ß induce protective activity Immunol. Today 19,586-587[Medline]This article has been cited by other articles:
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