Substance use & immunity in HIV-infected adolescents by systems biology

Transcription

1 Substance use & immunity in HIV-infected adolescents by systems biology Maureen M. Goodenow, Ph.D. Professor Stephany W. Holloway Endowed University Chair for AIDS Research Division of Experimental Pathology Department of Pathology, Immunology, & Laboratory Medicine Florida Center for AIDS Research College of Medicine University of Florida

2 Substance use & immunity in HIV-infected adolescents by systems biology 2 Multi-center, interdisciplinary collaborative study University of Florida University of South Florida University of California, San Diego Burnham Institute NICHD Adolescent Trials Network [ATN/IMPAACT] Tampa Jacksonville Miami

3 Substance use & immunity in HIV-infected adolescents by systems biology 3 Multi-center, interdisciplinary collaborative study Molecular virology Molecular immunology Substance use marijuana Drug experts and toxicologists Bioinformatics Biostatistics Data base and data management Behavioral psychology and neurocognition

4 Substance use & immunity in HIV-infected adolescents by systems biology 4 Multi-center, interdisciplinary collaborative study: Develop novel bioprofiles that relate marijuana use to HIVrelated inflammation and neurocognitive impairment in vivo in HIV-1 infected adolescents ex vivo in primary human macrophages Apply systems biology to discover global profiles of complex systems that are unbiased by preconceived paradigms Translate discoveries to improved diagnosis, prognosis and treatment of HIV-1 associated neurocognitive impairment in adolescents

5 Study objectives 5 1. Define ex vivo effects of THC on transcriptome and proteome of primary human macrophages in the presence or absence of HIV-1 infection. 2. Define the relationship between marijuana use and modulation of global immune transcriptome and proteome profiles in peripheral blood mononuclear cells within a cohort of HIV-infected adolescents with or without neurocognitive impairment.

6 Approach 6 Transcriptome analysis by Affymetrix Next-gen deep sequencing with Illumina and 454 platforms Luminex multiplex analysis Multiparameter flow cytometry Toxicology assays ACASI self report substance use Neurocognitive assessments

7 Cohort HIV infected 7 ATN 071 [Sharon Nichols, UCSD] Longitudinal 3 year study of neurocognitive impairment in HIV-infected adolescents 150 adolescents [17 to 25 yrs of age] across 15 U.S. sites 3 groups Standard of care/no ART [CD4 >350] Early ART [CD4 > 350] Standard of care/on ART [CD4 <350] 6 neurocognitive assessments over 3 years

8 Neurocognitive Assessments 8 Global functioning Memory Psychomotor speed Executive functioning Emotional/behavioral Adherence ASSIST

9 Cohorts: HIV-infected and uninfected 9 HIV-infected ATN 071/101 Concept sheer for ATN 101 for blood draws Approval by ATN leadership MOU for data sharing, analysis, etc New version of protocol and informed consent HIV-uninfected Collaboration with John Sleasman N = 50 Balanced for age, gender, ethnicity, socioeconomics ASSIST

10 Benefits of the collaborative partnership 10 ATN study gains an R01-funded biology component not included in the original protocol AND verification of selfreport substance use. Systems biology project is based on a well-structured clinical study in progress with a cross-sectional and longitudinal component. Uninfected comparison group necessary for the project, but not included in the ATN study.

11 Substance use: self-report and toxicology 11 Concordant Marijuana and tobacco: ~ one-third of subjects Tobacco or marijuana: <10% Opiates, cocaine, amphetamines: <5% None: ~50% Similar distribution between HIV-infected and uninfected groups for types of substances and frequency.