Skip to main content

Advertisement

SpringerLink
Log in

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

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

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.

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
Fig. 6

Similar content being viewed by others

Abbreviations

c-ART:

Combination antiretroviral therapy

HAART:

Highly active anti-retroviral therapy

AIDS:

Acquired immune deficiency syndrome

CNS:

Central nervous system

HIV:

Human immunodeficiency virus

SIV:

HIV/simian immunodeficiency virus

SIVE:

Simian immunodeficiency virus encephalitis

HAND:

HIV-associated neurocognitive disorders

HAD:

HIV-infected with neurocognitive impairment or HIV associate dementia

ANI:

Asymptomatic neurocognitive impairment

HIVE:

HIV encephalitis

BBB:

Blood-brain barrier

CSF:

Cerebrospinal fluid

CXCL10:

C-X-C motif chemokine 10

FDR:

False discovery rate

IFIT3:

Interferon-induced protein with tetratricopeptide repeats 3

OAS1:

2′-5′-Oligoadenylate synthetase 1

OAS2:

2′-5′-Oligoadenylate synthetase 2

OAS3:

2′-5′-Oligoadenylate synthetase 3

OASL:

2′-5′-Oligoadenylate synthetase-like

MeV:

MultiExperiment Viewer

IQR:

Interquartile range

BVL:

Brain viral load

References

  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):2660–2667

    CAS  PubMed  Google Scholar 

  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):2413–2419

    CAS  PubMed  Google Scholar 

  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

    Article  PubMed  Google Scholar 

  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):1377–1388

    CAS  PubMed  Google Scholar 

  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):1257–1270

    CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):276–288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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):247–264

    Article  CAS  PubMed  Google Scholar 

  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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):466–472

    Article  CAS  PubMed  Google Scholar 

  24. Pulliam L (2014) Cognitive consequences of a sustained monocyte type 1 IFN response in HIV-1 infection. Curr HIV Res 12(2):77–84

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  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

    Article  CAS  PubMed  Google Scholar 

  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):298–306

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Section of Neurosciences, Department G.F. Ingrassia, University of Catania, Via Santa Sofia 78, 95123, Catania, Italy

    C. Sanfilippo

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

    M.R. Pinzone

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

    D. Cambria, A. Longo, M. Palumbo, L. Malaguarnera & M. Di Rosa

  4. Department of Medicine and Health Sciences, University of Molise, Campobasso, Italy

    R. Di Marco

  5. Department of Pharmacological Sciences, Università del Piemonte Orientale, A. Avogadro, 28100, Novara, Italy

    F. Condorelli

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

    G. Nunnari

Authors
  1. C. Sanfilippo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M.R. Pinzone
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D. Cambria
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. Longo
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. M. Palumbo
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. R. Di Marco
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. F. Condorelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. G. Nunnari
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. L. Malaguarnera
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. M. Di Rosa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to M. Di Rosa.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Sanfilippo, C., Pinzone, M., Cambria, D. et al. OAS Gene Family Expression Is Associated with HIV-Related Neurocognitive Disorders. Mol Neurobiol 55, 1905–1914 (2018). https://doi.org/10.1007/s12035-017-0460-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-017-0460-3

Keywords

Search

Navigation