Pro- and anti-inflammatory cytokines in human immunodeficiency virus infection and acquired immunodeficiency syndrome

Pharmacology & Therapeutics 95 (2002) 295 – 304

Associate editor: P.K. Chiang

Pro- and anti-inflammatory cytokines in human immunodeficiency virus infection and acquired immunodeficiency syndrome Elizabeth Crabb Breen* David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1740, USA

Abstract In persons with human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS), the immune system becomes dysfunctional in many ways. There is both immunodeficiency due to the loss of CD4-positive T helper cells and hyperactivity as a result of B-cell activation. Likewise, both decreases and increases are seen in the production and/or activity of cytokines. Cytokine changes in HIV infection have been assessed by a variety of techniques, ranging from determination of cytokine gene expression at the mRNA level to secretion of cytokine proteins in vivo and in vitro. Changes in cytokine levels in HIV-infected persons can affect the function of the immune system, and have the potential to directly impact the course of HIV disease by enhancing or suppressing HIV replication. In particular, the balance between the pro-inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor-a, which up-regulate HIV expression, and IL-10, which can act both as an anti-inflammatory cytokine and a B-cell stimulatory factor, may play an important role in the progression to AIDS. In light of its ability to suppress the production of pro-inflammatory cytokines and, under some conditions, suppress HIV replication, increased IL-10 may be viewed as beneficial in slowing HIV disease progression. However, an association between increased IL-10 and the development of AIDS-associated B-cell lymphoma highlights the bifunctional nature of IL-10 as both an anti-inflammatory and B-cell-stimulatory cytokine that could have beneficial and detrimental effects on the course of HIV infection and AIDS. D 2002 Elsevier Science Inc. All rights reserved. Keywords: HIV; Cytokine; IL-6; TNF-a; IL-10; Lymphoma Abbreviations: AIDS, acquired immunodeficiency syndrome; AIDS-lymphoma, AIDS-associated non-Hodgkin’s B-cell lymphoma; CD4+, CD4-expressing; HIV, human immunodeficiency virus; HIV+, HIV-infected; IFN, interferon; IL, interleukin; mØ, monocyte/macrophage; NF-kB, nuclear factor-kB; Th, T helper; TNF, tumor necrosis factor.

Contents 1. 2. 3.

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Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Evaluation of cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Pro-inflammatory cytokines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.1. An inflammatory trio . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3.2. Interleukin-1, interleukin-6, and tumor necrosis factor-a in human immunodeficiency virus infection and acquired immunodeficiency syndrome . . . . . . . . . . . . . . Interleukin-10 as an anti-inflammatory cytokine . . . . . . . . . . . . . . . . . . . . . . . 4.1. The actions of interleukin-10 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2. Interleukin-10 in human immunodeficiency virus infection and acquired immunodeficiency syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . The balance of cytokines in human immunodeficiency virus infection and acquired immunodeficiency syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

* Tel.: 310-206-6846; fax: 310-206-5387. E-mail address: [email protected] (E.C. Breen). 0163-7258/02/$ – see front matter D 2002 Elsevier Science Inc. All rights reserved. PII: S 0 1 6 3 - 7 2 5 8 ( 0 2 ) 0 0 2 6 3 - 2

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5.1. 5.2. 5.3.

The T helper 1/T helper 2 cytokine hypothesis in human immunodeficiency virus disease Interleukin-10 versus the inflammatory trio in human immunodeficiency virus infection . Interleukin-10 as a bifunctional mediator of human immunodeficiency virus disease progression . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The first cases of what came to be known as acquired immunodeficiency syndrome (AIDS) were recognized in the early 1980s (Gottleib et al., 1981a; Friedman-Kien et al., 1981). They appeared as clusters of reports of previously healthy middle-aged persons with illnesses that were usually seen only in the context of profound immunosuppression (Pneumocystis carinii pneumonia) and/or more advanced age (Kaposi’s sarcoma). It was immediately observed that the major immune system deficit in persons with AIDS was the loss of a critical subset of lymphocytes, the CD4expressing (CD4+) T-cells (Gottleib et al., 1981b). As the immunologic changes associated with AIDS were better defined, it was shown that CD4+ T-cells declined not only in number, but also in function, with a loss of the ability to serve as helper cells to other white blood cells of the immune system (Mildvan et al., 1982; Schroff et al., 1983; Fahey et al., 1984). It was also observed that while T helper (Th) cells were underactive, B lymphocytes were hyperactive in persons with AIDS, as indicated by elevated levels of immunoglobulin and increased numbers of activated B-cells in the circulation (Lane et al., 1983; Lane & Fauci, 1985; Yarchoan et al., 1986; Martı´nez-Maza et al., 1987; Miedema et al., 1988). This hyperactivity was nonspecific, with the result that B-cells of persons with AIDS were less able to mount specific antibody responses when challenged. These basic, but paradoxical, observations in the early years of the AIDS epidemic were merely a hint of the complex immune system dysregulation that was to be characterized in the future. With the isolation of human immunodeficiency virus (HIV)-1 in 1983 and 1984 (Barre-Sinoussi et al., 1983; Gallo et al., 1984; Levy et al., 1984) and the development of HIV-specific antibody testing in 1985, the scope of studies of the immunobiology of the AIDS epidemic broadened tremendously, as it was now possible to examine immune system changes in individuals who were infected with HIV, but not yet showing external signs of immunodeficiency (Rosenberg & Fauci, 1989). The observation of concomitant T-cell deficiency and B-cell hyperactivity in AIDS was expanded to show that evidence of both immunodeficiency and immune system hyperactivity could be found in HIVinfected (HIV+) persons long before the clinical development of AIDS (Fauci, 1993). In particular, it was shown that the production and/or activity of a number of different cytokines, the soluble secreted proteins that serve as mes-

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senger molecules between cells, were clearly dysregulated in the context of HIV infection and/or AIDS. Similar to the earlier observations of T- and B-cells in AIDS, the production of some cytokines was decreased while others were increased in association with HIV infection. As the understanding of the virology of HIV improved, it also became apparent that some cytokines could directly impact the life cycle of HIV, thus potentially contributing to disease pathogenesis (Fauci, 1993, 1996; Poli, 1999). While there are many aspects of cytokine changes in HIV infection and AIDS, this review will focus on the pro-inflammatory cytokines interleukin (IL)-1, IL-6, and tumor necrosis factor (TNF)-a that have been demonstrated to increase HIV replication; the anti-inflammatory cytokine IL-10; and the potential significance of the balance between these two types of cytokines in HIV disease.

2. Evaluation of cytokines Cytokines are a heterogeneous group of proteins that typically are secreted in order to exert an effect upon a target cell (Goldsby et al., 2000). Occasionally, this is an autocrine effect, with a secreted cytokine acting upon the cell that produced it. However, in most cases, cytokines act in a paracrine fashion, being secreted by one cell and acting on another (Fig. 1). The action of a secreted cytokine is limited to those target cells that express the appropriate cell-surface receptor. Once a receptor on the target cell surface has specifically bound the soluble cytokine, it must transmit a signal to the interior of the target cell. Upon receipt of such a signal, the target cell responds in some fashion, usually with new gene expression, leading to cellular proliferation and/or differentiation. There are many ways to evaluate the activity, production, and/or expression of cytokines. When various cytokines were first described (using highly descriptive names), it was on the basis of biologic activity observed in crude culture supernatants in vitro. The identification and cloning of cytokine genes permitted the production of recombinant cytokine proteins [and often led to the renaming of cytokines with more specific terms, such as ILs or interferons (IFNs)]. In turn, pure cytokine preparations enabled the development of more specific biologic assays utilizing cell lines as targets and of monoclonal antibodies and enzymelinked immunosorbent assays for quantitating cytokine protein levels in body fluids or culture supernatants. With

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Fig. 1. The paracrine action of a cytokine on a target cell. While a cell can secrete multiple cytokines (represented by different shapes), a cytokine can act on a target cell only if that cell is expressing the proper cytokine receptor. Upon binding to the receptor, the cytokine transmits a signal to the nucleus of the cell. Adapted from Breen (2000).

further technical advances utilizing reverse-transcription and polymerase-chain reaction, cytokine gene expression could be analyzed at the mRNA level. Therefore, the evaluation of cytokines in health and disease can be accomplished in many different ways. When reviewing studies of cytokine changes, it is important to take into account the type of cytokine measurement being made (Romagnani, 2000). Cytokine measurements at the most basic molecular level, i.e., mRNA transcribed from cytokine genes, may be a valuable indicator of the extent of transcriptional activation of cytokine genes within a cell, but may not reflect the actual production of cytokine protein due to post-transcriptional and posttranslational events. Measurement of secreted cytokines, either in culture supernatants produced in vitro or circulating levels in vivo in serum or other body fluids, are the most direct indicator of cytokine protein production, but may be affected by the half-life of a particular protein and/or the amount of a cytokine that is bound to receptors on the surface of target cells. Finally, biologic assays, while most representative of the actual activity of a cytokine of interest, may be influenced by mixtures of cytokines that may be present. This is not to say that valid comparisons of cytokine changes in health or disease cannot be made utilizing any one of these techniques. Rather, it is a reminder that data obtained by different means of cytokine measurement may not be directly comparable. One additional aspect of evaluating and comparing results of cytokine measurements bears mention. Regardless of the technique used to obtain a cytokine measurement, it is important to note whether the measurement reflects cytokine activity in vivo or the capacity to produce cytokine

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in vitro in response to stimulation. In vivo cytokine activity can be determined by examining cytokine gene expression in or cytokine secretion by cells taken directly from the body, with no additional stimulation, or by measuring circulating cytokine levels in body fluids, such as serum, cerebrospinal fluid, etc. In vitro stimulation of cells and measurement of secreted cytokine following stimulation does not reveal differences in the basal level of cytokine production in vivo, but rather, demonstrates the ability of the cells ex vivo to mount a response to a defined stimulus. In the field of cytokines and HIV, both types of observations have been made, often with conflicting results (Romagnani et al., 1994). Therefore, just as different techniques of measuring cytokines may not be strictly comparable, these two different approaches to assessing cytokine activity may not necessarily produce the same result.

3. Pro-inflammatory cytokines The main producers of cytokines are CD4+ Th cells and monocytes/macrophages (mØs). Th cells are antigen-specific, and so become activated in vivo to secrete cytokines only after recognizing and interacting with a particular antigen. In contrast, monocytes (in the circulation) and macrophages (in the tissues) are nonspecific phagocytic cells that become activated and secrete cytokines following phagocytosis of nearly any type of foreign material or cellular debris. mØs are an essential part of the nonspecific or innate immune response, and the secretion of cytokines by activated mØs (sometimes referred to as ‘‘monokines’’) facilitates the development of a localized inflammatory reaction at a site of injury or infection, as well as the production of acute-phase proteins and complement components that contribute to inflammation. 3.1. An inflammatory trio There are many cytokines secreted by activated mØs. However, there is a trio of pro-inflammatory cytokines that warrant consideration as a group: IL-1, TNF-a, and IL-6. These three cytokines, whose expression is linked, are responsible for many aspects of both localized and systemic inflammatory responses. mØ activation by phagocytosis induces IL-1 and TNF-a gene expression, which, in turn, activates IL-6 gene expression and production. While all three cytokines have pro-inflammatory effects, they differ somewhat in their particular effects on various target cells. IL-1 is a highly pleiotropic cytokine, with a wide range of activities on many different target cells, both within and beyond the immune system. In addition to acting locally as a chemotactic factor to draw mØs and neutrophils to an inflammatory site, IL-1 also acts systemically on the hypothalamus as the primary inducer of fever (one of the first lines of defense of the innate immune system) (Goldsby et

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al., 2000). IL-1 also amplifies the secretion of pro-inflammatory cytokines by activated mØs by inducing IL-6 gene expression. TNF-a originally was described for its ability to induce cell death (necrosis) in tumor cells, but not in normal healthy cells, and has also been shown to be responsible for tissue wasting or cachexia (Goldsby et al., 2000). Its role as an inflammatory cytokine is to initiate a cascade of cytokine production by inducing secretion of other cytokines (including IL-6) by its target cells. TNF-a exerts this effect by activating a cellular transcription factor, nuclear factor-kB(NF-kB), which then induces the expression of cytokine and other cellular genes (Fauci, 1996). IL-6 was first identified and cloned as ‘‘B-cell differentiation factor,’’ which is produced by antigen-activated Th cells and drives antigen-activated B-cells to mature into antibody-secreting plasma cells (Kishimoto, 1989; Goldsby et al., 2000). However, in its role as a pro-inflammatory cytokine, IL-6 is produced by mØs in response to activation and IL-1 and TNF-a secretion, and acts systemically by inducing the production of acute-phase proteins (such as Creactive protein) by hepatocytes. 3.2. Interleukin-1, interleukin-6, and tumor necrosis factora in human immunodeficiency virus infection and acquired immunodeficiency syndrome The first possible link between pro-inflammatory cytokines and HIV disease was demonstrated by the ability of HIV, or its cell surface glycoprotein, to induce secretion in vitro of IL-1, IL-6, and/or TNF-a by monocytes isolated from the peripheral blood of HIV-uninfected individuals (Nakajima et al., 1989; Merrill et al., 1989; Wahl et al., 1989). These reports indicated that exposure to HIV or recombinant HIV proteins, not infection, was sufficient to induce the production of these monokines, suggesting that only cell-surface interactions were necessary. Additional reports of elevated levels of IL-1, IL-6, and TNF-a in serum and culture supernatants of cells from HIV+ individuals provided evidence that pro-inflammatory cytokines were being overproduced in vivo in association with HIV infection (Molina et al., 1989; Roux-Lombard et al., 1989; Weiss et al., 1989; Breen et al., 1990; Fauci, 1996). At nearly the same time, it was observed that IL-1, IL-6, and especially TNF-a, alone and in synergy with one another, could act on HIV+ cells to up-regulate HIV replication and production (Fauci, 1996; Poli, 1999). Thus, a full (and potentially vicious) circle had been described where exposure to and/ or infection of mØs by HIV could induce secretion of this trio of cytokines, which could, in turn, increase HIV replication and raise the likelihood of further secretion of IL-1, IL-6, and TNF-a. This raised the possibility that the dysregulation of these cytokines in an HIV+ person was not merely a by-product of the effects of HIV on the immune system, but rather, could be contributing directly to the pathogenesis of HIV disease and the progression to AIDS.

The molecular mechanism for up-regulation of HIV expression by pro-inflammatory cytokines is best characterized for TNF-a, which activates NF-kB, a transcription factor that is sequestered in an inactive form in the cytoplasm of cells (Fauci, 1996, Poli, 1999). TNF-a exerts its effects on HIV+ cells by activating NF-kB, which translocates to the nucleus, binds near the transcription start site of HIV (located in the long terminal repeat sequences of the viral genome), and initiates and/or enhances HIV expression and viral production. IL-1 is thought to act in a similar manner, perhaps also involving NF-kB, to initiate and upregulate HIV transcription, while IL-6 has been shown to enhance HIV replication by both transcriptional and posttranscriptional mechanisms (Poli, 1999).

4. Interleukin-10 as an anti-inflammatory cytokine 4.1. The actions of interleukin-10 The identification of IL-10, and eventual isolation and cloning of the human IL-10 gene, rested primarily on its ability to inhibit the synthesis of cytokines by T-cells, natural killer cells, and mØs (Fiorentino et al., 1989; Vieira et al., 1991). This was reflected in its original name, ‘‘cytokine synthesis inhibitory factor’’ (Fiorentino et al., 1989). However, as so often has been the case in cytokine biology, once purified and/or recombinant protein was available, it became apparent that IL-10 had other activities (as reviewed in Moore et al., 2001). These included direct inhibition of mØs as antigen-presenting cells, primarily through the reduction of cell surface expression of major histocompatibility complex Class II molecules (which, in turn, indirectly inhibits antigen-specific T-cell proliferation) (Fiorentino et al., 1991; de Waal Malefyt et al., 1991; Ding and Shevach, 1992) and the ability to act as a stimulatory factor for B-cells (Rousset et al., 1992). IL-10 exerts multiple effects on B-cells, where it can serve as a potent cofactor for proliferation of activated cells, drive isotype switching and/or differentiation into antibody-secreting plasma cells, and enhance the survival of B-cells by protection from apoptosis (Moore et al., 2001). Upon the isolation and sequencing of the human gene for IL-10, it was discovered that it was highly homologous (84% amino acid identity) to a gene that previously had been reported within the genome of the Epstein-Barr virus (Moore et al., 1990; Vieira et al., 1991). This was the first example of capture of a human cytokine gene by a virus, with expression of the viral version of the cytokine gene during the lytic phase of virus infection (Hudson et al., 1985; Stewart et al., 1994). Since human IL-10 and viral IL10 are quite similar, except for the N-terminal region, viral IL-10 has some of the same activities of human IL-10 (especially B-cell stimulatory activity), and most anti-IL10 antibodies will recognize both proteins (Moore et al., 2001).

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As discussed in Section 3, when mØs become activated following phagocytosis, a number of cytokines, including the IL-1/TNF-a/IL-6 trio, are rapidly secreted to facilitate an inflammatory response. This burst of inflammatory cytokines can be effectively inhibited by IL-10, which is also produced by activated mØs, but not until 8 – 10 hr after activation (Takeshita et al., 1995). IL-10 exerts both transcriptional and post-transcriptional controls to prevent the generation of mRNA and/or protein, not only for IL-1/ TNF-a/IL-6, but also for other inflammatory cytokines, such as IL-8 and IL-12, and even itself (Moore et al., 2001). Therefore, when acting as an anti-inflammatory cytokine, IL-10 may serve as the natural terminator of cytokine synthesis by activated mØs, ensuring that a chronic state of inflammation does not develop. 4.2. Interleukin-10 in human immunodeficiency virus infection and acquired immunodeficiency syndrome Since its description a little more than a decade ago, IL10 has been the subject of many studies in the context of HIV infection and AIDS. Similar to the pro-inflammatory monokines described in Section 3, secretion of IL-10 by monocytes can be induced by infection with or exposure to HIV or HIV components (Akridge et al., 1994; Ameglio et al., 1994a; Masood et al., 1994; Takeshita et al., 1995; Barcova et al., 1998). Increased production of IL-10 in vivo and in vitro has often been reported in association with HIV infection (Emilie et al., 1990; Fauci, 1993; Ameglio et al., 1994b; Graziosi et al., 1994; Mu¨ller et al., 1998; Stylianou et al., 1999; Poli, 1999). However, there are other reports (Emilie et al., 1992, 1997; Blay et al., 1993; Edelman et al., 1996), including a very recent one from our laboratory (Breen et al., 2002), suggesting that increased IL-10 in vivo, as measured by serum IL-10 levels or in situ detection of IL10 in lymph nodes, is associated not with HIV infection or AIDS in general, but rather, specifically with the development of AIDS-associated non-Hodgkin’s lymphoma. These conflicting observations may reflect the use of different assays for IL-10 with varying levels of sensitivity and specificity, as many antibodies that recognize IL-10 are unable to distinguish between human IL-10 and viral IL-10 produced by Epstein-Barr virus. It also highlights the different interpretations that can result from examining gene expression at the mRNA level, circulating levels in serum, and secretion of protein in vitro. Taken as a whole, the published record indicates that IL-10 may be overproduced in at least some proportion of HIV+ individuals, and so, should be viewed as part of the cytokine changes seen in HIV infection and AIDS. An additional approach to evaluating the potential contribution of IL-10 to HIV infection and AIDS was reported recently (Shin et al., 2000), utilizing genetic analyses of single-nucleotide polymorphisms in the promoter region of the IL-10 gene that have been shown to affect IL-10 expression in vitro (Rossenwasser & Borish, 1997; Crawley

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et al., 1999). Analysis of a single-nucleotide polymorphism at the 50 – 592 position in the IL-10 gene in more than 3000 subjects showed that individuals bearing a genotype associated with lower IL-10 expression (IL-10-50 – 592 A/A or C/ A) progressed more rapidly to AIDS after 5 years. Conversely, a high IL-10-expressor genotype (IL-10-50 –592 C/ C), which presumably gave rise to higher levels of IL-10 in vivo, appeared to be protective against HIV disease progression.

5. The balance of cytokines in human immunodeficiency virus infection and acquired immunodeficiency syndrome 5.1. The T helper 1/T helper 2 cytokine hypothesis in human immunodeficiency virus disease In the mid-1980s, a new paradigm emerged regarding the production of cytokines by Th cells. Based on observations originally made using cloned murine T-cells (Mosmann et al., 1986), Th cells were viewed as being composed of two distinct subsets, Th1 and Th2, that were distinguished by mutually exclusive patterns of cytokine secretion in vitro (Fig. 2). Th1 cells produced cytokines, such as IL-2 and IFN-g, that promoted cell-mediated immunity, while Th2 cells produced cytokines that promoted antibody-mediated immunity, i.e., B-cell stimulatory factors, such as IL-4 and IL-6, or inhibited the activity of Th1 cells (Mosmann & Coffman, 1989). IL-10 was included as a Th2 cytokine because of its indirect inhibition of Th1 cells via its direct effects on antigen-presenting cells, including mØs (Mosmann & Moore, 1991; Moore et al., 2001). In addition, the inhibition by IL-10 of the production of inflammatory cytokines by mØs was viewed as promoting Th2 responses by reducing the overall effectiveness of the cell-mediated immunity promoted by Th1 cells. The Th1/Th2 paradigm was shown to apply in a more limited way to human cells, as cloned or stimulated Th cells from normal individuals secreted both Th1 and Th2 cytokines, with a clear division of subsets only apparent in certain chronic diseases (Romagnani, 1995). Based on measurements of cytokine secretion following in vitro stimulation of peripheral blood mononuclear cells, a hypothesis was introduced suggesting that a shift in the balance of production of Th1 versus Th2 cytokines was a major contributor to HIV disease progression (Clerici & Shearer, 1993, 1994). It was proposed that early in HIV infection, a vigorous cell-mediated immune response, facilitated by Th1 cells, effectively controlled the amount of HIV in the body. However, with time, the predominant cytokine response shifted to a Th2 response, leading to a loss of effective cell-mediated immunity against HIV, permitting increased levels of viral replication, extensive damage to the immune system, and progression to AIDS. According to this hypothesis, this placed IL-10 in the position of contributing to

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Fig. 2. Cross-regulation of Th1 and Th2 cytokines. Cytokines produced by Th1 and Th2 cells not only stimulate different types of immune responses, but also act to inhibit each other’s functions. Solid arrows indicate cytokine production and/or stimulatory effects; dashed arrows indicate inhibitory effects. Adapted from Goldsby et al. (2000).

HIV disease progression by dampening cell-mediated immunity. Although there were (and continue to be) reports supporting the idea of a Th1 to Th2 shift contributing to HIV disease, many of these were based on observations of cytokine production following in vitro stimulation of peripheral blood mononuclear cells, which are composed of both CD4+ Th and CD8+ T cytotoxic cells, as well as Bcells, natural killer cells, and monocytes. As discussed in Section 2, this experimental approach may reveal differences between the capacities of individuals’ cells to secrete cytokines in response to stimuli in vitro, but may not accurately reflect physiologically relevant differences in the in vivo cytokine status of cells. In addition, many studies focused on only IL-2 and IL-4 as representative of Th1 and Th2 activity, respectively, failing to take into account other Th1 or Th2 cytokines, such as IFN-g or IL-10. This approach also often did not consider the production of cytokines by non-T-cells, especially the pro-inflammatory trio of IL-1/IL-6/TNF-a. As additional studies used other experimental approaches that might be considered to more accurately reflect the status of cytokine production in vivo (such as cytokine gene expression and/or secretion by unstimulated cells), and the contribution of other cell types besides CD4+ Th cells, it became apparent that the cytokine changes associated with HIV disease were far more complex than suggested by the simple Th1/Th2 shift hypothesis, with increases and decreases observed among the cytokines in both the Th1 and Th2 groups, and among different cell types (Graziosi et al., 1994; Maggi et al., 1994; Romagnani et al., 1994; Breen et al., 1997; Fakoya et al., 1997; Canaris et al., 1998). 5.2. Interleukin-10 versus the inflammatory trio in human immunodeficiency virus infection While the Th1/Th2 hypothesis may not have sufficiently addressed the variety of cytokine changes observed in HIV

infection and progression to AIDS, it made a valuable contribution by focusing attention on the concept of crossregulation by cytokines (Fig. 2) (Goldsby et al., 2000). Under normal immune system conditions, cytokines affect one another and the cells that produce them in a complex web of synergistic and antagonistic actions. In the context of HIV infection and AIDS, increases and decreases in various cytokines have the potential to alter the balance between synergy and antagonism, not only among the cytokines themselves, but also between the immune system and the replication of HIV. Under normal (non-HIV infected) conditions, one type of cross-regulation that can be clearly demonstrated is the ability of the anti-inflammatory cytokine IL-10 to suppress the production of the pro-inflammatory cytokines IL-1, IL6, and TNF-a (Moore et al., 2001). When it became apparent that IL-1, IL-6, and TNF-a were overproduced in association with HIV infection, the obvious question was raised: Can and does IL-10 still act in an antagonistic fashion towards these cytokines when HIV is involved? This became more than an illustration of immunologic principle when the abilities of IL-1, IL-6, and TNF-a to up-regulate HIV expression and/or replication were described, as the antagonistic potential of IL-10 now was relevant not just to the production of pro-inflammatory cytokines, but to the production of HIV as well. This was in direct contrast to the Th1/Th2 hypothesis, which had suggested that increased IL-10 (as part of a shift toward Th2 cytokines) was contributing to HIV disease progression. Rather, higher levels of IL-10 could be viewed as desirable, due to its ability to inhibit IL-1, IL-6, and TNF-a production by mØs, which, in turn, would reduce the amount of HIV replication in the body (Fig. 3). It was demonstrated that when IL-10 was used in vitro, either at low concentrations that did not measurably affect the production of inflammatory cytokines or at high concentrations that clearly blocked HIV-induced TNF-a and IL6 secretion, HIV replication within primary cells or cell lines of the mØ lineage was inhibited (Saville et al., 1994; Weissman et al., 1994). The ability of IL-10 to inhibit or reduce HIV replication in mØs, but not T-cells, under similar conditions was also observed by others (Masood et al., 1994; Montaner et al., 1994; Akridge et al., 1994; Kootstra et al., 1994). In addition, treatment of HIV+ individuals with a single bolus of IL-10 temporarily blocked TNF-a and IL-1 production and reduced plasma levels of HIV in vivo (Fauci, 1996). All of these observations were consistent with the expectation that IL-10 would antagonize pro-inflammatory cytokines and HIV replication. However, this was not always the result, as it was also observed that, under different experimental conditions in vitro, IL-10 served to synergize with TNF-a, IL-6, and/or other cytokines to enhance HIV replication induced by those cytokines (Angel et al., 1995; Weissman et al., 1995; Finnegan et al., 1996). Additional studies suggested that the contradictory results regarding the ability of IL-10 to suppress or enhance

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Fig. 3. The effects of IL-10 on pro-inflammatory cytokines and HIV replication. An mØ will secrete pro-inflammatory cytokines in response to HIV, which, in turn, will increase HIV replication (left side). In the presence of high levels of IL-10, pro-inflammatory cytokine production and HIV replication are suppressed, presumably resulting in a slower progression to AIDS (upper right). In the presence of low levels of IL-10, proinflammatory cytokine production and HIV replication increase, leading to a more rapid progression to AIDS (lower right). Solid arrows indicate cytokine and HIV production; dashed arrows indicate inhibition of cytokine and HIV production.

HIV replication may be related to the state of maturation of cultured primary cells (monocytes maturing into macrophages over time) or monocyte-lineage cell lines (Naif et al., 1996; Chang et al., 1996). Taken together, these observations have now led to a perception of IL-10 as a bifunctional cytokine, capable of both suppressing and enhancing HIV replication (Poli, 1999).

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support for targeted strategies mimicking or enhancing the inhibitory role of IL-10 in order to slow AIDS progression. Such a suggestion, particularly to enhance IL-10 activity, may be too narrow in its focus, as it does not take into account the balance between anti-inflammatory and B-cell stimulatory properties of IL-10. We have examined a subset of the men that were included in the study by Shin et al. (2000) using a similar genetic analysis of IL-10 promoter genotypes, as well as direct measurement of serum IL-10 levels (Breen et al., 2002). Our focus, however, was on the possible contribution of IL-10 as a B-cell stimulatory factor to the development of AIDS-associated non-Hodgkin’s B-cell lymphoma (AIDSlymphoma). This B-cell malignancy, which is the secondmost common AIDS-associated cancer, occurs in  10% of persons with AIDS (Knowles, 1997; Frisch et al., 2001). Compared with the general population, persons with AIDS have a > 70-fold increase in the risk of developing AIDSlymphoma, which is thought to be a result of the widespread, non-specific B-cell hyperactivity associated with HIV infection (Knowles, 1997; Martı´nez-Maza et al., 1998; Frisch et al., 2001). We had observed previously that other cytokines and molecules associated with B-cell activation and/or differentiation were elevated in the serum of men who go on to develop AIDS-lymphoma, compared with matched controls with AIDS (Yawetz et al., 1995; Breen et al., 1999; Widney et al., 1999; Schroeder et al., 1999a, 1999b). Therefore, we were interested in determining whether increased serum levels of IL-10 or a high IL-10expressor genotype were similarly associated with the development of AIDS-lymphoma.

5.3. Interleukin-10 as a bifunctional mediator of human immunodeficiency virus disease progression The bifunctional nature of IL-10 in HIV disease may extend beyond its role in HIV replication. While it may be beneficial when acting as an anti-inflammatory cytokine that suppresses the production of HIV, IL-10 can also act as Bcell stimulatory factor that could be contributing to the Bcell hyperactivity seen in association with HIV infection. This is illustrated by the results of two recent studies on the role of IL-10 in HIV disease. Shin et al. (2000) reported that a genotype for the IL-10 gene that is associated with high IL-10 expression in vitro appears to be protective for progression to AIDS when examining rates of progression 5 years or more after HIV infection. While it is not a direct measure of IL-10 production by cells, this genetic analysis is consistent with the view that higher IL-10 levels are desirable, presumably acting as a suppressor of inflammatory cytokines and HIV replication (Fig. 3). In fact, the authors suggest that their data offer

Fig. 4. The balance between IL-10 as an anti-inflammatory and B-cell stimulatory cytokine in AIDS. While a high level of IL-10 might be viewed as beneficial in slowing progression to AIDS (upper right), it may also be detrimental by contributing to the development of AIDS-lymphoma through inappropriate B-cell activation (lower right).

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We observed that detectable levels of serum IL-10 were rarely seen in HIV+ controls with and without AIDS (2 – 4%), and were not seen in any uninfected controls. However, subjects who went on to develop AIDS-lymphoma had a significantly higher frequency (21%) of detectable IL-10 in serum samples obtained prior to lymphoma diagnosis compared with the control subjects ( P  0.002). In a parallel analysis of IL-10 promoter genotypes, a highly significant increase was also seen in the frequency of the high IL-10 expressor genotype in men who developed lymphoma compared with men who did not develop lymphoma ( P = 0.007). Therefore, by both direct measure and predicted IL-10 production based on genotyping, our data suggest that increased IL-10 in HIV+ persons is an undesirable outcome associated with the development of AIDSassociated B-cell lymphoma. A possible model to account for the conflicting interpretation of the role of IL-10 in the progression of HIV disease and AIDS is shown in Fig. 4. In addition to the antiinflammatory role thought to be beneficial by suppressing HIV replication and slowing progression to AIDS (Shin et al., 2000), IL-10 could also be acting in a detrimental fashion as a B-cell stimulatory factor to contribute to B-cell hyperactivity and increased risk of AIDS-lymphoma (Breen et al., 2002). Since AIDS-lymphoma occurs in a minority of persons with AIDS, the B-cell stimulatory effects of IL-10 may have been masked in the study of Shin et al. (2000) by the larger proportion of HIV+ persons who were benefiting from its antagonistic effects on proinflammatory cytokines and HIV replication. This serves to emphasize the fact that with IL-10, as with many other cytokines that are dysregulated in HIV infection and AIDS, it is important to remember that it is the balance between different functions of a single cytokine, or between the synergistic and antagonistic actions of different cytokines, that may determine the ultimate effect of cytokine changes in an HIV+ person.

Acknowledgements Many thanks to Otto Martı´nez-Maza, Ph.D., for his longstanding collaboration on studies of cytokines in HIV infection, and to Julia Gage, Ph.D., for her reading of the manuscript. This work was supported by grants from the National Institutes of Health (CA57152, CD73475, AI35040), the University-wide AIDS Research Program of the State of California, and the UCLA AIDS Institute.

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