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

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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.

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Acknowledgments

We thank the Dana-Farber/Harvard Cancer Center Molecular Biology Core for the NanoString nCounter platform services. This work was supported by National Institutes of Health grants to D.G. (R01 MH097659 and R01 DA40391). Financial support for the NNTC was provided through the following cooperative agreements from the National Institutes of Health: U24MH100930, U24MH100931, U24MH100928, U24MH100929, and U24MH100925. This study was supported in part with federal funds from the National Cancer Institute, National Institutes of Health, under contract no. HSN261200800001E. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of any trade names, commercial products, or organizations imply endorsement by the US government.

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  1. Isaac H. Solomon and Sukrutha Chettimada contributed equally to this work.

Authors and Affiliations

  1. Department of Pathology, Brigham and Women’s Hospital, Boston, MA, USA

    Isaac H. Solomon

  2. Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, CLS 1010, 450 Brookline Ave, Boston, MA, 02215, USA

    Isaac H. Solomon, Sukrutha Chettimada, Vikas Misra, David R. Lorenz & Dana Gabuzda

  3. AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA

    Robert J. Gorelick

  4. Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA

    Benjamin B. Gelman

  5. Department of Neurology, Icahn School of Medicine of Mount Sinai, New York, NY, USA

    Susan Morgello

  6. Department of Neurology, Harvard Medical School, Boston, MA, USA

    Dana Gabuzda

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Solomon, I.H., Chettimada, S., Misra, V. et al. White Matter Abnormalities Linked to Interferon, Stress Response, and Energy Metabolism Gene Expression Changes in Older HIV-Positive Patients on Antiretroviral Therapy. Mol Neurobiol 57, 1115–1130 (2020). https://doi.org/10.1007/s12035-019-01795-3

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