Inflammation Research

, Volume 66, Issue 12, pp 1107–1116 | Cite as

SERPING1 mRNA overexpression in monocytes from HIV+ patients

  • C. Sanfilippo
  • D. Cambria
  • A. Longo
  • M. Palumbo
  • R. Avola
  • M. Pinzone
  • G. Nunnari
  • F. Condorelli
  • G. Musumeci
  • R. Imbesi
  • P. Castogiovanni
  • L. Malaguarnera
  • Michelino Di Rosa
Original Research Paper



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.


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.


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.


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.


SERPING1 C1-INH Monocyte Complement HIV-1 IFN-gamma 



Low viral load


High viral load


Human immunodeficiency virus 1








Acute human immunodeficiency virus (HIV) infection


C1 inhibitor


50% Tissue culture infective dose


Interferon-induced transmembrane protein 1


Highly active anti-retroviral therapy


Complement component 4 fragment d


Type I and II hereditary angioedema


Plasma viral load


Acute phase


Human peripheral blood mononuclear cells


Blood viral load



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.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interests.

Supplementary material

11_2017_1091_MOESM1_ESM.tif (1.2 mb)
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 (40 kb)
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 (113 kb)
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 (13 kb)
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 (4.3 mb)
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)


  1. 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.CrossRefPubMedGoogle Scholar
  2. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 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.CrossRefPubMedGoogle Scholar
  4. 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.CrossRefPubMedGoogle Scholar
  5. 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.CrossRefPubMedGoogle Scholar
  6. 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.CrossRefGoogle Scholar
  7. 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.CrossRefPubMedGoogle Scholar
  8. 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.CrossRefPubMedGoogle Scholar
  9. 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.CrossRefPubMedGoogle Scholar
  10. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 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.CrossRefPubMedGoogle Scholar
  12. 12.
    Gerencer M, Burek V. Identification of HIV-1 protease cleavage site in human C1-inhibitor. Virus Res. 2004;105:97–100.CrossRefPubMedGoogle Scholar
  13. 13.
    Germenis AE, Speletas M. Genetics of hereditary angioedema revisited. Clin Rev Allergy Immunol. 2016;51:170–82.CrossRefPubMedGoogle Scholar
  14. 14.
    Nzeako UC, Frigas E, Tremaine WJ. Hereditary angioedema: a broad review for clinicians. Arch Intern Med. 2001;161:2417–29.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 16.
    Frank MM, Gelfand JA, Atkinson JP. Hereditary angioedema: the clinical syndrome and its management. Ann Intern Med. 1976;84:580–93.CrossRefPubMedGoogle Scholar
  17. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 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.CrossRefPubMedGoogle Scholar
  22. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 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.CrossRefPubMedGoogle Scholar
  24. 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.CrossRefPubMedPubMedCentralGoogle Scholar
  25. 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.CrossRefPubMedGoogle Scholar
  26. 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.CrossRefPubMedGoogle Scholar
  27. 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.CrossRefPubMedGoogle Scholar
  28. 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.CrossRefPubMedGoogle Scholar
  29. 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.CrossRefPubMedGoogle Scholar
  30. 30.
    Wang X, Seed B. A PCR primer bank for quantitative gene expression analysis. Nucleic Acids Res. 2003;31:e154.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 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.CrossRefGoogle Scholar
  32. 32.
    Burek V, Gerencer M. Inhibition of classical complement activation by sera from HIV-1-positive patients. Clin Immunol Immunopathol. 1996;81:114–21.CrossRefPubMedGoogle Scholar
  33. 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.CrossRefPubMedGoogle Scholar
  34. 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.CrossRefPubMedGoogle Scholar
  35. 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.CrossRefPubMedGoogle Scholar
  36. 36.
    Martensen PM, Justesen J. Small ISGs coming forward. J Interf Cytokine Res. 2004;24:1–19.CrossRefGoogle Scholar
  37. 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.CrossRefPubMedGoogle Scholar
  38. 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.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2017

Authors and Affiliations

  • C. Sanfilippo
    • 1
  • D. Cambria
    • 1
  • A. Longo
    • 1
  • M. Palumbo
    • 1
  • R. Avola
    • 1
  • M. Pinzone
    • 2
  • G. Nunnari
    • 3
  • F. Condorelli
    • 4
  • G. Musumeci
    • 5
  • R. Imbesi
    • 5
  • P. Castogiovanni
    • 5
  • L. Malaguarnera
    • 1
  • Michelino Di Rosa
    • 1
    • 5
  1. 1.Department of Biomedical and Biotechnological SciencesUniversity of CataniaCataniaItaly
  2. 2.Department of Pathology and Laboratory Medicine, School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Unit of Infectious Diseases, Department of Clinical and Experimental MedicineUniversity of MessinaMessinaItaly
  4. 4.Department of Pharmacological SciencesUniversità del Piemonte Orientale “A. Avogadro”NovaraItaly
  5. 5.Human Anatomy and Histology Section, Department of Biomedical and Biotechnological Sciences, School of MedicineUniversity of CataniaCataniaItaly

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