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(Journal of Leukocyte Biology. 2000;68:391-399.)
© 2000 by Society for Leukocyte Biology

Regulation of chemokine/cytokine network during in vitro differentiation and HIV-1 infection of human monocytes: possible importance in the pathogenesis of AIDS

Laura Fantuzzi*, Lucia Conti*, Maria Cristina Gauzzi*, Pierre Eid{dagger}, Manuela Del Cornò*, Barbara Varano*, Irene Canini*, Filippo Belardelli* and Sandra Gessani*

* Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy; and
{dagger} 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


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 CORRELATION BETWEEN THE...
 HIV-1 RECEPTOR AND CORECEPTOR...
 POSSIBLE MECHANISMS AFFECTING...
 FINAL REMARKS
 REFERENCES
 
The monocyte/macrophage lineage represents heterogeneous cell populations characterized by major differences in the phenotype and functional activities. These cells are a major source of soluble factors, such as cytokines and chemokines, which can both affect HIV replication and AIDS pathogenesis. Although monocytes/macrophages are unanimously considered important targets of HIV-1 infection, the HIV-induced alterations in their physiological functions at different stages of differentiation are still matter of debate. In this article, we review our data on the regulation of chemokine/cytokine network with regard to macrophage differentiation and HIV-1 infection, in comparison with studies from other groups. The ensemble of the results emphasizes that: 1) macrophages markedly differ with respect to monocytes for a variety of responses potentially important in the pathogenesis of HIV infection; and 2) the experimental conditions can influence the HIV-monocyte/macrophage interactions, reflecting the possible in vivo existence of a spectrum of responses among macrophage populations.

Key Words: macrophage • interferons • receptors • soluble mediators


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
CORRELATION BETWEEN THE...
 HIV-1 RECEPTOR AND CORECEPTOR...
 POSSIBLE MECHANISMS AFFECTING...
 FINAL REMARKS
 REFERENCES
 
Monocytes and macrophages are involved differently in a variety of immunoregulatory, phagocytic, and secretory functions. During the maintenance of immune homeostasis, monocytes circulate, transmigrate through vascular endothelium, and localize in peripheral tissues by means of the involvement of many complex adhesion molecule-counter receptor interactions [1 , 2 ]. Peripheral blood monocytes mature into different types of tissue histiocytes when they migrate from the bloodstream to various tissues. This differentiation is essential for their functional competence and is triggered by environmental signals. In vitro culture of human peripheral blood monocytes results in their adherence to the plastic surface and in the initiation of a series of morphological, biochemical, and functional changes closely resembling those occurring during their in vivo maturation to macrophages [3 , 4 ]. A scheme describing the main changes occurring during the in vitro differentiation of monocytes to macrophages, largely based on the results obtained by our group, is shown in Figure 1 . This process is characterized by an increased expression of certain surface markers, such as transferrin receptors, CD11/CD18, intercellular adhesion molecule-1 (ICAM-1), human leukocyte antigen (HLA) -DR, and CD14 antigens [5 6 7 ]. It results in marked changes in cell behavior, such as an enhanced production of some cytokines [i.e., tumor necrosis factor (TNF)-{alpha}, 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-{alpha}, IL-6, IFN-ß, and MCP-1) are involved in macrophage-mediated immune regulation and share {kappa}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)-{kappa}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-{alpha} and IL-1 [20 21 22 ].



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  		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.

 
Peripheral blood monocytes/macrophages and resident macrophages are cellular targets of HIV infection and their role in the pathogenesis of AIDS has been well established [23 24 25 ]. These cells generally survive HIV replication and may serve as a virus reservoir during the apparent latency period in the course of HIV infection. Moreover, they function as immunoregulatory cells through the production of a variety of cytokines and chemokines in response to HIV or HIV products. Thus, because of the role of macrophages in HIV-1 persistence and subsequent activation/spread of virus infection, it is important to define those cellular factors and mechanisms involved in the regulation of virus expression in these cells. In fact, such knowledge would be extremely helpful in defining selective approaches to control HIV replication and virus spread in patients.

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.


   CORRELATION BETWEEN THE DIFFERENTIATION STAGE OF MACROPHAGES AND SUSCEPTIBILITY TO HIV INFECTION
TOP
 ABSTRACT
 INTRODUCTION
 CORRELATION BETWEEN THE...
HIV-1 RECEPTOR AND CORECEPTOR...
 POSSIBLE MECHANISMS AFFECTING...
 FINAL REMARKS
 REFERENCES
 
Many studies have investigated the cellular requirements for the establishment of a productive infection in monocytes. Table 1 summarizes some representative studies showing that susceptibility of monocytes to HIV infection in vitro is correlated, at least in part, with their level of differentiation. In this regard, HIV-1 resembles some of the other members of the lentivirus subfamily of retroviruses, which replicate more efficiently in tissue macrophages than in blood monocytes [28 , 29 ]. In addition, growth and differentiation factors, such as granulocyte-macrophage colony-stimulating factor (GM-CSF) and macrophage (M)-CSF, can increase HIV replication in monocytes, providing further evidence that the process of differentiation can lead to an enhanced susceptibility to HIV infection [30 31 32 33 34 ]. Although blood monocytes are resistant to productive HIV-1 infection in vitro immediately after isolation, monocytes cultured for as little as 24 h become susceptible to infection [12 ]. Likewise, an increased susceptibility to viral infection is observed with time in culture in monocyte-derived macrophages [8 9 10 11 12 ]. Moreover, a greater permissiveness to HIV infection of human peritoneal macrophages as well as of alveolar macrophages with respect to blood monocytes has been shown [26 , 27 ]. Cord-blood monocyte-derived macrophages also exhibited a higher susceptibility to HIV primary isolates infection. However, no differences were observed with respect to the differentiation state when these cells were infected with laboratory-adapted HIV-1 strains [27 ]. In contrast, some studies demonstrated an inverse correlation between differentiation and susceptibility to HIV infection. In particular, a higher viral replication has been observed in cord-blood monocytes vs. adult monocytes [35 ]. In fact, the less differentiated cells (cord and adult monocytes/macrophages infected at early times of culture) were found to be more productively infected than the more differentiated monocytes/macrophages at later times of culture. Similarly, a decreased susceptibility to HIV infection was also shown by Valentin and colleagues [8 ] in macrophages cultured for 30 days with respect to freshly isolated monocytes and maturing macrophages after 7 days of in vitro culture. Finally, Olafsson and colleagues [27 ] failed to show significant differences in the extent of HIV replication in cultured macrophages with respect to freshly isolated cells. This discrepancy of results is likely related to differences in the viral strain used as well as to technical differences in the manipulation of primary cells. In this regard, it is well established that monocytes/macrophages are extremely responsive to a variety of stimuli, which can markedly affect their phenotype and functional activities [36 ]. Thus, slight variations in the protocols used for monocytes purification and culture may result in major differences in the experimental results and be partly responsible for some of the controversial data available on the differentiation state and susceptibility to HIV infection.


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  		Table 1. Correlation between the Differentiation State of Monocytes and Their Susceptibility to HIV-1 Infection

 

   HIV-1 RECEPTOR AND CORECEPTOR CHANGES DURING MONOCYTE DIFFERENTIATION TO MACROPHAGES
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 ABSTRACT
 INTRODUCTION
 CORRELATION BETWEEN THE...
 HIV-1 RECEPTOR AND CORECEPTOR...
POSSIBLE MECHANISMS AFFECTING...
 FINAL REMARKS
 REFERENCES
 
The recent discovery that certain chemokine receptors are essential coreceptors for HIV and simian immunodeficiency virus (SIV) entry has added an important clue to the comprehension of the mechanisms regulating HIV infection of cells of the macrophage lineage [37 ]. The chemokine receptor CCR5 has recently been identified as the major coreceptor for the entry of nonsyncytium-inducing (NSI) HIV strains into primary CD4 lymphocytes and macrophages [38 39 40 ]. In contrast, T cell line-adapted or symcytium-inducing (SI) strains of HIV-1 use the chemokine receptor CXCR4 as an entry coreceptor [41 ], and dual-tropic strains can use CCR5 and CXCR4 [42 , 43 ]. These findings correlate with inhibition of infection of T cell lines with SI isolates by SDF-1, the natural ligand for CXCR4, and inhibition of infection of primary lymphocytes or macrophages with NSI strains by the chemokines RANTES (regulated on activation, normal T expressed and secreted), macrophage-inflammatory protein (MIP)-1{alpha}, 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.



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  		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.

 

   POSSIBLE MECHANISMS AFFECTING HIV-1 INFECTION OF MONOCYTES/MACROPHAGES
TOP
 ABSTRACT
 INTRODUCTION
 CORRELATION BETWEEN THE...
 HIV-1 RECEPTOR AND CORECEPTOR...
 POSSIBLE MECHANISMS AFFECTING...
FINAL REMARKS
 REFERENCES
 
Cellular transcription factors
It is generally accepted that initiation of HIV transcription is under the control of cellular factors interacting with sequences located in the long-terminal repeat (LTR). Among the multiple regulatory elements described in the HIV LTR, the main inducible regulatory domain is the core enhancer sequence, which binds and responds to the NF-{kappa}B/Rel family of transcription factors [58 , 59 ]. High levels of viral gene expression and replication result in part from the activation of NF-{kappa}B family members, which, in addition to driving viral RNA transcription, orchestrate the host inflammatory response. In fact, NF-{kappa}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-{kappa}B can affect HIV replication and pathogenesis at many different levels, rendering the relationships between HIV expression and NF-{kappa}B activation very complex.

HIV infection has been shown to induce a constitutive NF-{kappa}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-{kappa}B activity [60 ]. Moreover, an increased transcription and processing of the p105 precursor gives rise to increased intracellular pools of NF-{kappa}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 I{kappa}B{alpha}, which could generate a reservoir of NF-{kappa}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-{kappa}B family members in primary monocytes/macrophages [64 65 66 ]. In this regard, we examined the induction of NF-{kappa}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-{kappa}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-{kappa}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-{kappa}B binding activity, p50/p65 and p50/RelB heterodimers expression was detected in Teflon-cultured monocyte-derived macrophages [64 ].



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  		Figure 3. Effect of HIV-1 infection on the expression of p65 and on NF-{kappa}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-{kappa}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.

 
On the whole, the ensemble of these results on the effects of HIV infection on the NF-{kappa}B family expression/activity of NF-{kappa}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-{kappa}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-{alpha}, IFN-ß, and IFN-{gamma} [68 ]. In light of the anti-HIV activities observed in certain in vitro systems, some studies have subsequently documented the efficacy of recombinant IFN-{alpha} 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-{alpha}, previously described in certain autoimmune diseases [73 ]. IFN-{alpha} 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-{alpha} 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-{alpha}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-{alpha} 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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  		Table 2. Dysregulation of the Endogenous IFN System in HIV-1-Infected Individuals

 
We have shown previously that infection of monocytes/macrophages with HIV-1 results in the induction of low levels of IFN-ß, which are very effective in restricting viral replication in differentiated macrophages but not in monocytes [11 ]. Likewise, gp120 treatment induced an IFN-ß-mediated antiviral state to vesicular stomatitis virus (VSV) in 7-day-cultured macrophages but not in 1-day-cultured monocytes [11 ]. This enhanced response of macrophages was a result of the unusually high sensitivity of these cells to IFN with respect to 1-day-cultured monocytes. In this regard, we have shown that differentiation of monocytes to macrophages is associated with an increased expression of type I IFN receptors on the cell surface [14 ]. A progressive reduction of IFN-{alpha}-receptor expression on PBMC during the disease progression to AIDS has been demonstrated previously [75 ]. The reduced binding of IFN-{alpha} 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.



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  		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-{alpha}2 equilibrium saturation-binding studies, as previously described [14]. Cells were incubated with various amounts of [125I]-IFN-{alpha}2. After incubation for 2 h at 4°C, cell pellets were washed extensively, and the radioactivity was measured in a {gamma}-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-{alpha}; nonspecific binding did not exceed 15% of total binding. Each point represents the average of duplicate measurements. ({lozenge}) Control, 1-day-cultured monocytes; ({square}) control, 8-day-cultured monocytes; ({blacksquare}) HIV-infected, 8-day-cultured monocytes; ({circ}) 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).

 
Other soluble mediators
The role of natural soluble factors (cytokines, chemokines), capable of regulating HIV replication by affecting defined molecular pathways (transcription factors) or by modifying the level of cell activation and differentiation, represents an important aspect in the complex network of regulatory pathways governing HIV infection of monocytes/macrophages. Several members of the cytokine network play an important role in controlling HIV replication in monocytes/macrophages as well as in other cell types [82 83 84 ]. Their effects can be inductive or suppressive on HIV replication, and for some of them, multiple and opposite effects have also been described [83 ]. Several macrophage functions are profoundly influenced by cytokines. Indeed, the functional state of these cells can be considered as the end result of the balance of various cytokines (produced by the macrophages themselves as well as by other cell types) capable of regulating, in a positive or negative manner, specific cell functions. Notably, unbalanced cytokine production has been described extensively in AIDS [85 , 86 ], and it is considered to play an important role in the HIV-1 pathogenesis. Several studies have shown that monocytes/macrophages produce a variety of cytokines in response to HIV infection [reviewed in ref. 82 ]. This effect is dependent largely on the initial virus/cell interaction, because it can be mimicked by the exposure of cells to the HIV-1 envelope glycoprotein gp120 [87 ]. In this regard, we have shown previously that gp120 treatment of monocytes/macrophages resulted in the induction of low levels of IFN-ß as well as in a marked increase in IL-10 secretion [88 ]. In contrast, no secretion of IL-12 was detected in monocyte/macrophage cultures treated with gp120 alone. However, consistent secretion of IL-12 was found in 7-day-cultured macrophages primed with IFN-{gamma} and subsequently stimulated with gp120 [13 ]. Thus, macrophages responded more efficiently to the priming effect of IFN-{gamma} for IL-12 production. This was consistent with a stronger IFN-{gamma}-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.


   FINAL REMARKS
TOP
 ABSTRACT
 INTRODUCTION
 CORRELATION BETWEEN THE...
 HIV-1 RECEPTOR AND CORECEPTOR...
 POSSIBLE MECHANISMS AFFECTING...
 FINAL REMARKS
REFERENCES
 
Understanding the mechanisms involved in the regulation of HIV expression in monocytes/macrophages is an issue of crucial importance for the development of novel therapeutic strategies against HIV infection. Regulation of HIV expression is probably the result of a complex network of extracellular signals, such as those provided by certain cytokines and chemokines, together with transcriptional and posttranscriptional effects mediated endogenously by viral and cellular factors.

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-{kappa}B (Fig. 3) . In this regard, we found qualitative differences in the expression of NF-{kappa}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-{kappa}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-{kappa}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.


   ACKNOWLEDGEMENTS
 
This work was supported in part by grants from the Italian Ministry of Health (Progetto di Ricerca sull’AIDS 1999, 40C/H and 40C/C). We are grateful to C. F. Perno for promoting multiple occasions of active discussion on topics relevant to this article. We thank Sabrina Tocchio and Romina Tomasetto for excellent secretarial assistance.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
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