A parallel genome-wide mRNA and microRNA profiling of the frontal cortex of HIV patients with and without HIV-associated dementia shows the role of axon guidance and downstream pathways in HIV-mediated neurodegeneration.

TitleA parallel genome-wide mRNA and microRNA profiling of the frontal cortex of HIV patients with and without HIV-associated dementia shows the role of axon guidance and downstream pathways in HIV-mediated neurodegeneration.
Publication TypeJournal Article
Year of Publication2012
AuthorsZhou, L, Pupo, GM, Gupta, P, Liu, B, Tran, SL, Rahme, R, Wang, B, Rua, R, Rizos, H, Carroll, A, Cairns, MJ, Saksena, NK
JournalBMC Genomics
Volume13
Pagination677
Date Published2012
ISSN1471-2164
KeywordsAdult, AIDS Dementia Complex, Axons, Early Diagnosis, Frontal Lobe, Gene Expression Profiling, Genome, Human, Genomics, HIV, HIV Infections, Humans, Male, MicroRNAs, Middle Aged, Oligonucleotide Array Sequence Analysis, RNA, Messenger, Signal Transduction
Abstract

BACKGROUND: HIV-associated dementia (HAD) is the most common dementia type in young adults less than 40 years of age. Although the neurotoxins, oxidative/metabolic stress and impaired activity of neurotrophic factors are believed to be underlying reasons for the development of HAD, the genomic basis, which ultimately defines the virus-host interaction and leads to neurologic manifestation of HIV disease is lacking. Therefore, identifying HIV fingerprints on the host gene machinery and its regulation by microRNA holds a great promise and potential for improving our understanding of HAD pathogenesis, its diagnosis and therapy.RESULTS: A parallel profiling of mRNA and miRNA of the frontal cortex autopsies from HIV positive patients with and without dementia was performed using Illumina Human-6 BeadChip and Affymetrix version 1.0 miRNA array, respectively. The gene ontology and pathway analysis of the two data sets showed high concordance between miRNA and mRNAs, revealing significant interference with the host axon guidance and its downstream signalling pathways in HAD brains. Moreover, the differentially expressed (DE) miRNAs identified in this study, in particular miR-137, 153 and 218, based on which most correlations were built cumulatively targeted neurodegeneration related pathways, implying their future potential in diagnosis, prognosis and possible therapies for HIV-mediated and possibly other neurodegenerative diseases. Furthermore, this relationship between DE miRNAs and DE mRNAs was also reflected in correlation analysis using Bayesian networks by splitting-averaging strategy (SA-BNs), which revealed 195 statistically significant correlated miRNA-mRNA pairs according to Pearson's correlation test (P<0.05).CONCLUSIONS: Our study provides the first evidence on unambiguous support for intrinsic functional relationship between mRNA and miRNA in the context of HIV-mediated neurodegeneration, which shows that neurologic manifestation in HIV patients possibly occurs through the interference with the host axon guidance and its downstream signalling pathways. These data provide an excellent avenue for the development of new generation of diagnostic/prognostic biomarkers and therapeutic intervention strategies for HIV-associated neurodegeneration.

DOI10.1186/1471-2164-13-677
Alternate JournalBMC Genomics
PubMed ID23190615
PubMed Central IDPMC3560210
Grant List5U01MH083500 / MH / NIMH NIH HHS / United States
N01MH32002 / MH / NIMH NIH HHS / United States
R24 NS45491 / NS / NINDS NIH HHS / United States
R24MH59724 / MH / NIMH NIH HHS / United States
R24MH59745 / MH / NIMH NIH HHS / United States
U01 MH083506 / MH / NIMH NIH HHS / United States
U01MH083501 / MH / NIMH NIH HHS / United States
U01MH083506 / MH / NIMH NIH HHS / United States
U01MH083507 / MH / NIMH NIH HHS / United States
U01MH083545 / MH / NIMH NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States