Antiretroviral therapy (ART) has dramatically changed the HIV epidemic, delaying disease, prolonging life, and altering HIV-associated neurocognitive disorders (HAND) from encephalitis/dementia (HAD) to milder but nevertheless debilitating disorders such as minor cognitive/motor disorder (MC/MD) and asymptomatic neurocognitive impairment (ANI). However, despite ART, HAND prevalence has increased with patient longevity, and mild to moderate disorders are diagnosed in 50-60% of ART patients. There are currently no biomarkers used to diagnose or predict HAND. Plasma biomarkers developed for AIDS (viral load and CD4+ T cell count), were essential in developing treatment paradigms. It is critical to develop similarly sensitive, reliable, and accessible biomarkers for HAND. MicroRNAs (miRNAs), which are linked to various diseases including cancers and Alzheimer's disease, are a promising source of novel biomarkers. These small, non- coding RNAs are abundant and stable in plasma, providing a unique opportunity for biomarker discovery. Reflecting disease states, plasma miRNAs may also present novel therapeutic targets. Using our SIV/macaque model of CNS disease and ART, we identified a plasma miRNA signature of acute infection and CNS disease-predictive miRNAs with roles in neurologic disorders and/or senescence. Here, we will identify plasma miRNA biomarkers during different stages of infection (Aim 1);characterize miRNA profiles in cerebrospinal fluid (CSF) and brain during infection;and identify miRNAs that predict the development of CNS disease (untreated macaques) or correlate with persistent levels of inflammatory cytokines in brain of ART treated macaques (Aim 2). We will extend these studies to HIV-infected individuals with HAND using matched plasma and CSF from the NorthEast AIDS Dementia (NEAD) cohort to identify and validate plasma miRNA biomarkers for HAD, MC/MD, and ANI (Aim 3). Finally, plasma miRNA biomarkers will be studied in brain and specific plasma fractions to identify cellular sources of circulating miRNAs and the vehicles (vesicles, lipoprotein particles, protein complexes) of disease-predictive plasma miRNAs (Aim 4). The goal of these studies is to identify plasma miRNA biomarkers that diagnose and predict the development of HAND and that provide insights into HAND pathogenesis. Our hypothesis is that a unique combination of differentially expressed plasma miRNAs will be diagnostic for HIV/SIV infection stage, predictive of CNS disease, and reflective of the impact of both viral and host responses in brain. Some of these miRNAs will originate from brain, while others will stem from peripheral processes that affect or parallel CNS processes. Results of these studies will represent a substantial advance in the understanding of how plasma miRNAs originate and circulate during health and infectious disease. Importantly, our findings will have significance fo HAND diagnostics and therapeutics, facilitating functional characterization of pathways that are dysregulated in brain during the development of HAND: potential targets of small-RNA based therapeutics.
microRNAs, a novel class of non-coding RNA, have emerged as plasma biomarkers for cancer and neurological diseases such as Alzheimer's Disease. Using an animal model of HIV neurocognitive disorders and CNS disease, we have demonstrated that plasma miRNA biomarkers provide a diagnostic for acute infection and the development of CNS disease. We will extend these studies to develop much needed diagnostic and predictive biomarkers for the stage of HIV infection and for HIV-infected individuals who have or will develop neurocognitive disorders such as dementia, minor cognitive motor disorder, or asymptomatic neurological impairment. The incidences of these neurological complications of HIV are all increasing in HIV-infected individuals treated with HAART.
|Hu, Guoku; Yelamanchili, Sowmya; Kashanchi, Fatah et al. (2017) Proceedings of the 2017 ISEV symposium on ""HIV, NeuroHIV, drug abuse, & EVs"". J Neurovirol 23:935-940|
|Williams, Dionna W; Engle, Elizabeth L; Shirk, Erin N et al. (2016) Splenic Damage during SIV Infection: Role of T-Cell Depletion and Macrophage Polarization and Infection. Am J Pathol 186:2068-2087|
|Avalos, Claudia R; Price, Sarah L; Forsyth, Ellen R et al. (2016) Quantitation of Productively Infected Monocytes and Macrophages of Simian Immunodeficiency Virus-Infected Macaques. J Virol 90:5643-5656|
|Beck, Sarah E; Queen, Suzanne E; Witwer, Kenneth W et al. (2015) Paving the path to HIV neurotherapy: Predicting SIV CNS disease. Eur J Pharmacol 759:303-12|
|Witwer, Kenneth W; Hirschi, Kendal D (2014) Transfer and functional consequences of dietary microRNAs in vertebrates: concepts in search of corroboration: negative results challenge the hypothesis that dietary xenomiRs cross the gut and regulate genes in ingesting vertebrates, but important questio Bioessays 36:394-406|
|Yu, Ian W; Espinoza, Diego A; McAlexander, Melissa A et al. (2014) OpenArray profiling reveals no differential modulation of miRNA by positive and negative CD4+ T cell immunoselection. Exp Hematol 42:11-3|
|Witwer, Kenneth W; McAlexander, Melissa A; Queen, Suzanne E et al. (2013) Real-time quantitative PCR and droplet digital PCR for plant miRNAs in mammalian blood provide little evidence for general uptake of dietary miRNAs: limited evidence for general uptake of dietary plant xenomiRs. RNA Biol 10:1080-6|
|Liu, Jonathan; Sisk, Jeanne M; Gama, Lucio et al. (2013) Tristetraprolin expression and microRNA-mediated regulation during simian immunodeficiency virus infection of the central nervous system. Mol Brain 6:40|
|Witwer, Kenneth W (2013) Data submission and quality in microarray-based microRNA profiling. Clin Chem 59:392-400|
|Sisk, Jeanne M; Witwer, Kenneth W; Tarwater, Patrick M et al. (2013) SIV replication is directly downregulated by four antiviral miRNAs. Retrovirology 10:95|
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