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Originally published online as doi:10.1189/jlb.0403175 on August 21, 2003

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(Journal of Leukocyte Biology. 2003;74:719-725.)
© 2003 by Society for Leukocyte Biology

Monocyte/macrophage-derived CC chemokines and their modulation by HIV-1 and cytokines: A complex network of interactions influencing viral replication and AIDS pathogenesis

Laura Fantuzzi, Filippo Belardelli and Sandra Gessani1

Laboratory of Virology, Istituto Superiore di Sanità, Rome, Italy

1 Correspondence: Laboratory of Virology, Istituto Superiore di Sanità, Viale Regina Elena, 299, 00161 Rome, Italy. E-mail: gessani{at}iss.it


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ABSTRACT
 
Monocytes/macrophages are cells of the innate arm of the immune system and exert important regulatory effects on adaptive immune response. These cells also represent major targets of HIV infection and one of the main reservoirs. Notably, macrophage-tropic viruses are responsible for the initial infection, predominate in the asymptomatic phase, and persist throughout infection, even after the emergence of dual-tropic and T-tropic variants. Functional impairment of HIV-infected macrophages plays an important role in the immune dysregulation typical of AIDS. Recent studies have underlined the pivotal role of chemokines, cytokines, and their receptors in HIV pathogenesis. It is becoming increasingly apparent that the expression level of chemokine receptors, serving as HIV coreceptors, influences the susceptibility of a CD4+ cell to viral infection and to certain HIV envelope-induced alterations in cellular functions. Numerous pathogens, including HIV, can stimulate the production of chemokines and cytokines, which in turn can modulate coreceptor availability, resulting in differential replication potential for R5 and X4 strains, depending on the microenvironment milieu. Thus, a complex network of interactions involving immune mediators produced by monocytes/macrophages and other cell types as a direct/indirect consequence of HIV infection is operative at all stages of the disease and may profoundly influence the extent of viral replication, dissemination, and pathogenesis.

Key Words: infection • immune mediators • regulation


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INTRODUCTION
 
The monocyte/macrophage lineage represents heterogeneous cell populations characterized by major differences in the phenotype and functional activities. Monocytes and macrophages from various tissues are distinct cell populations that are involved differently in a variety of immunoregulatory, phagocytic, and secretory functions [1 ]. These cells are found in all tissues and organs of HIV-infected individuals and play an important role in the pathogenesis of the disease at all stages of infection. They may serve as primary targets for infection and as agents for virus dissemination [2 3 4 ]. Monocyte/macrophage infection is characterized by a viral dynamic substantially different from that of T lymphocytes. In fact, in vivo HIV infection of activated CD4+ T lymphocytes accounts for the majority of the daily production of virus particles. However, a large number of lymphocytes are in a resting state, thus unable to sustain a complete and productive virus life cycle, and contribute only minimally to the daily virus production [5 6 7 ]. Because of the limited HIV-induced cytopathic effect and of their ability to accumulate high levels of HIV particles in intracellular compartments, HIV-infected macrophages may serve as "Trojan horses" exploited by the virus to favor its dissemination in different organs.

This review focuses on our current knowledge on the regulation of peripheral blood monocyte/macrophage-derived CC chemokine production, with a special emphasis to those known to affect HIV replication and their regulation by cytokines. The possible role of the complex network of interactions between these compounds and monocytes/macrophages in the pathogenesis of AIDS will be discussed.


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CC CHEMOKINES PRODUCED BY MONOCYTES/MACROPHAGES AND ROLE OF CYTOKINES IN MODULATING THEIR SECRETION
 
Monocytes and macrophages are highly secretory cells and represent an important source for a variety of soluble immune mediators, including cytokines and chemokines. At the same time, their functions are strongly regulated through the activity of these mediators [8 , 9 ]. HIV infection at all stages of the disease is associated with chronic immune activation and dysfunctional cytokine production [10 , 11 ]. Both monocytes and macrophages are major contributors to the alteration of the cytokine/chemokine network. HIV infection of macrophages is associated with increased production of proinflammatory cytokines, including IL-1, IL-6, IL-8, and TNF-{alpha}, as well as of Th2 cytokines, such as IL-10 [11 ]. Finally, HIV-1 infection of monocytes/macrophages also results in the production of type I interferons (IFNs). In particular, we reported that HIV infection leads to the secretion of low levels of IFN-ß, which is very effective in restricting viral replication in monocyte-derived macrophages (MDM) but not in freshly isolated monocytes [12 ]. The HIV-mediated induction of cytokine expression does not necessarily require productive infection of monocytes/macrophages as, at least for some cytokines (IFN-ß and IL-10), secretion can be observed upon exposure of these cells to HIV-1 surface components, such as gp120 [12 , 13 ]. Chemokines have become the focus of intense investigation since the discovery that at least some of their receptors function as coreceptors for HIV entry into target cells [14 ]. Moreover, accumulating evidence suggests that their function is not restricted to chemotaxis, but they can also directly influence both the innate and acquired immune responses, as well as angiogenesis, collagen production and proliferation of hematopoietic precursors [15 , 16 ]. Chemokines are divided into subclasses on the basis of the spacing of the N-terminal cysteine residues. In the CC family, these residues are located side by side.

On target cells, chemokines bind to seven trans-membrane-domain receptors that are coupled to heterotrimeric G1 proteins [16 ]. Chemokine receptors are divided in families according to the chemokines they bind. In particular, CC chemokines bind to the CCR family, which currently includes at least 10 different members (CCR1 to CCR10). CC chemokines are responsible for attracting monocytes and lymphocytes and to a lesser degree basophils and eosinophils, but not neutrophils [16 ]. The chemokines belonging to the CC family are generally classified in molecules that are made in physiological conditions (constitutive chemokines) and those that are produced in response to diverse signals (inducible or inflammatory chemokines) [9 ]. The general significance of the constitutive CC chemokine compartment is to direct the normal traffic of leukocytes under normal conditions. These molecules include CCL14 (formerly HCC-1), present in the plasma of healthy people, and CCL18 (formerly MIP-4/PARC), constitutively expressed by dendritic cells. In the recent years, it has become evident that a number of CC chemokines are constitutively expressed by peripheral blood monocytes and MDM. As shown in Table 1 , a spontaneous expression of CCL2, CCL3, CCL4 (formerly MCP-1, MIP-1{alpha} and MIP1-ß, respectively) and CCL22 (formerly MDC) has been consistently detected in monocytes and MDM [17 18 19 20 21 22 23 ]. Interestingly, the constitutive secretion of these chemokines is regulated in a differentiation-dependent manner. In particular, we have shown that CCL2, CCL3, and CCL4 secretion increases with time in culture, even though no change in the accumulation of the corresponding mRNA was detected [17 ]. Likewise, CCL22 expression is first detected in monocytes and reaches maximum levels in fully matured macrophages [18 ]. Interestingly, the levels of CC chemokine secretion can vary considerably among donors, and at least for CCL22, an inverse correlation is observed between the levels of secreted chemokine and the efficiency of different HIV-1 strains to replicate in monocytes/macrophages [23 ].


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  		Table 1. Constitutive Expression of CC Chemokines in Monocytes/Macrophages and Their Regulation by Cytokines

Chemokine production is stimulated by a variety of signals interacting with diverse cellular receptors, and represents, together with the cytokines, one of the earliest host response to pathogens [15 ]. As chemokines are part of the circuit involved in generation and amplification of polarized type 1 and type 2 responses, it is not surprising that cytokines capable of activating these responses can regulate chemokine production. For instance, a number of studies have shown that several cytokines, including LIF, IFN-{gamma}, IL-1ß, TNF-{alpha}, IL-4, IL-6 and IL-15, up-regulate the synthesis of CCL2 in monocytes/macrophages [22 , 24 25 26 27 28 ], whereas CCL5 (formerly RANTES) secretion was shown to be up-modulated by IFN-{gamma} and TNF-{alpha} [28 , 29 ]. Moreover, it has been reported that CCL22 production is regulated in a negative or positive manner by a variety of cytokines (Table 1 ). In particular, IL-4, IL-13, IL-1ß and TNF-{alpha} up-modulate CCL22 secretion [18 , 20 , 21 ], whereas IFN-{gamma} and IL-10 have been reported to suppress its expression [20 , 21 ].

Type I IFNs are cytokines spontaneously produced at low levels under normal physiological conditions in freshly isolated macrophages, and their expression is rapidly enhanced upon cell exposure to viruses and other stimuli [30 , 31 ]. In this regard, we reported that IFN-ß is a potent inducer of CC chemokine production, such as CCL2, CCL3, and CCL4, in human monocytes/macrophages, whereas other chemokines, including CCL5 and CCL22, are not up-modulated [17 ]. Interestingly, CCL2 is preferentially secreted by monocytes stimulated with type I IFNs, whereas CCL3 and CCL4 are only produced by differentiated macrophages [17 ].


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REGULATION OF CC CHEMOKINE EXPRESSION BY HIV-1 AND ITS GENE PRODUCTS IN MONOCYTES/MACROPHAGES
 
During HIV infection, large numbers of macrophages and lymphocytes traffic into the brain and lymph nodes, and this characteristic enhancement of cellular migration is believed to play a pivotal role in the pathogenesis of HIV disease [2 3 4 ]. Therefore, selective expression of chemoattractant cytokines by HIV-infected monocytes/macrophages could intervene in this process. Notably, macrophages and other cells of monocytic origin are among the first to be infected by HIV-1. Thus, during initial infection, expression of chemokines would allow the generation of an inflammation center, recruiting and activating various populations of responding cells, thus creating an improved environment for HIV-1 dissemination.

In keeping with this hypothesis, a number of studies have indeed shown that changes in the production of specific chemokines occur in the course of HIV infection. As shown in Table 2 , an increased production of CCL2, CCL3, CCL4, and CCL5 have been observed in macrophages infected in vitro with HIV-1 [32 33 34 35 ]. HIV-1-mediated stimulation of chemokine production in these cells has been generally observed in the presence of active viral replication [32 , 33 , 35 ]. Interestingly, a role in the control of chemokine production during HIV-1 infection of macrophages has been attributed to the accessory protein vpr. In fact, it has been reported that infection of macrophages with vpr-negative viruses leads to an enhanced production of CCL3, CCL4, and CCL5 as compared with vpr-positive viruses [36 ].


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  		Table 2. Chemokine Expression in Monocytes/Macrophages Upon HIV-1 Infection or Exposure to HIV-1 Gene Products

However, a number of studies have clearly demonstrated that exposure of monocytes/macrophages to soluble viral products can trigger CC chemokine production. In this regard, it has been reported that early interactions between monocytes/macrophages cell surface and HIV-1 external components can stimulate CC chemokine production in the absence of productive infection. In fact, we have reported that exposure of monocytes/macrophages to recombinant R5 (JRFL) and X4 (IIIB) HIV-1 gp120, as well as to aldrithiol-2 (AT-2) inactivated viruses (strains BaL and IIIB) up-modulates the production of CCL2, CCL4, and CCL5. Notably, CC-chemokine secretion was also induced upon engagement of CCR5 and CXCR4, but not CD4 receptors, by specific antibodies or ligands [37 ].

Moreover, it has been shown that, independently of their coreceptor phenotype and of virus replication, exposure to certain R5 and X4 HIV-1 species, but not to others, results in the secretion of CCL3, CCL4, and CCL5, [38 ]. Likewise, CCL2 secretion was observed in differentiated macrophages stimulated with exogenous tat [35 ], whereas adenovirus-mediated expression of nef in these cells was sufficient to induce transient production of CCL3 and CCL4 [39 ].


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CC CHEMOKINES AS MODULATORS OF PRODUCTIVE HIV INFECTION OF MONOCYTES/MACROPHAGES
 
Since the discovery of the importance of chemokine receptors in the regulation of HIV entry into target cells, it became evident that certain ligands for these receptors could inhibit HIV-1 infection [14 ]. However, it soon appeared that other chemokine effects were also possible, namely the enhancement of HIV-1 replication, as opposed to its inhibition [40 ]. Moreover, alternative mechanisms of chemokine-mediated inhibition of HIV-1 replication involving postentry events in the virus life cycle have also been reported [40 ]. A summary of the main regulatory effects of CC chemokines on HIV-1 replication in monocytes/macrophages is shown in Table 3 . Some studies reported the expected inhibition of macrophage infection by R5 HIV-1 strains in the presence of CCR5 binding chemokines [41 42 43 44 45 ]. The molecular basis for this effect relies on competition between the virus and the chemokines for binding sites on the common CCR5 receptor, receptor down-regulation in response to chemokine binding and signaling, which may act by reducing the density of available CCR5 receptors on the cell surface [46 ].


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  		Table 3. Regulatory Effects of Chemokines on HIV-1 Replication in Monocytes/Macrophages

The effect of CC chemokines on HIV infection of macrophages has been reported to be highly dependent on the macrophage maturation stage, as well as the time of chemokine addition relative to virus infection. In fact, exposure of MDM to CC chemokines at the time of HIV-1 infection, or after infection, significantly inhibited HIV-1 replication. However, stimulation of freshly isolated monocytes with CC chemokines prior to HIV-1 infection rendered them more susceptible to infection and increased virus replication [42 ].

In addition to their blocking effect on viral entry, CCR5-binding chemokines have been shown to stimulate HIV attachment, replication, and cell-mediated transmission [42 , 47 48 49 ]. The stimulatory effects of CC chemokines were shown to be dependent on cell-signaling events involving pertussis toxin-sensitive G protein-linked pathways [42 ]. Therefore, CC chemokines might stimulate a number of intracellular mechanisms in macrophages as observed in lymphocytes, ultimately leading to increased HIV replication [49 50 51 ]. Furthermore, up-modulation of HIV replication might also be due to chemokine-mediated macrophage activation [42 ]. Gordon and colleagues [52 ] reported that CCL5 can enhance HIV infection in macrophages, in a manner independent of CCR5 or any other known receptor, and even independent of the normal route of virus entry. In particular, the enhancing effect of CCL5 on HIV-1 replication has been linked to its tendency to form aggregates at high concentrations. In fact, at lower concentrations, CCL5 would act in a monomeric or dimeric form by directly binding to its receptors, whereas, at high concentrations, it would self-aggregate and interact with cell surface glycosaminoglycans. This interaction would result in transducing signals, which render cells more permissive to HIV infection [47 48 49 , 52 ].

Exogenous CCL2, like CCL5, has been shown to enhance the replication of X4 HIV-1 strains in activated PBMCs, and a positive correlation between CCL2 expression and enhancement of HIV-1 replication in the majority of CD8-depleted PBMCs from infected individuals has been reported [53 ]. Interestingly, depletion of CD14+ cells (mostly monocytes) from allogeneic T cell blasts resulted in the down-modulation of virus replication in cocultivation experiments [54 ], whereas addition of exogenous CCL2 restored control levels of virus replication in some of these cultures [53 ], suggesting that this chemokine can directly activate virus replication. Finally, it has been recently reported that CCL22 exhibits a postentry inhibitory effect on the replication of the R5 HIV-1 strain BaL in MDM [23 ], suggesting that chemokines can affect the HIV-1 life cycle at different levels through the action of multiple mechanisms.


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EARLY INTERACTIONS BETWEEN HIV-1 SURFACE COMPONENTS AND MACROPHAGES LEADING TO CC CHEMOKINE EXPRESSION: ROLE IN THE CONTROL OF VIRAL REPLICATION AND PATHOGENESIS
 
The intense research on the mechanisms of HIV entry into, and replication within, host target cells and the generation of HIV-specific immunity has provided important knowledge on the viral transmission mechanisms and disease progression, events collectively called HIV pathogenesis. However, the molecular and immunological basis of HIV pathogenesis still remains one of the central challenging issues of AIDS research. The immunological deficit typical of AIDS is generally described as a progressive decline of CD4+ T cells. However, this description is insufficient, as it overlooks a multifactorial process starting at the moment of infection. In fact, substantial loss of CD4+ T cells is preceded by a series of events including repeated cycles of target cell activation and subsequent immune dysregulation [55 , 56 ].

Strong evidence suggests that M-tropic variants are critical for AIDS pathogenesis. In fact, the majority of viruses implicated in the transmission of HIV infection are CCR5 coreceptor users. This is supported by the fact that variants commonly isolated after primary infection are M-tropic and CCR5 is the major coreceptor for entry of M-tropic strains into target cells [14 ].

Initial interaction of HIV-1 with target cells takes place through binding of gp120 to CD4, which leads to conformational changes allowing the interaction of viral glycoproteins with a chemokine receptor, usually CXCR4 or CCR5. Envelope/coreceptor engagement triggers gp41 rearrangement and exposure of the fusogenic domain leading to fusion [57 ]. In addition, HIV target cells can also be exposed to different HIV gene products, expressed at the cell surface of infected cells, secreted, or released in the microenvironment as a consequence of the death of infected cells. HIV-soluble products are likely to exert bystander effects on neighboring cells in the absence of productive infection. For instance, it has been shown that gp120 is released in the circulation of HIV-infected subjects, and it is thought to have a role in the progressive immune derangement observed in these patients [58 ].

A hypothetical model illustrating the effects of early interactions between macrophages and HIV-1 leading to CC chemokine production and their role in the pathogenesis of AIDS is shown in Fig. 1 . In light of our results as well as of previously published data, we can envisage that, upon initial contact between gp120 and macrophage surface components, the production of a panel of CC chemokines (i.e., CCL2, CCL3, CCL4, CCL5) is induced. This effect has been shown to be mediated through the direct engagement of both CXCR4 and CCR5 receptors and apparently does not involve CD4 [37 ].



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  		Figure 1. Hypothetical model illustrating the effects of early interactions between macrophages and HIV-1 surface components leading to CC chemokine production and their role in the pathogenesis of AIDS. The model mostly reflects the results obtained by our group [12 ,17 ,37 ]. Other non-CC chemokines induced by HIV infection as well as by viral components may play additional roles in the control of viral replication, spreading, and pathogenesis.

Concomitantly, interaction of HIV surface components with macrophages also leads to the production of low levels of IFN-ß, which can act on macrophages further stimulating CC chemokine production (i.e., CCL2, CCL3, CCL4). Likewise, macrophages can produce a number of other cytokines (i.e., IL-6, TNF-{alpha}, IL-1ß, IL-10) in response to HIV-1 infection or after exposure to envelope proteins, which may also contribute to the regulation of CC chemokine expression.

The capacity of gp120 to induce CC chemokines in macrophages is not restricted to specific viral strains, suggesting that this gp120-mediated effect can be operative during all stages of disease. Thus, the interaction of both X4 and R5 HIV-1 envelope glycoproteins with chemokine receptors can, even in the absence of HIV-1 entry and replication, result in the activation of signal transduction pathways leading to chemokine expression. These soluble mediators, produced by both infected cells and bystander uninfected cells triggered by viral products (i.e., tat, nef, and gp120), may regulate the course of HIV infection by either directly controlling the extent of viral infection/replication or through their chemoactractive effect on immune cells. Production of chemokines may represent a protective response of macrophages to HIV infection and contribute to limit viral spreading by blocking specific coreceptors usage in still uninfected cells. Moreover, the release of these factors can play a role in the recruitment of specific immune effectors endowed with the capacity to mount HIV-specific antiviral responses. It is also reasonable to assume that at least some of these chemokines can contribute to maintain the infection of macrophages to an extent compatible with their survival. On the other hand, hyper-production of CC chemokines, during the course of infection, may enhance viral spreading by favoring the infection of newly recruited immune cells, thus contributing to the AIDS pathogenesis. In fact, CCL2, CCL3, CCL4, and CCL5 exhibit chemoactractant properties on monocytes/macrophages, dendritic cells and activated lymphocytes, all susceptible to viral infection. Although the in vivo biological relevance for the enhanced chemokine production remains to be elucidated, it is reasonable to assume that the balance of their negative vs. positive effects on HIV spreading may contribute to different outcomes of the HIV disease.


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FINAL REMARKS
 
The chemokine/cytokine network is profoundly involved in the control of HIV infection as it is both a main target of the HIV-induced dysregulation and, at the same time, a complex modulator of the susceptibility of immune cells to infection and replication. The recent findings that chemokines can affect binding, entry, and post-entry events, and that cytokines can influence HIV infection by modulating the expression of chemokines and their receptors as well as the extent of viral replication, further support the general model that multiple steps of the life cycle of HIV are regulated by this network (Table 2 and 3) . Macrophages serve as a major reservoir and vehicle for dissemination of HIV in different tissues. Thus, HIV harbored in these cells may escape immune surveillance and antiviral therapy. Although highly active antiretroviral therapy (HAART) significantly suppresses viral replication, ongoing viral replication and spreading has been observed during HAART, especially in macrophages with respect to resting T cells [59 ]. Therefore, macrophages can play a key role in regulating the intensity and progression of HIV disease even during therapy, and their secretory products have been implicated in the pathogenesis of AIDS [2 3 4 , 10 , 11 ]. In conclusion, exploitation of knowledge on the interactions between HIV and macrophages in their milieu of cytokines and chemokines may lead to novel and more effective strategies of preventive or therapeutic interventions. Unraveling this complex network of interactions is of relevance for the eradication of tissue viral reservoirs of long-lived, latently infected cells, as well as for the development of molecules capable of interfering with HIV entry by targeting chemokine receptors.


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ACKNOWLEDGEMENTS
 
We thank Lucia Conti for helpful discussion and support, Stefano Billi, and Anna Maria Fattapposta for editorial assistance. This work was supported by grants from the Italian Ministry of Health (Progetto di ricerca sull’AIDS).

Received April 23, 2003; revised July 7, 2003; accepted July 7, 2003.


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