White Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy.

TitleWhite Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy.
Publication TypeJournal Article
Year of Publication2020
AuthorsSolomon, IH, Chettimada, S, Misra, V, Lorenz, DR, Gorelick, RJ, Gelman, BB, Morgello, S, Gabuzda, D
JournalMol Neurobiol
Volume57
Issue2
Pagination1115-1130
Date Published2020 Feb
ISSN1559-1182
Abstract

Neurocognitive impairment (NCI) remains a significant cause of morbidity in human immunodeficiency virus (HIV)-positive individuals despite highly active antiretroviral therapy (HAART). White matter abnormalities have emerged as a key component of age-related neurodegeneration, and accumulating evidence suggests they play a role in HIV-associated neurocognitive disorders. Viral persistence in the brain induces chronic inflammation associated with lymphocytic infiltration, microglial proliferation, myelin loss, and cerebrovascular lesions. In this study, gene expression profiling was performed on frontal white matter from 34 older HIV+ individuals on HAART (18 with NCI) and 24 HIV-negative controls. We used the NanoString nCounter platform to evaluate 933 probes targeting inflammation, interferon and stress responses, energy metabolism, and central nervous system-related genes. Viral loads were measured using single-copy assays. Compared to HIV- controls, HIV+ individuals exhibited increased expression of genes related to interferon, MHC-1, and stress responses, myeloid cells, and T cells and decreased expression of genes associated with oligodendrocytes and energy metabolism in white matter. These findings correlated with increased white matter inflammation and myelin pallor, suggesting interferon (IRFs, IFITM1, ISG15, MX1, OAS3) and stress response (ATF4, XBP1, CHOP, CASP1, WARS) gene expression changes are associated with decreased energy metabolism (SREBF1, SREBF2, PARK2, TXNIP) and oligodendrocyte myelin production (MAG, MOG), leading to white matter dysfunction. Machine learning identified a 15-gene signature predictive of HIV status that was validated in an independent cohort. No specific gene expression patterns were associated with NCI. These findings suggest therapies that decrease chronic inflammation while protecting mitochondrial function may help to preserve white matter integrity in older HIV+ individuals.

DOI10.1007/s12035-019-01795-3
Alternate JournalMol Neurobiol
PubMed ID31691183
PubMed Central IDPMC7035207
Grant ListU24 MH100929 / MH / NIMH NIH HHS / United States
U24 MH100925 / MH / NIMH NIH HHS / United States
U24 MH100931 / MH / NIMH NIH HHS / United States
R01 MH097659 / NH / NIH HHS / United States
U24 MH100928 / MH / NIMH NIH HHS / United States
R01 DA40391 / NH / NIH HHS / United States
U24 MH100929 / NH / NIH HHS / United States
HSN261200800001E / CA / NCI NIH HHS / United States
U24 MH100925 / NH / NIH HHS / United States
U24 MH100931 / NH / NIH HHS / United States
R01 DA040391 / DA / NIDA NIH HHS / United States
U24 MH100930 / MH / NIMH NIH HHS / United States
U24 MH100930 / NH / NIH HHS / United States
R01 MH097659 / MH / NIMH NIH HHS / United States
U24 MH100928 / NH / NIH HHS / United States