Abstract
Monocytes/macrophages contribute to the neuropathogenesis of HIV-related cognitive impairment (CI); however, considerable gaps in our understanding of the precise mechanisms driving this relationship remain. Furthermore, whether a distinct biological profile associated with HIV-related CI resides in immune cell populations remains unknown. Here, we profiled DNA methylomes and transcriptomes of monocytes derived from HIV-infected individuals with and without CI using genome-wide DNA methylation and gene expression profiling. We identified 1,032 CI-associated differentially methylated loci in monocytes. These loci related to gene networks linked to the central nervous system (CNS) and interactions with HIV. Most (70.6%) of these loci exhibited higher DNA methylation states in the CI group and were preferentially distributed over gene bodies and intergenic regions of the genome. CI-associated DNA methylation states at 12 CpG sites associated with neuropsychological testing performance scores. CI-associated DNA methylation also associated with gene expression differences including CNS genes CSRNP1 (P = 0.017), DISC1 (P = 0.012), and NR4A2 (P = 0.005); and a gene known to relate to HIV viremia, THBS1 (P = 0.003). This discovery cohort data unveils cell type-specific DNA methylation patterns related to HIV-associated CI and provide an immunoepigenetic DNA methylation “signature” potentially useful for corroborating clinical assessments, informing pathogenic mechanisms, and revealing new therapeutic targets against CI.
Highlights
Many studies have focused on peripheral immune cells of the monocyte/macrophage lineage since these cells can be infected by HIV, functionally altered, and enter the central nervous system (CNS) either across a permeable blood brain barrier or potentially through the recently described meningeal lymphatic conduit[3,4,5]
We examined cryopreserved peripheral blood mononuclear cells (PBMC) specimens from 21 HIV-infected individuals enrolled in the Hawaii Aging with HIV Cohort study classified as having cognitive impairment (CI) based on meeting criteria for HIV-associated Dementia (HAD, n = 6) or Mild Cognitive Motor Disorder (MCMD, n = 5) using the American Academy of Neurology (AAN) 1991 as previously described (Supplemental Table S1)[24]
The predominant differences were enriched in CpG sites located within gene bodies (30.92% expected, 34.4% observed, P < 0.01) and intergenic regions (24.7% expected, 38.8% observed, P < 0.01), but less than expected were located within gene promoters (41.2% expected, 23.9% observed, P < 0.01) (Fig. 1c). Since regulatory elements such as gene enhancers preferentially occur in gene body and intergenic regions, we examined whether the methylation differences we observed were enriched at annotated enhancer regions
Summary
Many studies have focused on peripheral immune cells of the monocyte/macrophage lineage since these cells can be infected by HIV, functionally altered, and enter the central nervous system (CNS) either across a permeable blood brain barrier or potentially through the recently described meningeal lymphatic conduit[3,4,5]. Human studies suggest changes to cells of the monocyte/macrophage lineage influence the development of CI in the setting of HIV, as evidenced by the established associations between impaired cognitive performance and surface markers of CD14(+)CD16(+) monocytes[17], monocyte activation markers in plasma[18], and amount of HIV DNA in CD14(+) monocytes[19]. These studies have been inconsistent in identifying biomarkers linked to HIV-related CI, prompting the notion that epigenetic mechanisms may serve as a more reliable biomarker[20]. We report novel evidence for epigenetic changes related to HIV-related CI in peripheral monocytes and CD8+T cells
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