Skip to main content

Advertisement

SpringerLink
Log in

SERPING1 mRNA overexpression in monocytes from HIV+ patients

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

Objective

The HIV-1 virus activates the complement system, an essential element of the immune system. SERPING1 is a protease inhibitor that disables C1r/C1s in the C1 complex of the classical complement pathway.

Methods

In this paper, we performed an analysis of several microarrays deposited in GEO dataset to demonstrate that SERPING1 mRNA is modulated in CD14+ monocytes from HIV-1-infected individuals. In addition, data were validated on monocytes isolated from seronegative healthy volunteers, treated with IFNs.

Results

Our analysis shows that SERPING1 mRNA is overexpressed in monocytes from HIV-1+ patients and the expression levels correlate positively with viral load and negatively with the CD4+ T-cell count. Of note, anti-retroviral therapy is able to reduce the levels of SERPING1 mRNA, ex vivo. In addition, we found that 30% of the SERPING1 genes network is upregulated in monocytes from HIV-1+ patients. Noteworthy, the expression levels of IFITM1—an antiviral molecule belonging to the genes network—correlate positively with SERPING1 expression. Interestingly, the monocytes treatment with IFN-gamma, IFN-beta and IFN-alpha significantly upregulates the SERPING1 mRNA expression levels.

Conclusions

From the outcome of our investigation, it is possible to conclude that SERPING1 and its network serve as important components of the innate immune system to restrict HIV-1 infection.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

Abbreviations

LVL:

Low viral load

HVL:

High viral load

HIV-1:

Human immunodeficiency virus 1

IFNγ:

Interferon-gamma

IFNα:

Interferon-alpha

IFNβ:

Interferon-beta

AHI:

Acute human immunodeficiency virus (HIV) infection

C1-INH or SERPING1 :

C1 inhibitor

TCID50:

50% Tissue culture infective dose

IFITM1:

Interferon-induced transmembrane protein 1

HAART:

Highly active anti-retroviral therapy

C4d:

Complement component 4 fragment d

HAE:

Type I and II hereditary angioedema

PVL:

Plasma viral load

AP:

Acute phase

PBMCs:

Human peripheral blood mononuclear cells

BVL:

Blood viral load

References

  1. Saifuddin M, Parker CJ, Peeples ME, Gorny MK, Zolla-Pazner S, Ghassemi M, et al. Role of virion-associated glycosylphosphatidylinositol-linked proteins CD55 and CD59 in complement resistance of cell line-derived and primary isolates of HIV-1. J Exp Med. 1995;182:501–9.

    Article  CAS  PubMed  Google Scholar 

  2. Huber M, Fischer M, Misselwitz B, Manrique A, Kuster H, Niederost B, et al. Complement lysis activity in autologous plasma is associated with lower viral loads during the acute phase of HIV-1 infection. PLoS Med. 2006;3:e441.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Stoiber H, Kacani L, Speth C, Wurzner R, Dierich MP. The supportive role of complement in HIV pathogenesis. Immunol Rev. 2001;180:168–76.

    Article  CAS  PubMed  Google Scholar 

  4. Stoiber H, Soederholm A, Wilflingseder D, Gusenbauer S, Hildgartner A, Dierich MP. Complement and antibodies: a dangerous liaison in HIV infection? Vaccine. 2008;26(Suppl 8):I79–85.

    Article  CAS  PubMed  Google Scholar 

  5. Pruenster M, Wilflingseder D, Banki Z, Ammann CG, Muellauer B, Meyer M, et al. C-type lectin-independent interaction of complement opsonized HIV with monocyte-derived dendritic cells. Eur J Immunol. 2005;35:2691–8.

    Article  CAS  PubMed  Google Scholar 

  6. Nunnari G, Coco C, Pinzone MR, Pavone P, Berretta M, Di Rosa M, et al. The role of micronutrients in the diet of HIV-1-infected individuals. Front Biosci. 2012;4:2442–56.

    Article  Google Scholar 

  7. Prohaszka Z, Nemes J, Hidvegi T, Toth FD, Kerekes K, Erdei A, et al. Two parallel routes of the complement-mediated antibody-dependent enhancement of HIV-1 infection. Aids. 1997;11:949–58.

    Article  CAS  PubMed  Google Scholar 

  8. Malhotra R, Thiel S, Reid KB, Sim RB. Human leukocyte C1q receptor binds other soluble proteins with collagen domains. J Exp Med. 1990;172:955–9.

    Article  CAS  PubMed  Google Scholar 

  9. Tomasselli AG, Howe WJ, Hui JO, Sawyer TK, Reardon IM, DeCamp DL, et al. Calcium-free calmodulin is a substrate of proteases from human immunodeficiency viruses 1 and 2. Proteins. 1991;10:1–9.

    Article  CAS  PubMed  Google Scholar 

  10. Shoeman RL, Honer B, Stoller TJ, Kesselmeier C, Miedel MC, Traub P, et al. Human immunodeficiency virus type 1 protease cleaves the intermediate filament proteins vimentin, desmin, and glial fibrillary acidic protein. Proc Natl Acad Sci USA. 1990;87:6336–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Pinzone MR, Cacopardo B, Condorelli F, Di Rosa M, Nunnari G. Sirtuin-1 and HIV-1: an overview. Curr Drug Targets. 2013;14:648–52.

    Article  CAS  PubMed  Google Scholar 

  12. Gerencer M, Burek V. Identification of HIV-1 protease cleavage site in human C1-inhibitor. Virus Res. 2004;105:97–100.

    Article  CAS  PubMed  Google Scholar 

  13. Germenis AE, Speletas M. Genetics of hereditary angioedema revisited. Clin Rev Allergy Immunol. 2016;51:170–82.

    Article  CAS  PubMed  Google Scholar 

  14. Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161:2417–29.

    Article  CAS  PubMed  Google Scholar 

  15. Agostoni A, Aygoren-Pursun E, Binkley KE, Blanch A, Bork K, Bouillet L, et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol. 2004;114:S51–131.

    Article  PubMed  Google Scholar 

  16. Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med. 1976;84:580–93.

    Article  CAS  PubMed  Google Scholar 

  17. Rempel H, Sun B, Calosing C, Pillai SK, Pulliam L. Interferon-alpha drives monocyte gene expression in chronic unsuppressed HIV-1 infection. Aids. 2010;24:1415–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Tilton JC, Johnson AJ, Luskin MR, Manion MM, Yang J, Adelsberger JW, et al. Diminished production of monocyte proinflammatory cytokines during human immunodeficiency virus viremia is mediated by type I interferons. J Virol. 2006;80:11486–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Brown JN, Kohler JJ, Coberley CR, Sleasman JW, Goodenow MM. HIV-1 activates macrophages independent of Toll-like receptors. PLoS One. 2008;3:e3664.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Hyrcza MD, Kovacs C, Loutfy M, Halpenny R, Heisler L, Yang S, et al. Distinct transcriptional profiles in ex vivo CD4+ and CD8+ T cells are established early in human immunodeficiency virus type 1 infection and are characterized by a chronic interferon response as well as extensive transcriptional changes in CD8+ T cells. J Virol. 2007;81:3477–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Szklarczyk D, Morris JH, Cook H, Kuhn M, Wyder S, Simonovic M, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45:D362–8.

    Article  PubMed  Google Scholar 

  22. Greene CS, Krishnan A, Wong AK, Ricciotti E, Zelaya RA, Himmelstein DS, et al. Understanding multicellular function and disease with human tissue-specific networks. Nat Genet. 2015;47:569–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Fagone P, Nunnari G, Lazzara F, Longo A, Cambria D, Distefano G, et al. Induction of OAS gene family in HIV monocyte infected patients with high and low viral load. Antiviral Res. 2016;131:66–73.

    Article  CAS  PubMed  Google Scholar 

  24. Thomas PD, Campbell MJ, Kejariwal A, Mi H, Karlak B, Daverman R, et al. PANTHER: a library of protein families and subfamilies indexed by function. Genome Res. 2003;13:2129–41.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Mi H, Muruganujan A, Casagrande JT, Thomas PD. Large-scale gene function analysis with the PANTHER classification system. Nat Protoc. 2013;8:1551–66.

    Article  PubMed  Google Scholar 

  26. Mi H, Lazareva-Ulitsky B, Loo R, Kejariwal A, Vandergriff J, Rabkin S, et al. The PANTHER database of protein families, subfamilies, functions and pathways. Nucleic Acids Res. 2005;33:D284–8.

    Article  CAS  PubMed  Google Scholar 

  27. Di Rosa M, Tibullo D, Vecchio M, Nunnari G, Saccone S, Di Raimondo F, et al. Determination of chitinases family during osteoclastogenesis. Bone. 2014;61:55–63.

    Article  PubMed  Google Scholar 

  28. Di Rosa M, Zambito AM, Marsullo AR, Li Volti G, Malaguarnera L. Prolactin induces chitotriosidase expression in human macrophages through PTK, PI3-K, and MAPK pathways. J Cell Biochem. 2009;107:881–9.

    Article  PubMed  Google Scholar 

  29. Spandidos A, Wang X, Wang H, Seed B. PrimerBank: a resource of human and mouse PCR primer pairs for gene expression detection and quantification. Nucleic Acids Res. 2010;38:D792–9.

    Article  CAS  PubMed  Google Scholar 

  30. Wang X, Seed B. A PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res. 2003;31:e154.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Spandidos A, Wang X, Wang H, Dragnev S, Thurber T, Seed B. A comprehensive collection of experimentally validated primers for polymerase chain reaction quantitation of murine transcript abundance. BMC Genom. 2008;9:633.

    Article  Google Scholar 

  32. Burek V, Gerencer M. Inhibition of classical complement activation by sera from HIV-1-positive patients. Clin Immunol Immunopathol. 1996;81:114–21.

    Article  CAS  PubMed  Google Scholar 

  33. Patston PA, Qi M, Schifferli JA, Schapira M. The effect of cleavage by a Crotalus atrox alpha-proteinase fraction on the properties of C1-inhibitor. Toxicon. 1995;33:53–61.

    Article  CAS  PubMed  Google Scholar 

  34. Gerencer M, Burek V, Barrett NP, Dorner F. Acquired deficiency of functional C1-esterase inhibitor in HIV type 1-infected patients. AIDS Res Hum Retrovir. 1997;13:813–4.

    Article  CAS  PubMed  Google Scholar 

  35. Reche M, Caballero T, Lopez-Trascasa M, Arribas JR, Lopez Serrano MC. Angioedema and transient acquired C1 inhibitor functional deficiency in HIV infection: case report. Aids. 2002;16:1561.

    Article  CAS  PubMed  Google Scholar 

  36. Martensen PM, Justesen J. Small ISGs coming forward. J Interf Cytokine Res. 2004;24:1–19.

    Article  CAS  Google Scholar 

  37. Lu J, Pan Q, Rong L, He W, Liu SL, Liang C. The IFITM proteins inhibit HIV-1 infection. J Virol. 2011;85:2126–37.

    Article  CAS  PubMed  Google Scholar 

  38. Raposo RA, de Mulder Rougvie M, Paquin-Proulx D, Brailey PM, Cabido VD, Zdinak PM, et al. IFITM1 targets HIV-1 latently infected cells for antibody-dependent cytolysis. JCI insight. 2017;2:e85811.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We would also like to show our gratitude to the authors of microarray dataset (GSE18464, GSE5220, GSE13395 and GSE25669) made available on line, for consultation and re-analysis.

Author information

Authors and Affiliations

  1. Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy

    C. Sanfilippo, D. Cambria, A. Longo, M. Palumbo, R. Avola, L. Malaguarnera & Michelino Di Rosa

  2. Department of Pathology and Laboratory Medicine, School of Medicine, University of Pennsylvania, Philadelphia, USA

    M. Pinzone

  3. Unit of Infectious Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy

    G. Nunnari

  4. Department of Pharmacological Sciences, Università del Piemonte Orientale “A. Avogadro”, 28100, Novara, Italy

    F. Condorelli

  5. Human Anatomy and Histology Section, Department of Biomedical and Biotechnological Sciences, School of Medicine, University of Catania, Catania, Italy

    G. Musumeci, R. Imbesi, P. Castogiovanni & Michelino Di Rosa

Authors
  1. C. Sanfilippo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Cambria
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Longo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. Palumbo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. R. Avola
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. M. Pinzone
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. G. Nunnari
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F. Condorelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. G. Musumeci
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. R. Imbesi
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. P. Castogiovanni
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. L. Malaguarnera
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Michelino Di Rosa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michelino Di Rosa.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interests.

Additional information

Responsible Editor: John Di Battista.

Electronic supplementary material

Below is the link to the electronic supplementary material.

11_2017_1091_MOESM1_ESM.tif

Supplementary Fig. 1: SERPING1 gene network constellation. The STRING network on 15 common genes to the HVL vs seronegative Healthy donors upregulated genes. The genes shown in red (58%) belong to the IFNs type I pathways (TIFF 1200 kb)

11_2017_1091_MOESM2_ESM.tif

Supplementary Fig. 2: SERPING1 levels correlate with IFNs gene family expression. The comparison analysis of the two sub-groups (> 85th and < 15th percentile of SERPING1 expression levels) have restituted 6002 significant modulated genes. The most significant genes belonged to the Interferon Family Genes (IFI44, IRF7, IFI44L, IFIT1, IFIT3, IFIT2, IFIH1, IFITM3 and IFITM1). P values < 0.05 were considered to be statistically significant (*p < 0.05; **p < 0.005;***p < 0.0005; ****p < 0.00005 and ns, not significant) (TIFF 39 kb)

11_2017_1091_MOESM3_ESM.tif

Supplementary Fig. 3: HIV-1 virus effect on SERPING1 mRNA expression levels in Peripheral blood lymphocytes. The HIV-1 virus not modulated SERPING1 expression levels (GSE13395) (A). The analysis of different leukocyte populations (GSE25669) showed that SERPING1 expression levels was significantly upregulated (p = 0.016) only in monocytes of HIV-1 patients compared to monocytes of seronegative healthy donors (B). Results are expressed as Log2 intensity expression levels and presented as bars (one bar per column) and mean ± SD. P values < 0.05 were considered to be statistically significant (*p < 0.05; **p < 0.005;***p < 0.0005; ****p < 0.00005 and ns, not significant) (TIFF 113 kb)

11_2017_1091_MOESM4_ESM.xlsx

Supplementary Table 1: The Genes Ontology. Complete list of functions obtained during the GIANT and PHANTER analysis (XLSX 12 kb)

11_2017_1091_MOESM5_ESM.xlsx

Supplementary Table 2: GSE18464 dataset centered on SERPING1 expression levels. Complete list of statistically significant genes obtained by the comparison analysis of the two sub-groups, high and low SERPING1 expression levels (XLSX 4375 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sanfilippo, C., Cambria, D., Longo, A. et al. SERPING1 mRNA overexpression in monocytes from HIV+ patients. Inflamm. Res. 66, 1107–1116 (2017). https://doi.org/10.1007/s00011-017-1091-x

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-017-1091-x

Keywords

Search

Navigation