New Players in Cytokine Control of HIV Infection Massimo Alfano, PhD, Andrea Crotti, MS, Elisa Vicenzi, PhD, and Guido Poli, MD
Corresponding author Guido Poli, MD P2/P3 Laboratories, DIBIT, Via Olgettina n. 58, 20132, Milano, Italy. E-mail:
[email protected] Current HIV/AIDS Reports 2008, 5:27–32 Current Medicine Group LLC ISSN 1548-3568 Copyright © 2008 by Current Medicine Group LLC
Cytokines are involved early in the pathogenesis of HIV infection and disease progression as a component of immunologic dysregulation and immunodeficiency and as determinants controlling virus replication. Several steps, before and after retroviral integration into host DNA in T cells and macrophages, are affected by cytokines whereas CCR5 and CXCR4 binding chemokines can interfere with viral entry. A growing number of potential players—including the H-common interleukin (IL)-7, IL-15, and IL-21 together with IL-17, IL-18, IL-19, IL-20, IL-23, and IL-27—are discussed in terms of their perturbation in HIV infection and of their effects on virus replication. Thus, an increasing intersection of HIV infection and the cytokine network represents a crucial determinant of virus replication and immunologic dysregulation and will likely play a key role in the development of effective strategies of HIV prevention and immunologic reconstitution.
Introduction A historical perspective of the role of cytokines in HIV infection Cytokines and chemokines are main controllers of immune cell activation, function, and motility. They are key mediators turning on and off the host inflammatory response to infectious agents. They are both determinants and effectors of polarized T-helper cell (Th)-1, Th2, and recently, Th17 cell responses. Their improper regulation may be the cause of either immunodeficiency or exacerbated responses, as observed in individuals with HIV infection developing inflammatory response syndrome after highly active antiretroviral therapy (HAART). Soon after the discovery of this novel disease (characterized by selective CD4+ T-cell depletion and
immunodeficiency), cytokines and their receptors have been investigated as markers and potential determinants of immunologic dysregulation, as illustrated by the profound defect in interleukin (IL)-2 expression. The molecular dissection of the proviral genome and the definition of the bimodal strategy of infection of T cells and macrophages by HIV, leading to productive and cytopathic (at least in vitro) viral replication and spreading or to viral latency, has revealed another crucial role of the cytokine network in the pathogenesis of HIV infection. Tumor necrosis factors (TNFs) were shown to trigger activation of the cellular transcription factor nuclear factor (NF)-LB, leading to its subsequent binding to the HIV long terminal repeats (LTR) and promotion of viral transcription. Several other cytokines have demonstrated the capacity to interfere at transcriptional and posttranscriptional levels in the HIV life cycle, with interferons (IFNs) interjecting at multiple levels, including budding and release of new progeny virions [1]. In the mid-1990s, the discovery of CCR5 and CXCR4 as obligate virion coreceptors for infecting CD4 + target cells and the inhibitory effects exerted by their ligands on HIV entry further reinforced this general concept: studying the interface between the virus and the cytokine network may lead to the discovery of effective antiviral therapies. The recent introduction of CCR5 antagonists among the effective anti-HIV therapeutic agents [2•] has demonstrated the validity of this hypothesis. In addition, intermittent administration of IL-2, leading to a sustained and prolonged expansion of circulating CD4 + T lymphocytes, and an almost complete phase III validation trial on thousands of individuals who are HIV positive worldwide (the results are expected some time in 2008) makes this cytokine a candidate to become a complementary approach for HIV infection. Other cytokines, including IL-7 and granulocyte-macrophage colony-stimulating factor, are under evaluation as adjuncts to HAART. Based on these data, the present article focuses on some of the most novel studies on the role of cytokines in HIV infection and replication. Due to space constraints, only the most recent contributions will be cited; some of
28 The Science of HIV Medicine
Table 1. New cytokines involved in HIV infection and replication In vivo*
Ex vivo*
In vitro
IL-7
Increased with high viremia and low CD4 cell counts. Correlation with CXCR4 use by HIV
HIV isolation from latently infected cells; increased NK cell activity; reduced apoptosis of CD4+ and CD8+ T cells
Enhancement of X4 HIV replication via NFAT in T cells and thymocytes. Increased HIV replication in MDM
IL-15
Low levels increased in PHI and decreased thereafter
IL-17
Unknown
Enhanced secretion from CD4+ T cells
Unknown
IL-18
Increased with high viremia in PHI and advanced disease with lipodystrophy or central nervous system infections
Reduced secretion from PBMC
Inhibition of acute infection of PBMC; enhancement of virus expression from latently infected cell lines via endogenous cytokines
Enhanced secretion in lymphoid Contrasting reports of either inhibition histocultures; reduced apoptosis or enhancement of CD8+ T cells; increased neutrophil function
IL-19, IL-20
Unknown
No information
Upregulation by Tat in epithelial cells
IL-21
Unknown
Proliferation and functional enhancement of CD8+ T cells; increased ADCC (with IL-15)
Unknown
IL-23, IL-27
Unknown
Increased dendritic cell function (mice)
Inhibition of R5 and X4 HIV replication
*Individuals with HIV infection. ADCC—antibody-dependent cellular cytotoxicity; IL—interleukin; MDM—monocyte-derived macrophages; NFAT—nuclear factor of activated T cells; NK—natural killer; PBMC—peripheral blood mononuclear cells; PHI—primary HIV infection.
the earlier studies, although in some cases seminal, will be found in the quoted articles.
Novel Cytokines Regulating HIV Replication Several cytokines have been implicated in the regulation of virus replication in CD4+ T cells, macrophages, microglia, and astrocytes of the central nervous system. In contrast to HIV-inhibitory IFN-B/C, proinflammatory cytokines, including IFN-H, predominantly favor virus replication by triggering signaling pathways, leading to intracellular activation of host transcription factors, such as NF-LB, nuclear factor of activated T cells (NFAT), and Jun-Fos (AP-1). These transcription factors are capable of binding to DNA binding sites in the HIV LTR. In the case of AP-1, binding to intragenic enhancer sequences also occurs [1]. Among the relatively novel cytokines, three (IL-7, IL-15, and IL-21) belong to the family of cytokines using the common H chain of the IL-2 receptor, which leads to the activation of the JAK/ STAT signal transduction pathways, particularly STAT5. STAT5 has recently joined the other host transcription factors capable of binding to the HIV LTR and influences viral transcription and expression [3•,4•].
IL-7 IL-7 is produced mostly by thymic epithelial cells but also by mononuclear phagocytes. It plays a major role in thymocyte survival and proliferation. In addition, IL-7 regulates Bcl-2 expression and survival of naïve T lym-
phocytes and participates in the T-cell response following antigenic stimulation. IL-7 was investigated early in the context of HIV infection, replication, and cell depletion in the thymus. This effect recently has been linked to skewed enhancement of CXCR4-dependent (X4) virus replication in mature thymocytes concomitantly with increased expression of CXCR4. IL-7 consistently enhanced X4, but not R5, HIV-1 replication in fetal thymus organ cultures [5]. IL-7 also enhanced HIV replication in resting naïve CD4+ T lymphocytes, and this was correlated with the autocrine/ paracrine release of other cytokines including IFN-H, IL-4, and IL-10 [6•]. In the same study, NFAT, but not NF-LB, was identified as the transcription factor responsible for IL-7–induced upregulation of HIV replication [6•]. When ex vivo CD8-depleted peripheral blood mononuclear cells (PBMC) of infected individuals under effective HAART were incubated with various stimuli, IL-7 was identified as the most effective HIV-inductive cytokine in terms of reactivation of latent proviral DNA, whereas IL-2 alone was ineffective unless combined with the mitogen phytohemagglutinin [7••]. Furthermore, an analysis of the viral quasispecies induced by IL-7 versus phytohemagglutinin plus IL-2 suggested that segregated pools of latently infected cells were activated by the two stimuli [7••]. However, more recent studies did not observe an inductive effect of IL-7 on latent, HIV-infected, CD8-depleted cells of infected individuals [4•,8], and synergistic antiviral effects have been reported by incubating these cells in combination with IFN-B [9] (Table 1).
New Players in Cytokine Control of HIV Infection Alfano et al. 29
Regarding the potential role of IL-7 in the modulation of infection of macrophages, no effect [10] and no enhancement of virus replication [11] were reported. In the latter study [11], either HIV infection or cell stimulation with extracellular Tat upregulated the levels of IL-7RB expression, increasing responsiveness to the related cytokine [11]. Both IL-7 and IL-15 have been shown to increase the function of natural killer (NK) cells from infected individuals, with IL-15 being more potent [12]. The two cytokines activated different cytolytic mechanisms, namely Fas and TNF-related apoptosis-inducing ligand, respectively, resulting in the ex vivo depletion of HIVinfected PBMC isolated from infected individuals [12]. In vivo, a correlation between plasma levels of IL-7 and increased CXCR4 expression by PBMC has been observed in children infected with X4 viruses, although reversion of the viral phenotype to R5 induced by HAART was associated with reduced plasma levels of both viremia and IL-7 [13]. Although a positive correlation between CXCR4 levels and the prevalence of X4 viruses was observed, the levels of circulating IL-7 did not correlate with CXCR4 expression on PBMC of infected adults in an independent study [14].
IL-15 IL-15 is a Th1 cytokine produced by mononuclear phagocytes and shares many activities with IL-2, such as T-cell proliferation and activation. In addition, IL-15 is more potent than IL-2 in stimulating NK cell function, including secretion of IFN-H and of CCR5-binding chemokines [15]. IL-15 has been shown to stimulate the function of immune cells of individuals who are HIV positive, particularly CD8+ memory T cells and NK cell survival and activity [15]. In addition, IL-15 induced increasing antibody-dependent cellular cytotoxicity and complement-dependent lysis of HIV-1 Env-expressing target cells through augmentation of specific IgG levels in immunized mice [16•]. IL-15 has been combined with IL-21, resulting in a synergistic expansion and functional enhancement of CD8+ T cells isolated from both mice [16•,17••] and individuals who are HIV positive [18••]. For these reasons, IL-15 has been tested as a vaccine adjuvant for experimental simian immunodeficiency virus (SIV) infection but with contrasting results. Administration of this cytokine enhanced cellmediated and humoral immune responses in chronically SIV-infected macaques [19] as well as in macaques immunized with SIV gag DNA resulting in an ameliorated clinical outcome after virus challenge [20]. In contrast, recent studies indicated that IL-15 did not improve the immune responses of macaques immunized with ALVAC-SIV-gpe expressing the gag, pol, and env genes of SIVmac251. It even abrogated the vaccine-induced decrease of the viral set point while not influencing the levels of viremia in chronically infected macaques [21].
Low levels of circulating IL-15 increased in response to effective HAART and were observed in individuals undergoing primary HIV infection (PHI). They decreased in both therapy-naïve patients in advanced stage of disease and in HIV-positive individuals in whom HAART failed [22]. Ex vivo, increased levels of IL-15 were detected in histocultures established from lymph nodes of individuals who were HIV positive in comparison to their uninfected counterparts [23•]. As similarly observed for IL-7 in both CD4+ and CD8+ T cells [8], IL-15 reduced the spontaneous apoptosis of HIV-specific CD8+ T cells [24] isolated from individuals during PHI. In addition, IL-15 induced chemotaxis and potentiated fungicidal activity of neutrophils from individuals who were HIV positive [25]. In vitro, IL-15 inhibited HIV-1 infection of activated PBMC likely as a consequence of its capacity for inducing expression of IFNs and CCR5-binding chemokines from NK cells [12]. In contrast, earlier studies observed that IL-15 either did not affect HIV replication in vitro or ex vivo or enhanced it in primary PBMC, CD4+ T lymphocytes, and T-cell lines. This latter effect has been recently linked to the capacity of IL-15 to induce expression of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G) and to promote its shift from an active (anti-HIV) to an inactive high molecular weight form in primary T cells [26••] (Table 1).
IL-17 In addition to classical Th1 and Th2 cells, a novel subset of CD4+ T cells has been identified by the production of IL-17 and consequently named Th17 [27]. Th17 cells are induced by costimulation of naïve T cells with IL-6 and transforming growth factor (TGF)-C, whereas stimulation of Th17 cells with IL-23 promotes their proliferation. Their role has been particularly linked to inflammatory conditions and autoimmunity [27]. Cell stimulation by IL-17 leads to a second wave of different proinflammatory cytokines and chemokines (mostly of the CXC family) and of granulocytecolony stimulating factor, leading to neutrophil recruitment [28]. In a single study, a significant increase in the constitutive production of IL-17 from peripheral CD4+ T cells of individuals who were HIV positive, further inducible by phorbol 12-myristate 13-acetate/ionomycin stimulation, has been reported [29].
IL-18 IL-18 is a proinflammatory/Th1 cytokine produced by activated PBMC and epidermal cells that induces the production of IFN-H from NK cells and enhances the cytolytic potential of both NK cells and CD8+ cytotoxic T lymphocytes. Regarding its ability to induce a Th1 response, IL-18 has been used as an adjuvant either in mice vaccinated with DNA expressing HIV-1 Nef, Gag/Tat/Nef, or Env [30]. As predicted, IL-18–treated animals showed an enhanced cellular response and decreased antibody production [31].
30 The Science of HIV Medicine
In vivo, increased serum IL-18 levels have been observed during PHI/early infection in association with high IFN-H levels and reduced expression of CXCR4 on leukocytes [32]. Serum IL-18 levels were recently found to be comparable in long-term nonprogressors and HIV progressors [33]. However, earlier studies indicated that these levels were higher in symptomatic versus both healthy seronegative controls and asymptomatic individuals who were HIV positive, including children, and were related to disease progression [34]. Higher levels of IL-18 have been observed in HIV-positive individuals with lipodystrophy compared with those without lipodystrophy [35,36] and in HIV-positive individuals with hypertriglyceridemia [37]. Successful HAART has been linked to reduction of IL-18 circulating levels [33]. In addition, increased IL-18 concentrations have been observed in the cerebrospinal fluid of HIV-positive individuals with opportunistic infections, although not in those with HIV-associated dementia [38]. A reduced capacity of secreting IL-18 from ex vivo stimulated PBMC was observed in patients with high circulating levels of this cytokine [39]. The apparent discrepancy between these reports of increased plasma levels, in addition to a functional exhaustion of PBMC, could be explained by the fact that IL-18 can be secreted by activated platelets [40] and by the adipose tissue [35]. In vitro, both acute HIV infection and incubation of the THP-1 cell line with the accessory viral protein Nef induced expression of IL-18 [41]. Like most proinflammatory cytokines, IL-18 induced HIV expression in chronically infected monocytic [42] and T-cell lines [43] via induction of the release of endogenous TNF-B and IL-6 [42]. In contrast, other studies have indicated that IL-18 inhibited acute in vitro infection of activated PBMC as a result of its capacity to induce CD4 downmodulation and release of IFN-H [44]. These apparent discrepancies are accounted for by the experimental design in that incubation of cells with high concentrations of these cytokines results in downregulation of different cell-surface receptors, including CD4 and chemokine receptors. However, stimulation of already infected cells (or lower concentrations IL-18 or TNF-B) increased virus expression via activation of transcription factors binding to virus LTR [1] (Table 1).
IL-19 and IL-20 IL-19 and IL-20 belong to the IL-10 family of cytokines and are produced mostly by monocytes during inflammation. Based on the distribution of their receptors they likely act predominantly on nonimmunologic tissue and organs, such as the skin, lungs, and various internal organs, including reproductive organs [45]. No information is available on their potential involvement in HIV infection, although upregulated expression of both cytokines has been reported following stimulation of mammary and amniotic epithelial cells with extracellular Tat [46].
IL-21 IL-21 is mostly secreted by activated T cells, including Th17 cells, acts as an amplifier of their function, and targets several immune cells belonging to both lymphocytic and myelomonocytic lineages, as reviewed elsewhere [47]. Concerning HIV infection, IL-21 has been shown to enhance CD8+ T-cell function, including secretion of IFNH [16•,17••] and expression of perforin without inducing broad cellular activation or proliferation, in individuals who are HIV positive [18••]. Furthermore, IL-21 has been shown to promote the expansion of HIV-specific CD8+ memory T cells [16•,17••] and the antibody-dependent cellular cytotoxicity and complement-mediated lysis of antigen-expressing cells in synergy with IL-15 [16•,17••]. IL-21 (both alone and in combination with IL-15) increased the magnitude of the response of mice vaccinated with HIV env DNA providing evidence of resistance to viral transmission [16•]. At present, no information is available on the potential effects of IL-21 on HIV replication either in vitro, ex vivo, or in vivo.
IL-23 and IL-27 IL-23 and IL-27 belong to the IL-6/IL-12 family and can exert both pro- and anti-inflammatory effects as well as affecting Th commitment, T-cell proliferation, and cytotoxic activity [48]. In addition, these cytokines have been shown to affect the maturation of the antibody response by inducing isotype switching in B cells [48]. The potential role of IL-27 in HIV infection has been investigated in the context of dendritic cells (DC) and antigen presentation. When DC derived from IFNB stimulation were compared with those generated in mice immunized with CD40 ligand and IL-4, they were found to be superior in inducing in vitro cross-priming of HIV-specific CD8+ T cells. This effect was correlated to an enhanced expression of IL-23 and IL-27 [49]. Furthermore, binding of human papillomavirus-like particles (VLP) to DC induced the expression of IFN-B, IFN-H and IL-10 and suppressed the replication of both X4 and R5 HIV-1 without affecting the expression of HIV receptors and coreceptors [50•]. VLP induced the expression of IL27 that inhibited HIV-1 replication in activated PBMC, CD4+ T cells, and macrophages, although no information on the antiviral mechanism triggered by this cytokine is currently available [50•] (Table 1).
Conclusions Cytokines, including chemokines and their receptors, represent a growing family of factors involved in the generation, maintenance, and modulation of innate and adaptive immunity. Their involvement in the pathogenesis of HIV infection, which includes the capacity to affect HIV replication and the induction of virus expression from latently infected cells, provides the evidence for their potential use in strategies aimed at the immunologic
New Players in Cytokine Control of HIV Infection Alfano et al. 31
reconstitution of infected individuals or to boost antiviral immunity with the goal of preventing infection.
Disclosures Dr. Alfano has received a grant from Creabilis Therapeutics SpA, Colletretto Giacosa (TO), Italy, to characterize HIV Tat-derived peptides in HIV infection. Dr. Vicenzi has received a grant from Ribovax Biotechnologies, SA, Geneva, Switzerland, for the discovery and characterization of human monoclonal antibodies against human viral pathogens. Dr. Poli has received a grant from Creabilis Therapeutics SpA, Colletretto Giacosa (TO), Italy, to characterize HIV Tat-derived peptides in HIV infection and from Ribovax Biotechnologies, SA, Geneva, Switzerland, for the discovery and characterization of human monoclonal antibodies against human viral pathogens. No further potential conflict of interest information relevant to this article has been reported.
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