RNA Landscapes of Brain and Brain-Derived Extracellular Vesicles in Simian Immunodeficiency Virus Infection and Central Nervous System Pathology

Background Brain tissue-derived extracellular vesicles (bdEVs) act locally in the central nervous system (CNS) and may indicate molecular mechanisms in human immunodeficiency virus (HIV) CNS pathology. Using brain homogenate (BH) and bdEVs from a simian immunodeficiency virus (SIV) model of HIV disease, we identified RNA networks in SIV infection and neuroinflammation.Methods Postmortem occipital cortex samples were obtained from uninfected controls and SIV-infected subjects (acute and chronic phases with or without CNS pathology [SIV encephalitis]). bdEVs were separated and characterized per international consensus guidelines. RNAs from bdEVs and BH were sequenced and quantitative polymerase chain reaction (qPCR)-amplified to detect levels of small RNAs (sRNAs, including microRNAs [miRNAs]) and longer RNAs including messenger RNAs (mRNAs) and circular RNAs (circRNAs).Results Dysregulated RNAs in BH and bdEVs were identified in acute and chronic infection with pathology groups, including mRNAs, miRNAs, and circRNAs. Most dysregulated mRNAs in bdEVs reflected dysregulation in source BH. These mRNAs are disproportionately involved in inflammation and immune responses. Based on target prediction, several circRNAs that were differentially abundant in source tissue might be responsible for specific differences in sRNA levels in bdEVs during SIV infection.Conclusions RNA profiling of bdEVs and source tissues reveals potential regulatory networks in SIV infection and SIV-related CNS pathology. RNA profiling of rigorously separated and characterized brain tissue-derived extracellular vesicles as well as source tissues from the simian immunodeficiency virus model of HIV disease reveal potential RNA regulatory networks associated with infection and CNS pathology.