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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA031017-03
Application #
8287150
Study Section
Special Emphasis Panel (ZDA1-EXL-T (13))
Program Officer
Pollock, Jonathan D
Project Start
2010-09-17
Project End
2015-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2012
Total Cost
$887,560
Indirect Cost
$237,856
Name
University of Florida
Department
Pathology
Type
Schools of Medicine
DUNS #
969663814
City
Gainesville
State
FL
Country
United States
Zip Code
32611
Zhang, Xinrui; Muller, Keith E; Goodenow, Maureen M et al. (2018) Internal pilot design for balanced repeated measures. Stat Med 37:375-389
Mullins, Tanya L Kowalczyk; Li, Su X; Bethel, James et al. (2018) Sexually transmitted infections and immune activation among HIV-infected but virally suppressed youth on antiretroviral therapy. J Clin Virol 102:7-11
Williams, Julie C; Zhang, Xinrui; Karki, Manju et al. (2018) Soluble CD14, CD163, and CD27 biomarkers distinguish ART-suppressed youth living with HIV from healthy controls. J Leukoc Biol 103:671-680
Appelberg, K Sofia; Wallet, Mark A; Taylor, Jared P et al. (2017) HIV-1 Infection Primes Macrophages Through STAT Signaling to Promote Enhanced Inflammation and Viral Replication. AIDS Res Hum Retroviruses 33:690-702
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
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
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 134:376-382
Williams, Julie C; Appelberg, Sofia; Goldberger, Bruce A et al. (2014) ?(9)-Tetrahydrocannabinol treatment during human monocyte differentiation reduces macrophage susceptibility to HIV-1 infection. J Neuroimmune Pharmacol 9:369-79
Chi, Yueh-Yun; Gribbin, Matthew J; Johnson, Jacqueline L et al. (2014) Power calculation for overall hypothesis testing with high-dimensional commensurate outcomes. Stat Med 33:812-27

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