Summary: Researchers have discovered a unique epigenetic footprint in specific immune cells that can identify people with HIV who have impaired cognitive function.
Source: University of Hawaii.
University of Hawaiʻi researchers have identified a unique epigenetic footprint in specific types of immune cells from blood that can identify individuals with HIV that have a range of impairments in cognitive function.
Reliable biomarkers such as that identified by the researchers offer insight into how HIV associated cognitive impairment develops but also promises improved diagnostic testing and improved treatment decisions.
The findings are published in the September 2016 issue of Scientific Reports by University of Hawaiʻi at Mānoa scientists Lishomwa Ndhlovu and Alika Maunakea at the John A. Burns School of Medicine (JABSOM) and collaborators at the University of Hawaiʻi at Mānoa and the University of California San Francisco.
“These results offer the first significant window into the mechanisms driving HIV-related brain damage and how to track the disease,” said Ndhlovu, an associate professor in the Department of Tropical Medicine, JABSOM.
Combination antiretroviral therapies have improved HIV survival. If started early and taken daily for life, antiretroviral therapies can result in fewer non-AIDS related complications. However, HIV still impacts the brain. Around 40 percent of individuals even on antiretroviral therapy still suffer HIV-related neurocognitive disorders that can affect living activities.
It has long been suspected that changes to cells of the monocyte/macrophage lineage, a type of immune cell, influence the development of cognitive impairment in HIV. Since HIV infection itself alters epigenetic processes in the immune system, the research team wondered whether a distinct DNA methylation profile, a major epigenetic modification where methyl groups are added to DNA, occurs in those with HIV associated-cognitive impairment and whether it exists in distinct immune cell populations from the blood.
By evaluating DNA methylation, the researchers discovered differences in gene networks and gene expression linked to the central nervous system and interactions with HIV that appeared uniquely in monocytes of HIV infected study participants with cognitive impairment.
“Strikingly, further analysis showed a strong association between DNA methylation levels of these markers in monocytes and neuropsychological test function, measured using a composite score of multiple cognitive domains” said Maunakea, an assistant professor in JABSOM’s Department of Native Hawaiian Health and co-senior author of the study.
According to Michael Corley, a junior researcher in JABSOM’s Department of Native Hawaiian Health and lead author of the study, the field of epigenetics has ushered in a new era of discovery in immunology and neuroscience. “Combined with the advancement of DNA sequencing technologies to capture epigenetic profiles in unique clinical samples, researchers can make discoveries that were previously not possible.”
Currently there is no treatment for individuals with HIV associated cognitive impairment. “The advancement in epigenetic therapeutics also affords promising new interventions that should be considered for the management of HIV associated cognitive impairment, provided they are selective to the appropriate immune cell target,” added Ndhlovu.
“There is still much we need to understand about how HIV affects the brain and several findings from this study are highly relevant to this field of neuroAIDS,” said Ndhlovu.
Source: Tina Shelton – University of Hawaii
Image Source: This NeuroscienceNews.com image is adapted from the University of Hawaii press release.
Original Research: Full open access research for “Comparative DNA Methylation Profiling Reveals an Immunoepigenetic Signature of HIV-related Cognitive Impairment” by Michael J. Corley, Christian Dye, Michelle L. D’Antoni, Mary Margaret Byron, Kaahukane Leite-Ah Yo, Annette Lum-Jones, Beau Nakamoto, Victor Valcour, Ivo SahBandar, Cecilia M. Shikuma, Lishomwa C. Ndhlovu and Alika K. Maunakea in Scientific Reports. Published online September 15 2016 doi:10.1038/srep33310
Comparative DNA Methylation Profiling Reveals an Immunoepigenetic Signature of HIV-related Cognitive Impairment
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.
“Comparative DNA Methylation Profiling Reveals an Immunoepigenetic Signature of HIV-related Cognitive Impairment” by Michael J. Corley, Christian Dye, Michelle L. D’Antoni, Mary Margaret Byron, Kaahukane Leite-Ah Yo, Annette Lum-Jones, Beau Nakamoto, Victor Valcour, Ivo SahBandar, Cecilia M. Shikuma, Lishomwa C. Ndhlovu and Alika K. Maunakea in Scientific Reports. Published online September 15 2016 doi:10.1038/srep33310