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Keywords:

  • Anti-inflammatory;
  • Chemokine;
  • CCL2;
  • HIV-1;
  • Pathogenesis

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

Chemokines are critical components of the immune system that participate in immune homeostasis and alterations in chemokine balance can result in severe inflammatory and autoimmune diseases. The role of chemokines and their receptors in viral infections including HIV-1 was predicted from the early studies of HIV-1 co-receptor CCR5 and its ligands and a divergent role of C-C chemokines in HIV-1 pathogenesis has been established. For example, CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) have been shown to possess antiviral effects by binding to the HIV-1 co-receptor CCR5, whereas CCL2, a pro-inflammatory chemokine, supports HIV-1 replication despite being a member of same chemokine family. Furthermore, the well-established role of CCL2 in driving the Th2 immune response supports its potential role in HIV-1/AIDS. Recent reports suggest multiple pathways of CCL2 affect HIV-1 infection. In this review, we provide a comprehensive overview of the role and potential mechanisms of the HIV-1-CCL2 interplay in driving virus-induced immuno-pathology, suggesting that CCL2 could be an anti-inflammatory target in the treatment of HIV-1 infection.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

Chemokines are a family of chemo-tactic cytokines that control the movement of seven-transmembrane G-protein coupled receptor (GPCR)-expressing cells. Physiologically, these small molecular weight proteins are expressed to recruit and direct cell trafficking/migration. Chemokines can be broadly classified into four subfamilies based on N-terminal cysteine-motifs. These include C, C–C (β), C–X–C (α) and C–X3–C subfamilies 1. In addition, based on their function, chemokines can also be classified into inflammatory or inducible, and homeostatic or constitutive chemokines 2. Inflammatory chemokines control recruitment during inflammation, while homeostatic chemokines regulate trafficking in BM and secondary lymphoid organs. Secretion of inflammatory chemokines depends on the extracellular signals and stimuli, such as danger signals and cytokines, resulting in recruitment of cells including cells of lymphoid and myeloid origin in a concentration-dependent manner. Chemokine expression is tightly regulated because an imbalance may result in severe autoimmune and inflammatory disorders. Moreover many inflammatory chemokines have been shown to play an important role in infection by pathogens, including viruses such as HIV-1.

CCL2

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

CCL2 also known as monocyte chemoattractant protein-1 (MCP-1) is a member of the C-C chemokine family and a highly potent chemo-attractor of monocytes and CD4+ T cells. Human CCL2 is composed of 76 amino acids, has an MW of 13 kDa, its gene is located on chromosome 17 (chr.17, q11.2) and the protein sequence displays a homology of 60–70% with CCL4, CCL7 and CCL8, the other members of the C-C chemokine family 3. Both hematopoietic and non-hematopoietic cells that includes monocytes/macrophages, DCs, astrocytes, endothelial cells and fibroblasts express CCL2. Nevertheless, monocytes/macrophages are found to be the major source of CCL2 in the peripheral blood 4, 5. CCL2 regulates the migration and infiltration of monocytes, CD4+ memory T lymphocytes and NK cells. From a clinical point of view, CCL2 is one of the most studied pro-inflammatory molecules among the C-C family members and a potential intervention point for the treatment of various inflammatory and autoimmune diseases. These include multiple sclerosis 6, atherosclerosis 7, insulin-resistant diabetes 8, rheumatoid arthritis 9–11 and lupus nephritis 12. CCL2 blockade is also a promising target of cancer immunotherapy in various cancer treatments 13 including breast cancer 14 and prostate cancer 15 among others. CCL2 has also been shown to polarize Th0 cells towards Th2 phenotype 16 and higher CCL2 levels favour Th2 responses which is evident from the studies of CCL2−/− mice that mount only Th1-mediated responses and thereby are resistant towards Leishmania major infection (reviewed in 3).

CCL2 receptor

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

Most of the C-C chemokine receptors (CCRs), including CCR2, have an affinity for, and respond to, more than one ligand. A possible exception is the recently identified chemokine CC motif receptor-like 2 (CCRL2), which displays a non-redundant role in lung DC trafficking, suggesting a role for this receptor in the control of excessive airway inflammatory responses 17. Understanding the implications of chemokines–receptor interactions for their in vivo functions is challenging but it seems that many regulatory mechanisms may come into play to eliminate redundancy and give each chemokine a unique and specific function 18. Based on their differing C-terminal tails, two alternatively spliced forms of CCR2, namely CCR2A and CCR2B, have been identified 19. These isoforms are expressed differentially on cell types with CCR2A being expressed by mononuclear cells and vascular smooth muscle cells 20, and CCR2B by monocytes and activated NK cells. Therefore, CCR2A and CCR2B may trigger different signaling pathways resulting in different immune responses. In this regard, it is interesting to note that rheumatoid arthritis (RA) patients display enhanced CCR2A, but not CCR2B, expression 21. However, in general CCR2−/− mice immunized with type II bovine collagen are more susceptible to collagen-induced arthritis than the WT mice 22, this adds further weight to the proposed role of CCR2 in arthritic disease.

Chemokines in HIV-1 pathogenesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

HIV-1 utilizes the host cellular environment for its survival, persistence and immune evasion. It is well established that HIV-1 infection leads to a state of persistent immune activation resulting in release of a series of host soluble inflammatory mediators including chemokines harbouring suppressive and/or supportive effects 4, 23–26. It should be noted that the suppressive effects of chemokines in HIV-1 pathogenesis were well anticipated before the discovery of HIV-1 co-receptors, CCR5 and CXCR5 27. In this regard heterozygote or homozygote individuals with a natural 32 bp gene deletion polymorphisms in HIV-1 co-receptor CCR5, confer resistance towards HIV-1 infection and disease progression 28–31. The cognate ligands of CCR5 co-receptor, CCL3 (MIP-1α), CCL4 (MIP-1β) and CCL5 (RANTES) that are produced by CD8+ T cells have been shown to inhibit infection with R5 HIV-1 strains 24. Similarly, the HIV-1 co-receptor CXCR4 cognate ligand CXCL12 (SDF-1), confers antiviral activity against X4 HIV-1 strains 25. Hence, production of these chemokines in the early stage of the disease presumably benefits the host to restrict virus dissemination 32. Therefore, induction of inhibitory molecules CCL3, CCL4, CCL5 and CXCL12 will contribute to sustained suppression of virus replication. Also of note, AOP-RANTES, an analogue of RANTES, has been shown to be a potent suppressor of HIV infection in vitro 33 and a compound blocking CCR5 has been approved for treatment of HIV-1 infection 34. In addition to the above chemokines, CCL2 has attracted the attention of researchers for its unique and predominant role in HIV-1 pathogenesis, as discussed in the following section.

CCL2 in HIV-1 pathogenesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

CCL2 is a pro-inflammatory chemokine that is induced during several human acute and chronic viral infections (Table 1). In addition to HIV-1 infection 35, virus-derived proteins such as gp120 36, Nef 37, matrix protein p17 38 and transactivator protein Tat 39, 40 significantly increase the expression and release of CCL2, suggesting the immunomodulatory capacity of virus-derived proteins in HIV/AIDS pathogenesis. Memory CD4+ T cells and monocytes/macrophages are the main target cells to be recruited by CCL2 owing to the high levels of CCR2 expression on these cells, making them primary targets for HIV-1 infection 41. Given that monocytes/macrophages are found to be the major source of CCL2 in vitro and in vivo, this may explain why HIV-1-infected migrating monocytes are considered to be a potent reservoir of the disease 42. Therefore, CCL2-loaded monocytes are the major players contributing to a positive feedback loop. Altered CCL2 expression may also contribute to HIV-associated dementia (HAD). Accordingly, CCL2 has been found to be markedly elevated in the cerebrospinal fluid (CSF) of HIV-infected patients with cytomegalovirus (CMV) encephalitis 42, 43. Of note, the plasma levels of CCL2 correlate with virus load in HIV-1 infection 4, 44, 45. Furthermore, SIV-infected macaques that develop moderate-to-severe encephalitis have significantly higher MCP-1 levels in the CSF than plasma, which suggests that the CSF:plasma MCP-1 ratio may be a valuable prognostic marker for the development of HIV-induced central nervous system (CNS) dysfunction 46. In addition a correlation between HIV-1 viremia and CCL2 levels has recently been shown in HIV-1 patients who develop atherosclerosis 47. Finally, the importance of CCL2 in HIV pathogenesis is further observed since CCL2 levels along with plasma viral load have been shown to diminish in HIV-1 patients after indinavir (a viral protease inhibitor) treatment resulted in an improved response 48.

Table 1. List of viruses inducing CCL2 in humans
VirusReferences
Human immunodeficiency virus (HIV)35–38, 58
Simian human immunodeficiency virus (SHIV)59
Hepatitis C virus (HCV)60, 61
Epstein–Barr virus (EBV)62
Respiratory synctitial virus (RSV)63
Severe acquired respiratory syndrome (SARS)64
Human herpes virus-6 (HHV-6)65
Herpes simplex virus-1 (HSV-1)66, 67
Human cytomegalovirus (HCMV)68, 69
Japanese encephalitis virus (JEV)70

CCL2–CCR2 polymorphism and HIV-1 infection

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

Genetic analyses of HIV-1-infected individuals homozygous for the CCL2-2518G allele, i.e. the GA/GA haplotype, have shown an association of this haplotype with accelerated progression to AIDS and mortality 49. An in vitro study using PBMCs from individuals homozygous or heterozygous for CCL2-2518G showed increased CCL2 production as compared with PBMCs from individuals homozygous for CCL2-2518A 50. This evidence is further supported by in vivo data, in which the CCL2-2518G haplotype correlated with increased serum CCL2 levels 49. Furthermore, HIV-patients with a mutated CCL2 allele have an undetectable viral load after treatment with protease inhibitor-based antiretroviral therapy 51, thus indicating a better response to protease inhibitor by those HIV-1 patients carrying a mutated CCL2.

The CCR2-V64I allele also has a significant influence on HIV-1 disease progression in adults, with the presence of CCR2-V64I being associated with slow progression to AIDS, although it has no impact upon HIV-1 transmission where the CCR5 using variants are dominant 51. Interestingly, although PBMCs isolated from CCR2-V64I heterozygous donors have normal levels of both CCR5 and CCR2, and the calcium flux mediated by CCL2 through CCR2-V64I is unaffected, they have reduced surface expression of CXCR4 52.

Lessons from case studies

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

A significant correlation of CCL2 gene expression and serum levels with HIV-1 viremia and disease progression has been demonstrated 4, 53. This observation has been further strengthened in a specific follow-up case study where an HIV-1-infected patient received short-term high-dose prednisolone therapy 54 and a >1 log reduction of HIV-1 viral load was found to be associated with a >100-fold reduction of CCL2 expression on day 3 post-prednisolone treatment. In vitro, HIV-1 infection of PBMC from healthy donors in the presence of prednisolone resulted in reduced HIV-1 replication coupled with decreased CCL2 54. Furthermore, at the molecular level, HIV-1-stimulated GHOST cells ((stably transfected cell line with HIV-1 LTR driving green fluorescent protein (GFP)) showed around a 50% reduction of GFP activity when cultured in the presence of prednisolone. This study indicates a direct suppressive effect of prednisolone on HIV-1 LTR-promoter activity 54. Taken together, these results suggest that this patient with high viremia and at an advanced stage of HIV-1 disease had highly upregulated CCL2 expression, which declined rapidly, together with the viral load, after prednisolone treatment.

Mechanisms of CCL2-driven HIV-1 pathogenesis

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

Evidence supporting a role of CCL2 in HIV-1 replication has been demonstrated in an in vitro HIV-1 infection model; decreased viral replication occurred when endogenous CCL2 was blocked by an anti-CCL2 antibody 35. Based on in vivo and in vitro findings three potential mechanisms of CCL2-mediated HIV-1 pathogenesis can be summarized (Fig. 1). First, a feed-back loop model where HIV-1 infection of monocytes triggers induction and release of CCL2, which recruits more potential HIV-1 targets, such as monocytes and CD4+ T cells to the site of infection, thus increasing the pool of susceptible cells for HIV-1 to replicate in and generating high plasma viral titers 4, 52, 53. A second possibility arises from the very recent evidence suggesting an increase in CXCR4 expression induced by CCL2 55. Since viremic, as compared with aviremic, patients produce more CCL2, it is possible that in vivo production of CCL2 by viremic patients at the late stage of HIV disease up-regulates the surface expression of CXCR4 on resting CD4+ T cells, thereby rendering the cells susceptible to X4 HIV-1 infection and contributing to the switch from R5- to X4-using viruses. The third possibility is the IL-4-mediated induction of CXCR4 expression. Unlike the other C-C chemokines, CCL2 regulates Th-cell differentiation by polarizing Th0 cells toward a Th2 phenotype 10, a hallmark of HIV-1 disease progression. Under these conditions, IL-4 secreted by Th2 cells induces CXCR4 expression on CD4+ T cells to make it a permissive target 56. The fourth potential mechanism of CCL2 in HIV-1 pathogenesis has been provided by an in vitro study using an anti-CCL2 antibody. This study demonstrated the autocrine role of CCL2 in enhancing virion production by altering the macrophage cytoskeleton 35.

thumbnail image

Figure 1. Potential mechanisms of CCL2-mediated HIV-1 replication and disease progression. HIV-1 primarily infects monocytes causing virus replication and production of viral progeny to start a new cycle of infection. At the same time infected monocytes secrete massive amounts of CCL2 resulting in the recruitment of more CCR2-expressing target cells to the site of infection to start another round of replication leading to a feed-back loop that eventually results in high plasma viremia. Secreted CCL2 also acts on CCR2-expressing Th0 driving Th2 polarization and the release of IL-4 and IL-10 that support HIV-1 replication and disease progression. In the late stages of the disease, CCL2 can act on CD4+ T cells causing them to express more CXCR4 and rendering them susceptible to the X-tropic HIV-1 strain and hence further viral replication. Mono and MP stands for monocytes and macrophages respectively.

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Concluding remarks and outlook

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

A growing body of evidence suggests that CCL2 can be exploited by HIV-1 to enhance viral replication by recruiting target cells, enhancing CXCR4 expression and a Th2 biased immune response, and thereby fuelling HIV-1 replication and hence disease progression. The prominent role of immune activation and immune senescence in HIV-1 pathogenesis has been clearly established 57. Immunomodulatory agents that interfere with the CCL2/CCR2 axis thus might be a promising target for the investigational treatment of HIV-associated comorbidities. Further detailed study using primate and humanised mouse models could provide more insights by permitting the selective inhibition of elevated CCL2 production.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References

This work was supported in part by the German Research Foundation (SFB 566 A02) and AWA was supported by a fellowship of the Hannover Biomedical Research School.

Confllict of interest: The authors declare no financial or commercial conflict of interest.

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  2. Abstract
  3. Introduction
  4. CCL2
  5. CCL2 receptor
  6. Chemokines in HIV-1 pathogenesis
  7. CCL2 in HIV-1 pathogenesis
  8. CCL2–CCR2 polymorphism and HIV-1 infection
  9. Lessons from case studies
  10. Mechanisms of CCL2-driven HIV-1 pathogenesis
  11. Concluding remarks and outlook
  12. Acknowledgements
  13. References
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