Abstract
Discovery of new mediators of immune cell activation and interaction facilitated elucidation of the various ways of defense against infectious agents and happened some 40 years ago. Each involved group of researchers named the mediators according to their scope of investigation; often the same molecules were published at the same time with different names. To avoid confusion resulting from using different names for the same mediators and to prevent a Babylonian confusion, standardization was implemented—as in the field of metrics, music, or science including virology. For cytokines and chemokines a standard nomenclature was proposed some 10 years ago and in conclusion it should be used. In this paper the most relevant biomarkers in HIV-1 and HBV infection and their contribution during viral pathogenesis are listed.
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Historical aspects
According to accepted definition cytokines are bio-active molecules as tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), as the interleukins IL-2, IL-4, Il-6 and Il-10, whereas under chemokines mediators such as CXCL8, CXCL9, CXCL10, CCL2, and CCL5 are found that regulate cell activity and cell trafficking during viral infection [1]. Cytokines and chemokines—chemokines are defined as chemotactic cytokines—have been detected some 40 years ago and more than 100 different proteins were described with more than 400 different names. Chemokines were ranked as inflammatory as CCL2, CCL3, CXCL10 and further ones by the involvement of immune cells in, for example, the defense of a viral disease; while other chemokines involved in the migration of leukocytes were named homeostatic chemokines as CCL14, CCL19 and others. CC-chemokines have been named also β-chemokines [2].
In 2000 the American Society for Bone and Mineral Research discussed the nomenclature for new tumor necrosis factor family members [3]. In 2002 the IUIS (International Union of Immunological Societies)-WHO committee published a list of systematic names for the CC-, CXC-, and CX3C- chemokine receptor family, including human and mouse ligands and the chemokine receptors [4]. In 2012, the chemokine superfamily and their receptors were revised, and the nomenclature updated [5]; a further comprehensive update was published in 2014 [6]. In 2015 Holdsworth and Gan made an effort for a fairly standardized ranking of those proteins involved in kidney diseases [7]. Jacobs et al. in their study of the activation of cytokines by HIV infection used the more recent designation of cytokines to support standardization [8], while Ehling et Tacke describing the HBV triggered pathways leading to hepatocellular carcinoma in 2016 used the proposed chemokine nomenclature and their alternative names [9].
An extended description of the bulk of cytokines is available by industry (Raybiotech, China) (https://www.raybiotech.cn/uploadfiles/2014/04/20140425153827.pdf- (upload list English—cytokinenomenclature-pdf) which can be downloaded; it was published in 2014. An extended chemokine nomenclature list (R&D, USA) can be opened (https://www.rndsystems.com/resources/technicalinformation/chemokinenomenclature) and gives the systematic names, chromosomal locus and alternate names; this list was actualized in 2019. The designation of the interleukins was less frequently changed, only interleukin 8 has two names: IL-8 and CXCL8; a review on interleukin structure, function and action was published in 2016 [10].
Per definition cytokines are signaling proteins made by various cell types including immune cells, while chemokines, as chemotactic cytokines, are a subfamily of cytokines made mainly by white immune cells—but nomenclature is partially overlapping. Cytokine action is by binding to a cellular receptor, usually a G-protein, followed by a cascade of protein activation and finally by inducing various reactions like cell proliferation, inflammation, apoptosis and antiviral activity, as seen by the multiple actions of interferons [11,12,13]. The molecular weight of cytokines is roughly between 10,000 and 90,000 Da. Most human chemokines have a functionally corresponding homolog in other primates [14], and species as mice [5] indicating a long evolutionary history.
General structure and action of cytokines
Chemokines are classified according to their first cysteine position in the protein as XC, CC, CXC and CXXXC; X can be any amino acid [15]. C chemokines have an amino acid sequence with one cysteine–cysteine disulfide bond, while CC have two cysteine–cysteines at different positions in the protein, and in CXC or CX3C 1 or 3 further amino acids, respectively, are inserted between the two cysteine residues [6, 15]. According to their function cytokines may be divided in either two groups as homeostatic cytokines for immune cell trafficking and inflammatory chemokines produced under inflammation [15] or subdivided in four groups as proinflammatory/involving T cells, anti-inflammatory/involving Th2 cells, chemoattractant chemokines, and growth factors as epidermal growth factor (EGF), fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF) [14]—a scheme is summarized in Table 1. Each of the growth factors is building up its own family, composed of several proteins with fairly modified function.
Chemokine receptors (CCR) are mostly structured as heterotrimers and are frequently G proteins spanning the plasma membrane of immune cells and further cells. A chemokine receptor may be used by several chemokines as for example CCR1 is used by CCL3, -5, -7, -8, -13, -14, -15, -16 and -23 (so called promiscuous receptors), while for example CCR10 is only co-used by CCL27 and CCL28 [5, 6]. CCR5 and CCR2 are structurally similar, sharing 70% amino acid identity. CCR5 can form oligomers and further conformational changes and thus influence distinct signaling responses on T cells and macrophages [2].
Antagonists of chemokine receptors
The function of chemokine receptors can be blocked by antagonists. An antagonist of CCR1 is for example CCL26, while for CCR10 no antagonist is known [5]. Chemokine receptors may be stimulated by antimicrobial peptides as known from beta-defensins, which are secreted from epithelial cells to attract dendritic cells and memory T cells via CCR6. Homing of dendritic cells and T cells in the lymph node is regulated by CCR7 [6]. An example of an atypical chemokine receptor is Duffy antigen receptor chemokine (DARC) which is involved in inflammation. Duffy protein is expressed on the erythrocyte surface of Europeans and is genetically deleted in indigenous people living in malaria endemic regions of Africa.
Monoclonal antibodies (mab) against chemokines and chemokine receptors
Besides therapy of unwanted inflammation the main interest using those mab is to support treatment of cancer. More than 20 different types of cancer have been selected for treatment using mab. Tumor size reduction was achieved by blocking various chemokine receptors and ligands as CCR2, CCL2, CXCR4 and further ones treating patients with multiple melanoma, colon carcinoma, pancreatic carcinoma and others [17]. Growth of hepatocellular carcinoma (HCC) could be reduced by CCR2 inhibition with a combination of Sorafenib, an inhibitor of Raf tyrosine kinase [17] of the VEGF complex in preclinical and clinical trials [17, 18]. Mab which suppress extensively inflammation are anti-IL-6 and anti-TNF-α, which are used in clinical trials for autoimmune diseases such as rheumatic arthritis, Crohn’s disease and systemic lupus erythematosus [19].
Cytokine turnover during HIV-1 infection
After CD4 binding via gp120/gp41 HIV uses as coreceptor either CXCR4, or CCR5 or both chemokine receptors. Blocking of CCR5 by maraviroc or vicriviroc is one arm of the established antiretroviral treatment (ART) to reduce HIV replication [20]. Blocking CXCR4 has initially failed to improve HIV therapy, but is used as supplementary therapy for various cancers, as described above [16]. A new monoclonal antibody—Ibalizumab (Trogarzo®) has recently been licensed; application of this monoclonal antibody prevents HIV binding without blocking further functions linked to the CD4 receptor [21]. Interaction of gp120 with CCR5 occurs on various sites with a structural plasticity [22] and adaptation of HIV to low expression of CCR5 molecules on the cell surface [23]. Amino acid mutations in CXCR4 and CXCL12 that alter interactions between CXCR4 and gp120/gp41 and thus impair HIV-1 attachment have been identified by deep sequencing [24]. Gp120 binding to TNF-receptor 1 and 2 leads by a cascade of intracellular mediators as TRAF (tumor necrosis factor receptor-associated factor), RIPK (receptor-interacting protein kinases 1, 3) and NF-κB via LTR binding to accelerated HIV transcription [25].
Viral Tat (trans-activator of transcription) causes impairment of macrophage autophagy, while Nef (negative regulatory factor) activates autophagy via IRGM (immunity related GTPase family M protein). Vpr (viral protein R), Tat and Nef contribute to apoptosis induced by CXCR4 and further mediators [25], thus regulating HIV release from cells. Binding of gp120 to CXCR4 forms a complex by which apoptosis of infected and uninfected T cells is mediated [26]. Chemokine levels of CCL14, -21, -27 and XCL1 and CXCL12 are higher in elite controllers [8]; they are as well involved in autophagy and apoptosis—which is summarized in Fig. 1. Th17 cells that express CCR6 are highly permissive to HIV; and HIV was found to be enriched in CCR6+ cells in gut and lymph node. When the studies describing the cytokine expression during HIV early infection are summarized the response to HIV induces the liberation of CCL2, CCL18, CCL19, CCL21 and additionally interleukin 6 and 10 (Fig. 1). A further aspect in the cytokine expression perturbation is microbial translocation from the damaged gut and bacterial components are further factors that influence the turnover and activity of cytokines such as CXCL13 and CCL20, and their receptors [27,28,29]. Blocking CCR6, and additionally CCR7 and CXCR3 might be a way to eliminate part of the latently HIV infected cell reservoir [30].
HIV neuropathogenesis is caused by viral gp120, Tat and Nef and host IFN-γ that induce the neurotoxic CXCL10 which is produced by macrophages and astrocytes, while PDGF (platelet derived growth factor) and CCL2 inhibit Tat toxicity [31]. Plasma CXCL10 levels correlate with HIV-associated neurocognitive disorders in women [32], indicating that gender related hormones might additionally influence cytokine expression.
Cytokine turnover during HBV infection
Following the infection of hepatocytes HBV is liberated in high amounts and after a week- or month-long delay an intensive immune response is following, leading in 90% to 95% of adult patients to clearance of HBV from the circulation—but the immune reaction is not sufficient to remove the ccc-DNA (circular covalently closed HBV-DNA) from the nucleus of the cell. During the peak of viraemia CXCL10 is increased roughly fivefold, CXCL9 twofold, while the levels of CCL5 and CXCL8 in serum remain roughly unchanged [1]. During the chronic course of HBV infection CXCL9, CXCL10, CXCL11 and IL-10 levels were highly elevated while GCSF (granulocyte colony stimulating factor), CCL7 and IFN-γ levels were found to be decreased, studying 69 patients in China [33]. A positive correlation between the IL-4 amount produced by CD4-cells and a high plasma level of HBV was found. There is as well a correlation between the IL-17 amount produced by CD4 cells and pre-core stop codon mutation and basal core promotor mutation [34]. Elevated IL-10 levels correlated to a hampered HBs protein response [32]. A slow reduction of the CXCL10 level was predictive to a pending HBe seroconversion in patients with chronic infection under entecavir treatment [35]; while in another study during entecavir treatment CCL22 levels were decreased and CXCL10 levels were increased [36]. IL-34 inhibited HBV replication [37]. HBV pathogenesis was enhanced by IL-17A generated by Th17 cells [38]. An increase of Tregs was inversely correlated to high HBV plasma levels; Tregs acted immune suppressive on CD4 and CD8 T cells by IL-2, IL-10, IL-35 and TGF-β release [39].
HBx protein increased TRAIL-induced apoptosis of renal tubular epithelial cells by enhancing the activation of NF-κB and upregulating death receptor 4 (DR4) [40]. Proinflammatory mediators released from Kupffer cells and monocytes/macrophages contribute to apoptosis of hepatocytes, and dying hepatocytes release mediators as TNF-α, RIPK1 (receptor-interacting protein kinase 1) or DRP1 (dynamin-related binding protein 1), hence establishing a hepatotoxic feedforward cycle of inflammation [40]. Most studies investigating cytokine reaction during acute HBV infection show that CXCL10 and IL-10 are highly increased, besides further chemokines [1, 33, 41,42,43,44]. HBV induced encephalopathy was associated by an elevated level of IL-6, IL-17a and IFNγ [45].
Relevant chemokines that are involved in the induction of hepatocellular carcinoma (HCC) are: CCL2, -3, -5, -20 and -22, and CXCL 5, -8 and -12; of major importance is the CXCL12–CXCR4 axis, of minor importance the CXCL8–CXCR2 and CXCL5–CXCR2 axis (Fig. 2). Chemokine action might be supported by oncogenes out of the Ras and Myc-family in the hepatic microenvironment [9].
A list of cytokines and their various names which are involved in the defense reaction against HIV-1 and HBV infection is shown in Table 2.
References
Wu HL, Kao JH, Chen TC, Wu WH, Liu CH, Su TH, Yang HC, Chen DS, Chen PJ, Liu CJ (2014) Serum cytokine/chemokine profiles in acute exacerbation of chronic hepatitis B: clinical and mechanistic implications. J Gastroenterol Hepatol 29:1629–1636
Brelot A, Chakrabati LA (2018) CCR5 revisited: how mechanisms of HIV entry govern AIDS pathogenesis. J Mol Biol 430:2557–2589
American Society of Bone Mineral Research (2000) Proposed standard nomenclature for new tumor necrosis factor family members involved in the regulation of bone resorption. J Bone Mineral Res 15:2293–2296
IUIS, WHO (2002) Chemokine/chemokine receptor nomenclature. J Interferon Cytokine Res 22:1067–1068
Zlotnik A, Yoshie O (2012) The chemokine superfamily revisited. Immunity 36:705–716
Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ et al (2014) International Union of Pharmacology. LXXXIX. Update of the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 66:1–79
Holdsworth SR, Gan PY (2015) Cytokines: names and numbers you should care about. Clin J Am Soc Nephrol 10:2243–2254
Jacobs ES, Keating SM, Abdel-Mohsen M, Gibb SL, Heitman JW, Inglis HC, Martin JN, Zhang J, Kaldarova Z, Deng X, Wu S, Anastos K, Crystal H, Villacres MC, Young M, Greenblatt RM, Lansay AL, Gange SJ, Deeks SG, Golub ET, Pillai SK, Norris PJ (2017) Cytokine elevated in HIV elite controllers reduce HIV replication in vitro and modulate HIV restriction factor expression. J Virol 91:e02051-16
Ehling J, Tacke F (2016) Role of chemokine pathway in hepatobiliary cancer. Cancer Lett 379:173–183
Akdis M, Aab A, Altunbulaki C, Azkur K, Costa RA, Crameri R et al (2016) Interleukins (from IL-1 to IL-38), interferons, transforming growth factor β, and TNF-α: receptors, functions, and roles in diseases. J Allergy Clin Immunol 138:984–1010
Pe’ery T, Mathews MB (2007) Chapter 7: Viral conquest of the host cell. In: Knipe DM, Howley PM (eds) Fields virology, 5th edn. Wolters Kluwer Lippinscott, Philadelphia, pp 197–199
Braciale TJ, Hahn YS, Burton DR (2007) Chapter 10: The adaptive immune response to viruses. In: Knipe DM, Howley PM (eds) Fields virology, 5th edn. Wolters Kluwer Lippinscott, Philadelphia, pp 316–320
Hasegawa H, Mizoguchi I, Chiba Y, Ohashi M, Xu M, Yoshimoto T (2016) Expanding diversity in molecular structures and functions of the IL-6/IL-12 heterodimeric cytokine family. Front Immunol 7:479
Van der Lee R, Wie L, Huynen MA (2017) Genome-scale detection of positive selection in nine primates predicts human-virus evolutionary conflicts. Nucleic Acid Res 45:10634–10648
Legler DF, Thelen M (2016) Chemokines: chemistry, biochemistry and biological function. Chimia 70:856–859
Keating SM, Golub ET, Nowicki M, Young M, Anastos K, Crystal H, Cohen MH, Zhang J, Greenblatt RM, Desai S, Wu S, Landay AL, Gange SJ, Norris PJ (2011) The effect of HIV infection and HAART on inflammatory biomarkers in a population-based cohort of women. AIDS 25:1823–1832
Poeta VM, Massara M, Capucetti A, Bonecchi R (2019) Chemokines and chemokine receptors: new targets for cancer immunotherapy. Front Immunol. https://doi.org/10.3389/fimmu.2019.00379
Jiang E, Shangguan AJ, Chen S, Tang L, Zhao S, Yu Z (2016) The progress and prospects of routine prophylactic antiviral treatment in hepatitis B-related hepatocellular carcinoma. Cancer Lett 379:262–267
Qu X, Tang Y, Hua S (2018) Immunological approaches towards cancer and inflammation: a cross talk. Front Immunol. https://doi.org/10.3389/fimmu.2018.00563
Gilliam B, Riedel DJ, Redfield RR (2011) Differential use of CCR5 versus CXCR4 by HIV-1. Pathogenic, translational and clinical open questions. J Translat Med 9(Suppl 1):S9
Emu B, Fessel J, Schrader S, Kumar P, Richmond G, Win S et al (2018) Phase 3 study of Ibalizumab for multidrug-resistant HIV-1. N Engl J Med 379:645–654
Zheng Y, Han GW, Abagyan R, Wu B, Stevens RC, Cherezov V, Kufareva I, Handel TM (2017) Structure of CC chemokine receptor 5 with a potent chemokine antagonist reveals mechanisms of chemokine recognition and molecular mimicry by HIV. Immunity 46:1005–1017
Espy N, Pacheco B, Sodroski J (2017) Adaptation of HIV-1 to cells with low expression of the CCR5 coreceptor. Virology 508:90–107
Heredia JD, Park J, Brubaker RJ, Szymanski SK, Gill KS, Procko E (2018) Mapping interaction sites on human chemokine receptors by deep mutational scanning. J Immunol 200:3825–3839
Pasquereau S, Kumar A, Herbein G (2017) Targeting TNF and TNF receptor pathway in HIV-1 infection: from immune activation to viral reservoirs. Viruses 9:64. https://doi.org/10.3390/v9040064
Tsou LK, Huang YH, Song JS, Ke YY, Huang JK, Shia KS (2018) Harnessing CXCR4 antagonists in stem cell mobilization, HIV infection, ischemic diseases, and oncology. Med Res Rev 38:1188–1234
Kroeze S, Wit FW, Rossouw TM, Steel HC, Kityo CM, Siwale M et al (2019) Plasma biomarkers of human immunodeficiency virus-related systemic inflammation and immune activation in Sub-Saharan Africa before and during suppressive antiretroviral therapy. J Infect Dis 220:1029–1033
Teigler JE, Levre L, Chomont N, Slike B, Jian N, Eller MA et al (2018) Distinct biomarker signatures in HIV acute infection associate with viral dynamics and reservoir size. JCI Insight. https://doi.org/10.1172/jci.insight.98420
Malhotra P, Haslett P, Sherry B, Shepp DH, Barber P, Abshier J et al (2019) Increased plasma levels of the TH2 chemokine CCL18 associated with low CD4+ T cell counts in HIV-1-infected patients with a suppressed viral load. Sci Rep 9(1):5963. https://doi.org/10.1038/s41598-019-41588-1
Evans VA, Khoury G, Saleh S, Cameron PU, Lewin SR (2012) HIV persistence: chemokines and their signaling pathways. Cytokine Growth Factor Rev 23:151–157
Yao H, Bethel-Brown C, Li CZ, Buch SJ (2010) HIV neuropathogenesis: a tight rope walk of innate immunity. J Neuroimmune Pharmacol 5:489–495
Burlacu R, Umlauf A, Marcotte TD, Soontornniyomkij B, Diaconu CC, Burlacu-Talnariu A et al (2019) Plasma CXCL10 correlates with HAND in HIV infected women. J Neurovirol. https://doi.org/10.1007/s13365-019-00785-4
Lian JQ, Yang XF, Zhao RR, Zhao YY, Li Y, Zhang Y, Huang CX (2014) Expression profiles of circulating cytokines, chemokines and immune cells in patients with hepatitis B virus infection. Hept Mon 14:e18892
Gu Y, Lian Y, Gu L, Chen L, Li X, Zhou L, Huang Y, Wang J, Huang Y (2019) Correlations between cytokines produced by T cells and clinical-virological characteristics in untreated chronic hepatitis B patients. BMC Infect Dis 19:216
Guo R, Mao H, Hu Y, Zheng N, Yan D, He J, Yang J (2016) Slow reduction of IP-10 levels predicts HBeAg seroconversion in chronic hepatitis B patients with 5 years of entecavir treatment. Sci Rep 6:37015
Kurihara M, Tsuage M, Murakami E, Mori N, Ohisi W, Uchida T et al (2018) The association between serum cytokine and chemokine levels and antiviral response by entecavir treatment in chronic hepatitis B patients. Antivir Ther 23:239–248
Cheng ST, Tang H, Ren JH, Chen X, Huang AL, Chen J (2017) Interleukin-34 inhibits hepatitis B virus replication in vitro and in vivo. PLoS ONE 12:e1079605
Parfeniuk-Kowerda A, Jaroszewicz J, Flisiak R (2015) Immune regulation and viral diversity as correlates of natural and treatment induced immune control in persistent hepatitis B virus (HBV) infection. Clin Exp Hepatol 2:35–38
Trehampati N, Vyas AK (2017) Immune regulation by T regulatory cells in hepatitis B virus-related inflammation and cancer. Scand J Immunol 85:175–181
Yang Y, Wang X, Zhang Y, Yuan W (2018) Hepatitis B virus X protein and proinflammatory cytokines synergize to enhance TRAIL-induced apoptosis of renal tubular cells by upregulation of DR4. Int J Biochem Cell Biol 97:62–72
Brenner C, Galuzzi L, Kepp O, Kroemer G (2013) Decoding cell death signals in liver inflammation. J Hepatol 59:583–594
Keating SM, Heitman JD, Wu S, Deng X, Stramer SL, Kuhns MC et al (2014) Cyokine and chemokine responses in the acute phase of hepatitis B virus replication in naïve and previously vaccinated blood and plasma donors. J Infect Dis 209:845–854
Yoshio S, Mano Y, Doi H, Shoji H, Shimagaki T, Sakamoto Y et al (2018) Cytokine and chemokine signatures associated with hepatitis B surface antigen loss in hepatitis B patients. JCI Insight. https://doi.org/10.1172/ici.insight.122268
Liu M, Guo S, Hibbert JM, Jain W, Singh N, Wilson NO, Stiles JK (2011) CXCL10/IP-10 in infectious diseases. Pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev 22:121–130
Li W, Li N, Wang R, Wu H (2015) Interferon gamma, interleukin-6, and -17a levels were correlated with minimal hepatic encephalopathy in HBV patients. Hepatol Int 9:218–223
Pastor L, Parker E, Carillo J, Urrea V, Fuente-Soro L, Respeito D, Jairoce C, Mandomando I, Blanco J, Naniche D (2017) A cytokine pattern that differentiate preseroconversion from postseroconversion phases of primary HIV infection. J Acquir Immune Defic Syndr 74:459–466
He D, Li M, Guo S, Zhu P, Huang H, Yan G, Wu Q, Tao S, Tan Z, Wang Y (2013) Expression pattern of serum cytokines in hepatitis B virus infected patients with persistently normal alanine aminotransferase levels. J Clin Immunol 33:1240–1249
Xia Y, Protzer U (2017) Control of hepatitis B virus by cytokines. Viruses 9:18
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
The author declares that they have no conflict of interest.
Research involving human participants and involving animal studies
Not applicable since no original studies were done.
Informed consent
The author takes all responsibilities for the content of this article.
Additional information
Edited by Wolfram H. Gerlich.
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Gürtler, L.G. Cytokines and chemokines involved in the defense reaction against HIV-1 and hepatitis B virus: isn’t it time to use a standardized nomenclature of the involved mediators?. Virus Genes 56, 120–127 (2020). https://doi.org/10.1007/s11262-019-01721-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11262-019-01721-8