Brain Tissue Transcriptomic Analysis of SIV-infected Macaques Identifies Several Altered Metabolic Pathways Linked to Neuropathogenesis and Poly (ADP-ribose) Polymerases (PARPs) As Potential Therapeutic Targets

Overview

Journal J Neurovirol

Publisher Springer

Specialties Microbiology
Neurology

Date 2021 Jan 6

PMID 33405206

Citations 6

Authors

Carla Mavian

Andrea S Ramirez-Mata

James Jarad Dollar

David J Nolan

Melanie Cash

Kevin White

Shannan N Rich

Brittany Rife Magalis

Simone Marini

Mattia C F Prosperi

David Moraga Amador

Alberto Riva

Kenneth C Williams

Marco Salemi

Affiliations

Soon will be listed here.

Abstract

Despite improvements in antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorders (HAND) remain prevalent in subjects undergoing therapy. HAND significantly affects individuals' quality of life, as well as adherence to therapy, and, despite the increasing understanding of neuropathogenesis, no definitive diagnostic or prognostic marker has been identified. We investigated transcriptomic profiles in frontal cortex tissues of Simian immunodeficiency virus (SIV)-infected Rhesus macaques sacrificed at different stages of infection. Gene expression was compared among SIV-infected animals (n = 11), with or without CD8+ lymphocyte depletion, based on detectable (n = 6) or non-detectable (n = 5) presence of the virus in frontal cortex tissues. Significant enrichment in activation of monocyte and macrophage cellular pathways was found in animals with detectable brain infection, independently from CD8+ lymphocyte depletion. In addition, transcripts of four poly (ADP-ribose) polymerases (PARPs) were up-regulated in the frontal cortex, which was confirmed by real-time polymerase chain reaction. Our results shed light on involvement of PARPs in SIV infection of the brain and their role in SIV-associated neurodegenerative processes. Inhibition of PARPs may provide an effective novel therapeutic target for HIV-related neuropathology.

Citing Articles

SIV infection induces alterations in gene expression and loss of interneurons in Rhesus Macaque frontal cortex during early systemic infection.

Crist R, Chehimi S, Divakaran S, Montague M, Tremblay S, Snyder-Mackler N Transl Psychiatry. 2025; 15(1):38.

PMID: 39890796 PMC: 11785960. DOI: 10.1038/s41398-025-03261-2.

Non-Human Primate Models of HIV Brain Infection and Cognitive Disorders.

Byrnes S, Angelovich T, Busman-Sahay K, Cochrane C, Roche M, Estes J Viruses. 2022; 14(9).

PMID: 36146803 PMC: 9500831. DOI: 10.3390/v14091997.

Soluble CD14-associated DNA methylation sites predict mortality among men with HIV infection.

Titanji B, Wang Z, Chen J, Hui Q, So-Armah K, Freiberg M AIDS. 2022; 36(11):1563-1571.

PMID: 35979830 PMC: 9394925. DOI: 10.1097/QAD.0000000000003279.

The Conserved Macrodomain Is a Potential Therapeutic Target for Coronaviruses and Alphaviruses.

Leung A, Griffin D, Bosch J, Fehr A Pathogens. 2022; 11(1).

PMID: 35056042 PMC: 8780475. DOI: 10.3390/pathogens11010094.

Transcriptomic and Genetic Profiling of HIV-Associated Neurocognitive Disorders.

Ojeda-Juarez D, Kaul M Front Mol Biosci. 2021; 8:721954.

PMID: 34778371 PMC: 8586712. DOI: 10.3389/fmolb.2021.721954.

References

Ame J, Spenlehauer C, de Murcia G . The PARP superfamily. Bioessays. 2004; 26(8):882-93. DOI: 10.1002/bies.20085. View

Ariumi Y, Turelli P, Masutani M, Trono D . DNA damage sensors ATM, ATR, DNA-PKcs, and PARP-1 are dispensable for human immunodeficiency virus type 1 integration. J Virol. 2005; 79(5):2973-8. PMC: 548471. DOI: 10.1128/JVI.79.5.2973-2978.2005. View

Atasheva S, Frolova E, Frolov I . Interferon-stimulated poly(ADP-Ribose) polymerases are potent inhibitors of cellular translation and virus replication. J Virol. 2013; 88(4):2116-30. PMC: 3911523. DOI: 10.1128/JVI.03443-13. View

Baekelandt V, Claeys A, Cherepanov P, De Clercq E, De Strooper B, Nuttin B . DNA-Dependent protein kinase is not required for efficient lentivirus integration. J Virol. 2000; 74(23):11278-85. PMC: 113232. DOI: 10.1128/jvi.74.23.11278-11285.2000. View

Bai P . Biology of Poly(ADP-Ribose) Polymerases: The Factotums of Cell Maintenance. Mol Cell. 2015; 58(6):947-58. DOI: 10.1016/j.molcel.2015.01.034. View

Bolger A, Lohse M, Usadel B . Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014; 30(15):2114-20. PMC: 4103590. DOI: 10.1093/bioinformatics/btu170. View

Bruder C, Hagleitner M, Darlington G, Mohsenipour I, Wurzner R, Hollmuller I . HIV-1 induces complement factor C3 synthesis in astrocytes and neurons by modulation of promoter activity. Mol Immunol. 2004; 40(13):949-61. DOI: 10.1016/j.molimm.2003.10.016. View

Budka H . Neuropathology of human immunodeficiency virus infection. Brain Pathol. 1991; 1(3):163-75. DOI: 10.1111/j.1750-3639.1991.tb00656.x. View

Bueno M, Reyes D, Valdes L, Saheba A, Urias E, Mendoza C . Poly(ADP-ribose) polymerase 1 promotes transcriptional repression of integrated retroviruses. J Virol. 2012; 87(5):2496-507. PMC: 3571415. DOI: 10.1128/JVI.01668-12. View

10.

Calandra T, Roger T . Macrophage migration inhibitory factor: a regulator of innate immunity. Nat Rev Immunol. 2003; 3(10):791-800. PMC: 7097468. DOI: 10.1038/nri1200. View

11.

Campbell J, Hearps A, Martin G, Williams K, Crowe S . The importance of monocytes and macrophages in HIV pathogenesis, treatment, and cure. AIDS. 2014; 28(15):2175-87. PMC: 6331181. DOI: 10.1097/QAD.0000000000000408. View

12.

Caprara G, Prosperini E, Piccolo V, Sigismondo G, Melacarne A, Cuomo A . PARP14 Controls the Nuclear Accumulation of a Subset of Type I IFN-Inducible Proteins. J Immunol. 2018; 200(7):2439-2454. DOI: 10.4049/jimmunol.1701117. View

13.

Cartwright E, Spicer L, Smith S, Lee D, Fast R, Paganini S . CD8(+) Lymphocytes Are Required for Maintaining Viral Suppression in SIV-Infected Macaques Treated with Short-Term Antiretroviral Therapy. Immunity. 2016; 45(3):656-668. PMC: 5087330. DOI: 10.1016/j.immuni.2016.08.018. View

14.

Cho S, Raybuck A, Wei M, Erickson J, Nam K, Cox R . B cell-intrinsic and -extrinsic regulation of antibody responses by PARP14, an intracellular (ADP-ribosyl)transferase. J Immunol. 2013; 191(6):3169-78. PMC: 3770464. DOI: 10.4049/jimmunol.1301106. View

15.

Clarke P, Leser J, Quick E, Dionne K, Beckham J, Tyler K . Death receptor-mediated apoptotic signaling is activated in the brain following infection with West Nile virus in the absence of a peripheral immune response. J Virol. 2013; 88(2):1080-9. PMC: 3911655. DOI: 10.1128/JVI.02944-13. View

16.

Cline A, Bess J, Piatak Jr M, Lifson J . Highly sensitive SIV plasma viral load assay: practical considerations, realistic performance expectations, and application to reverse engineering of vaccines for AIDS. J Med Primatol. 2005; 34(5-6):303-12. DOI: 10.1111/j.1600-0684.2005.00128.x. View

17.

Colonna M, Facchetti F . TREM-1 (triggering receptor expressed on myeloid cells): a new player in acute inflammatory responses. J Infect Dis. 2003; 187 Suppl 2:S397-401. DOI: 10.1086/374754. View

18.

Conesa A, Madrigal P, Tarazona S, Gomez-Cabrero D, Cervera A, McPherson A . A survey of best practices for RNA-seq data analysis. Genome Biol. 2016; 17:13. PMC: 4728800. DOI: 10.1186/s13059-016-0881-8. View

19.

Das B, Thapa P, Karki R, Das S, Mahapatra S, Liu T . Retinoic acid signaling pathways in development and diseases. Bioorg Med Chem. 2014; 22(2):673-83. PMC: 4447240. DOI: 10.1016/j.bmc.2013.11.025. View

20.

Demuth M, Czub S, Sauer U, Koutsilieri E, Haaft P, Heeney J . Relationship between viral load in blood, cerebrospinal fluid, brain tissue and isolated microglia with neurological disease in macaques infected with different strains of SIV. J Neurovirol. 2000; 6(3):187-201. DOI: 10.3109/13550280009015822. View