Molecular Neurobiology

, Volume 55, Issue 3, pp 1905–1914 | Cite as

OAS Gene Family Expression Is Associated with HIV-Related Neurocognitive Disorders

  • C. Sanfilippo
  • M.R. Pinzone
  • D. Cambria
  • A. Longo
  • M. Palumbo
  • R. Di Marco
  • F. Condorelli
  • G. Nunnari
  • L. Malaguarnera
  • M. Di Rosa


HIV-associated neurocognitive disorders are common in HIV-infected individuals, even in the combination antiretroviral therapy (c-ART) era. Several mechanisms are involved in neuronal damage, including chronic inflammation immune activation. Mammalian 2′-5′-oligoadenylate synthetase (OAS) genes are produced in response to interferon (IFN), mainly by monocytes, and exert their antiviral functions by activation of RNase L that degrades viral and cellular RNAs. In this study, we aimed at exploring OAS gene family RNA expression in simian immunodeficiency virus encephalitis (SIVE), in HIV-associated neurocognitive disorders (HAND), and in HIV-associate dementia (HAD). We analyzed three microarray datasets obtained from the NCBI in order to assess the expression levels of OAS gene family network in brain biopsies of macaques with SIVE vs uninfected animals, as well as post-mortem brain of individuals with HAND (on or off ART) vs uninfected controls and three brain regions of HIV-infected individuals with both neurocognitive impairment (HAD) and encephalitis (HIVE). All OAS genes were upregulated both in SIVE and in HAND. OAS expression was significantly higher in high-viremic individuals; increased expression levels persisted in cART subjects when compared to healthy controls. OAS gene network analysis showed that several genes belonging to the type I IFN pathway, especially CXCL10 and IFIT3, were similarly upregulated in SIVE/HAND. Furthermore, we identified a significant upregulation of OAS gene family RNA expression in basal ganglia, white matter, and frontal cortex of HIV-1, HAD, and HAD/HIVE patients compared to healthy subjects. OAS gene family expression is increased in brain sections from individuals with HAND, HAD, and HIVE as well as macaques with SIVE. OAS family expression is likely to be induced by IFN as a consequence of viral replication in the CNS. Its long-term upregulation may contribute to the chronic inflammatory status and neurocognitive impairment we still observe in virologically suppressed individuals on c-ART.





Combination antiretroviral therapy


Highly active anti-retroviral therapy


Acquired immune deficiency syndrome


Central nervous system


Human immunodeficiency virus


HIV/simian immunodeficiency virus


Simian immunodeficiency virus encephalitis


HIV-associated neurocognitive disorders


HIV-infected with neurocognitive impairment or HIV associate dementia


Asymptomatic neurocognitive impairment


HIV encephalitis


Blood-brain barrier


Cerebrospinal fluid


C-X-C motif chemokine 10


False discovery rate


Interferon-induced protein with tetratricopeptide repeats 3


2′-5′-Oligoadenylate synthetase 1


2′-5′-Oligoadenylate synthetase 2


2′-5′-Oligoadenylate synthetase 3


2′-5′-Oligoadenylate synthetase-like


MultiExperiment Viewer


Interquartile range


Brain viral load


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2017_460_Fig7_ESM.gif (14 kb)
Supplementary Figure 1 (GIF 14 kb)
12035_2017_460_MOESM1_ESM.tif (23 kb)
High Resolution (TIFF 23 kb)
12035_2017_460_Fig8_ESM.gif (43 kb)
Supplementary Figure 2 (GIF 43 kb)
12035_2017_460_MOESM2_ESM.tif (65 kb)
High Resolution (TIFF 64 kb)
12035_2017_460_Fig9_ESM.gif (277 kb)
Supplementary Figure 3 (GIF 276 kb)
12035_2017_460_MOESM3_ESM.tif (1.8 mb)
High Resolution (TIFF 1838 kb)
12035_2017_460_Fig10_ESM.gif (61 kb)
Supplementary Figure 4 (GIF 60 kb)
12035_2017_460_MOESM4_ESM.tif (82 kb)
High Resolution (TIFF 81 kb)
12035_2017_460_Fig11_ESM.gif (82 kb)
Supplementary Figure 5 (GIF 82 kb)
12035_2017_460_Fig12_ESM.gif (162 kb)
High Resolution (GIF 162 kb)
12035_2017_460_MOESM5_ESM.tif (104 kb)
Supplementary Figure 6 (TIFF 104 kb)
12035_2017_460_MOESM6_ESM.tif (21.7 mb)
High Resolution (TIFF 22212 kb)
12035_2017_460_MOESM7_ESM.xlsx (7.2 mb)
Supplementary Table 1 (XLSX 7355 kb)


  1. 1.
    Scarpino M, Pinzone MR, Di Rosa M, Madeddu G, Foca E, Martellotta F, Schioppa O, Ceccarelli G et al (2013) Kidney disease in HIV-infected patients. European review for medical and pharmacological sciences 17(19):2660–2667PubMedGoogle Scholar
  2. 2.
    Castronuovo D, Cacopardo B, Pinzone MR, Di Rosa M, Martellotta F, Schioppa O, Moreno S, Nunnari G (2013) Bone disease in the setting of HIV infection: update and review of the literature. European review for medical and pharmacological sciences 17(18):2413–2419PubMedGoogle Scholar
  3. 3.
    Pinzone MR, Berretta M, Cacopardo B, Nunnari G (2015) Epstein-barr virus- and Kaposi sarcoma-associated herpesvirus-related malignancies in the setting of human immunodeficiency virus infection. Semin Oncol 42(2):258–271. doi: 10.1053/j.seminoncol.2014.12.026 CrossRefPubMedGoogle Scholar
  4. 4.
    Pinzone MR, Fiorica F, Di Rosa M, Malaguarnera G, Malaguarnera L, Cacopardo B, Zanghi G, Nunnari G (2012) Non-AIDS-defining cancers among HIV-infected people. European review for medical and pharmacological sciences 16(10):1377–1388PubMedGoogle Scholar
  5. 5.
    Nunnari G, Berretta M, Pinzone MR, Di Rosa M, Berretta S, Cunsolo G, Malaguarnera M, Cosentino S et al (2012) Hepatocellular carcinoma in HIV positive patients. European review for medical and pharmacological sciences 16(9):1257–1270PubMedGoogle Scholar
  6. 6.
    Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, Ellis RJ, Letendre SL et al (2010) HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study. Neurology 75(23):2087–2096. doi: 10.1212/WNL.0b013e318200d727 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Hong S, Banks WA (2015) Role of the immune system in HIV-associated neuroinflammation and neurocognitive implications. Brain Behav Immun 45:1–12. doi: 10.1016/j.bbi.2014.10.008 CrossRefPubMedGoogle Scholar
  8. 8.
    Airoldi M, Bandera A, Trabattoni D, Tagliabue B, Arosio B, Soria A, Rainone V, Lapadula G et al (2012) Neurocognitive impairment in HIV-infected naive patients with advanced disease: the role of virus and intrathecal immune activation. Clinical & developmental immunology 2012:467154. doi: 10.1155/2012/467154 CrossRefGoogle Scholar
  9. 9.
    Kristiansen H, Gad HH, Eskildsen-Larsen S, Despres P, Hartmann R (2011) The oligoadenylate synthetase family: an ancient protein family with multiple antiviral activities. Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research 31(1):41–47. doi: 10.1089/jir.2010.0107 CrossRefGoogle Scholar
  10. 10.
    Fagone P, Nunnari G, Lazzara F, Longo A, Cambria D, Distefano G, Palumbo M, Nicoletti F et al (2016) Induction of OAS gene family in HIV monocyte infected patients with high and low viral load. Antivir Res 131:66–73. doi: 10.1016/j.antiviral.2016.04.009 CrossRefPubMedGoogle Scholar
  11. 11.
    Gersten M, Alirezaei M, Marcondes MC, Flynn C, Ravasi T, Ideker T, Fox HS (2009) An integrated systems analysis implicates EGR1 downregulation in simian immunodeficiency virus encephalitis-induced neural dysfunction. The Journal of neuroscience : the official journal of the Society for Neuroscience 29(40):12467–12476. doi: 10.1523/JNEUROSCI.3180-09.2009 CrossRefGoogle Scholar
  12. 12.
    Borjabad A, Morgello S, Chao W, Kim SY, Brooks AI, Murray J, Potash MJ, Volsky DJ (2011) Significant effects of antiretroviral therapy on global gene expression in brain tissues of patients with HIV-1-associated neurocognitive disorders. PLoS Pathog 7(9):e1002213. doi: 10.1371/journal.ppat.1002213 CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Gelman BB, Chen T, Lisinicchia JG, Soukup VM, Carmical JR, Starkey JM, Masliah E, Commins DL et al (2012) The National NeuroAIDS Tissue Consortium brain gene array: two types of HIV-associated neurocognitive impairment. PLoS One 7(9):e46178. doi: 10.1371/journal.pone.0046178 CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A et al (2015) STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res 43(Database issue):D447–D452. doi: 10.1093/nar/gku1003 CrossRefPubMedGoogle Scholar
  15. 15.
    Greene CS, Krishnan A, Wong AK, Ricciotti E, Zelaya RA, Himmelstein DS, Zhang R, Hartmann BM et al (2015) Understanding multicellular function and disease with human tissue-specific networks. Nat Genet 47(6):569–576. doi: 10.1038/ng.3259 CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Pathan M, Keerthikumar S, Ang CS, Gangoda L, Quek CY, Williamson NA, Mouradov D, Sieber OM et al (2015) FunRich: an open access standalone functional enrichment and interaction network analysis tool. Proteomics 15(15):2597–2601. doi: 10.1002/pmic.201400515 CrossRefPubMedGoogle Scholar
  17. 17.
    Maneglier B, Rogez-Kreuz C, Dereuddre-Bosquet N, Martal J, Devillier P, Dormont D, Clayette P (2008) Anti-HIV effects of IFN-tau in human macrophages: role of cellular antiviral factors and interleukin-6. Pathologie-biologie 56(7–8):492–503. doi: 10.1016/j.patbio.2008.06.002 CrossRefPubMedGoogle Scholar
  18. 18.
    Durudas A, Chen HL, Gasper MA, Sundaravaradan V, Milush JM, Silvestri G, Johnson W, Giavedoni LD et al (2011) Differential innate immune responses to low or high dose oral SIV challenge in rhesus macaques. Curr HIV Res 9(5):276–288CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Durudas A, Milush JM, Chen HL, Engram JC, Silvestri G, Sodora DL (2009) Elevated levels of innate immune modulators in lymph nodes and blood are associated with more-rapid disease progression in simian immunodeficiency virus-infected monkeys. J Virol 83(23):12229–12240. doi: 10.1128/JVI.01311-09 CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Sarkar S, Kalia V, Murphey-Corb M, Montelaro RC, Reinhart TA (2003) Expression of IFN-gamma induced CXCR3 agonist chemokines and compartmentalization of CXCR3+ cells in the periphery and lymph nodes of rhesus macaques during simian immunodeficiency virus infection and acquired immunodeficiency syndrome. J Med Primatol 32(4–5):247–264CrossRefPubMedGoogle Scholar
  21. 21.
    Stacey AR, Norris PJ, Qin L, Haygreen EA, Taylor E, Heitman J, Lebedeva M, DeCamp A et al (2009) Induction of a striking systemic cytokine cascade prior to peak viremia in acute human immunodeficiency virus type 1 infection, in contrast to more modest and delayed responses in acute hepatitis B and C virus infections. J Virol 83(8):3719–3733. doi: 10.1128/JVI.01844-08 CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Cinque P, Bestetti A, Marenzi R, Sala S, Gisslen M, Hagberg L, Price RW (2005) Cerebrospinal fluid interferon-gamma-inducible protein 10 (IP-10, CXCL10) in HIV-1 infection. J Neuroimmunol 168(1–2):154–163. doi: 10.1016/j.jneuroim.2005.07.002 CrossRefPubMedGoogle Scholar
  23. 23.
    Read SE, Williams BR, Coates RA, Evans WK, Fanning MM, Garvey MB, Shepherd FA (1985) Elevated levels of interferon-induced 2'-5' oligoadenylate synthetase in generalized persistent lymphadenopathy and the acquired immunodeficiency syndrome. The Journal of infectious diseases 152(3):466–472CrossRefPubMedGoogle Scholar
  24. 24.
    Pulliam L (2014) Cognitive consequences of a sustained monocyte type 1 IFN response in HIV-1 infection. Curr HIV Res 12(2):77–84CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Pulliam L, Gascon R, Stubblebine M, McGuire D, McGrath MS (1997) Unique monocyte subset in patients with AIDS dementia. Lancet 349(9053):692–695. doi: 10.1016/S0140-6736(96)10178-1 CrossRefPubMedGoogle Scholar
  26. 26.
    Kalter DC, Nakamura M, Turpin JA, Baca LM, Hoover DL, Dieffenbach C, Ralph P, Gendelman HE et al (1991) Enhanced HIV replication in macrophage colony-stimulating factor-treated monocytes. J Immunol 146(1):298–306PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  1. 1.Section of Neurosciences, Department G.F. IngrassiaUniversity of CataniaCataniaItaly
  2. 2.Department of Pathology and Laboratory Medicine, School of MedicineUniversity of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of Biomedical and Biotechnological SciencesUniversity of CataniaCataniaItaly
  4. 4.Department of Medicine and Health SciencesUniversity of MoliseCampobassoItaly
  5. 5.Department of Pharmacological SciencesUniversità del Piemonte OrientaleNovaraItaly
  6. 6.Unit of Infectious Diseases, Department of Clinical and Experimental MedicineUniversity of MessinaMessinaItaly

Personalised recommendations