A significant problem in the clinical management of HIV-1 infected patients is a lack of blood based biomarkers to monitor the effects of substance use on immune function and HIV pathogenesis in the central nervous system. Although incidence of HIV-1 associated dementia has declined with the advent of effective combination antiretroviral therapies, a greater prevalence of cognitive and motor problems now develop. Neurocognitive impairment is particularly relevant to infected adolescents, who face life-long disease. Impact of substance use, in particular marijuana, on neurocognitive functioning among HIV-infected adolescents is unknown. The cannabinoid ?9-tetrahydrocannabinol [TCH], the main psychoactive component in marijuana, targets endogenous cannabinoid receptors expressed by cells of brain and central nervous system [CB1], as well as by immune cells [CB2]. Pleiotropic consequences of HIV-1 infection and marijuana use on immune dysregulation, and the inflammatory response in the central nervous system and in the peripheral immune system, stand at the interface between HIV-1 pathogenesis and substance abuse. Combination of systems biology and studies of human peripheral blood provide an unprecedented opportunity to develop global profiles of complex systems that are unbiased by preconceived paradigms and define multiple parameters of human health and disease. Proposed studies are designed to address the four key points of RFA-10-014 Systems Biology, HIV/AIDS, and Substance Abuse and involve systems biology approaches by an interactive multi- disciplinary team of investigators to: 1. Define the global effects of TCH on transcriptome and proteome of primary human macrophages ex vivo in the presence or absence of HIV-1 infection. Macrophages ex vivo provide models for CD4-expressing macrophage targets for HIV-1 infection, as well as key regulators of inflammation, innate and adaptive immunity. The approach is fundamental to understanding the interface between HIV-1 infection and substance use in humans and links with in vivo studies of HIV-1 infection in humans proposed in Objective 2. 2. Define the relationship between marijuana use and modulation of global immune profiles in peripheral blood mononuclear cells within a cohort of HIV-infected adolescents with or without neurocognitive impairment. Adolescents enrolled through the Adolescent Trials Network in a three-year ongoing study of the effects of antiretroviral therapy on neurocognitive function will be assessed for substance use, based on self-reporting and blood toxicology. A systems biology study of peripheral blood cell transcriptome at end of study will be combined with plasma and cell-surface proteomics over time. The overall goal is to use systems biology to discover novel bioprofiles that relate use of marijuana and immunity to neurocognitive impairment in HIV-1 infected adolescents.
The proposed studies use systems biology strategy to develop novel bioprofiles that relate marijuana use to immune dysfunction in primary human macrophages ex vivo and systemically in vivo with neurocognitive impairment in HIV-1 infected adolescents. Combination of systems biology and studies of human peripheral blood provide an unprecedented opportunity to discover global profiles of complex systems that are unbiased by preconceived paradigms. Outcomes will translate to improved diagnosis, prognosis and treatment of HIV-1 associated neurocognitive impairment in adolescents.
|Appelberg, K Sofia; Goodenow, Maureen M (2015) Editorial: Passive aggressive avoidance of SAMHD1 restriction by HIV-1. J Leukoc Biol 98:1-3|
|Rudy, Bret J; Kapogiannis, Bill G; Worrell, Carol et al. (2015) Immune Reconstitution but Persistent Activation After 48 Weeks of Antiretroviral Therapy in Youth With Pre-Therapy CD4 >350 in ATN 061. J Acquir Immune Defic Syndr 69:52-60|
|Nichols, Sharon L; Lowe, Amanda; Zhang, Xinrui et al. (2014) Concordance between self-reported substance use and toxicology among HIV-infected and uninfected at risk youth. Drug Alcohol Depend 134:376-82|
|Andridge, Rebecca R; Shoben, Abigail B; Muller, Keith E et al. (2014) Analytic methods for individually randomized group treatment trials and group-randomized trials when subjects belong to multiple groups. Stat Med 33:2178-90|
|Simpson, Sean L; Edwards, Lloyd J; Styner, Martin A et al. (2014) Separability tests for high-dimensional, low sample size multivariate repeated measures data. J Appl Stat 41:2450-2461|
|Williams, Julie C; Appelberg, Sofia; Goldberger, Bruce A et al. (2014) Î”(9)-Tetrahydrocannabinol treatment during human monocyte differentiation reduces macrophage susceptibility to HIV-1 infection. J Neuroimmune Pharmacol 9:369-79|
|Nichols, Sharon L; Bethel, James; Garvie, Patricia A et al. (2013) Neurocognitive functioning in antiretroviral therapy-naÃ¯ve youth with behaviorally acquired human immunodeficiency virus. J Adolesc Health 53:763-71|
|Syed, Salma S; Balluz, Rula S; Kabagambe, Edmond K et al. (2013) Assessment of biomarkers of cardiovascular risk among HIV type 1-infected adolescents: role of soluble vascular cell adhesion molecule as an early indicator of endothelial inflammation. AIDS Res Hum Retroviruses 29:493-500|
|Lamers, Susanna L; Nolan, David J; Strickland, Samantha L et al. (2013) Longitudinal analysis of intra-host simian immunodeficiency virus recombination in varied tissues of the rhesus macaque model for neuroAIDS. J Gen Virol 94:2469-79|
|Gribbin, Matthew J; Chi, Yueh-Yun; Stewart, Paul W et al. (2013) Confidence regions for repeated measures ANOVA power curves based on estimated covariance. BMC Med Res Methodol 13:57|
Showing the most recent 10 out of 16 publications