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

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 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, Terms of use and reuse: academic research for non-commercial purposes, see here for full terms. http://www.springer.com/gb/openaccess/authors-rights/aam-terms-v1

Neuroinflammation and EIF2 Signaling Persist despite Antiretroviral Treatment in an hiPSC Tri-culture Model of HIV Infection

“…ISR and EIF2 activation has been implicated in establishing initial viral replication (Jiang et al, 2017). A recent study also found stress response genes, including the ISR-associated gene ATF4, upregulated in the brains of older HIV-positive patients (Solomon et al, 2019). The UPR and consequently EIF2 activation has been implicated in multiple neurodegenerative disorders (Scheper and Hoozemans, 2015), these findings bolster the possibility that UPR and ISR activation play important roles in HAND development or at least the initial response to HIV in the brain.…”

Mechanisms of neuronal dysfunction in HIV-associated neurocognitive disorders

“…Furthermore, white matter alterations in the expression of chemokines, cytokines, and β-defensins correlate with cognitive impairment in patients without HIV encephalitis [ 40 ]. A recent gene expression study also supports inflammatory dysregulation in older HAND patients on ART, as brain tissue from these patients showed upregulation of genes related to interferon signaling, stress, and immune responses, as well as decreased expression of genes involved in cellular metabolism and myelin production [ 41 ]. Overall, these studies shed light on some of the underlying changes contributing to HAND in patients with more controlled infection and further support the hypothesis that subtle neuronal disruption is an important component of modern HAND.…”

HIV‐induced neuroinflammation inhibits oligodendrocyte maturation via glutamate‐dependent activation of the PERK arm of the integrated stress response

“…Magnetic resonance and diffusion tensor imaging studies show numerous alterations including corpus callosum thinning and reduced blood flow in white matter (Hoare et al, 2010; Tate et al, 2011). Transcriptome analyses demonstrate downregulation of transcripts critical for oligodendrocyte (OL) maturation and myelination despite cART (Borjabad et al, 2011; Solomon et al, 2020). While the underlying mechanisms remain unclear, HIV and/or cART may play a role in these persistent white matter pathologies.…”