HIV-1 infection and drug of abuse have devastating effects on function of the entire organism. The macrophage is the prime member of the mononuclear phagocyte class of cells and a key part of innate immunity system. Because the macrophage is also a target of HIV, a reservoir of productive viral infection and a vehicle to spread infection to organs including the brain, its impact on the course of disease is central. The complexity of HIV infection is further complicated and intensified by use of drugs of abuse. Methamphetamine (METH) was chosen since it is a drug with increasing popularity among the drug-abusing population and used by those with, or at risk for, HIV. Treatment of these individuals is a very complex process because it has to target two entities that are quite different in nature. In addition, life-long cART treatment of HIV infection has adverse toxic effects. As two main avenues of Systems Biology, global profiling techniques and computational processing of large data sets, mature, it becomes feasible to start analyzing data from multivariate experiments (HIV/METH/cART). Prior reductionist approaches precluded performing experiments at this level of complexity. Moreover, despite substantive research efforts, the broad picture of molecular mechanisms underlying functions of macrophages in the complex environment of HIV-1 infection METH use and/or cART is far from being understood. Summarizing, we hypothesize that the systems biology approach will provide unique information which will lead to identification of new paradigm how the human macrophage is regulated in the complex environment of HIV infection, cART and METH. We expect that our experimemtal plan, examining transcription factors and other nuclear proteins through the use of omic techniques, computational biology and bioinformatic analyses, will provide unique information which will lead to identification of new paradigms in how the human macrophage is regulated in the complex environment of HIV infection, cART and METH.

Public Health Relevance

The transformation of HIV to a chronic disease represents a great success of therapy but has opened up a number of new clinical problems due to the long-term infection, effects of the anti-retroviral therapies, and coexisting factors such as drug abuse which affects many systems including the brain and cardiovascular systems. Macrophages, key component of immune system, play many roles in persistence of infection as well as disease causation. We propose to use a global approach to investigate the effects of HIV infection, drug abuse and anti-retroviral therapy on macrophage which should lead us to better understand molecular mechanisms of disease and propose new targets for therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA030962-04
Application #
8494031
Study Section
Special Emphasis Panel (ZDA1-EXL-T (13))
Program Officer
Satterlee, John S
Project Start
2010-09-17
Project End
2015-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
4
Fiscal Year
2013
Total Cost
$586,474
Indirect Cost
$152,075
Name
University of Nebraska Medical Center
Department
Pharmacology
Type
Schools of Medicine
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
Burns, Ariel; Ciborowski, Pawel (2016) Acute exposure to methamphetamine alters TLR9-mediated cytokine expression in human macrophage. Immunobiology 221:199-207
Gross, Andrew M; Jaeger, Philipp A; Kreisberg, Jason F et al. (2016) Methylome-wide Analysis of Chronic HIV Infection Reveals Five-Year Increase in Biological Age and Epigenetic Targeting of HLA. Mol Cell 62:157-68
Donnelly, Maire Rose; Ciborowski, Pawel (2016) Proteomics, biomarkers, and HIV-1: A current perspective. Proteomics Clin Appl 10:110-25
Villeneuve, Lance M; Purnell, Phillip R; Stauch, Kelly L et al. (2016) Neonatal mitochondrial abnormalities due to PINK1 deficiency: Proteomics reveals early changes relevant to Parkinson׳s disease. Data Brief 6:428-32
Thapa, Ishwor; Fox, Howard S; Bastola, Dhundy (2015) Coexpression Network Analysis of miRNA-142 Overexpression in Neuronal Cells. Biomed Res Int 2015:921517
Araínga, Mariluz; Guo, Dongwei; Wiederin, Jayme et al. (2015) Opposing regulation of endolysosomal pathways by long-acting nanoformulated antiretroviral therapy and HIV-1 in human macrophages. Retrovirology 12:5
DeBoer, Jason; Jagadish, Teena; Haverland, Nicole A et al. (2014) Alterations in the nuclear proteome of HIV-1 infected T-cells. Virology 468-470:409-20
Wooden, Jessica; Ciborowski, Pawel (2014) Chromatin immunoprecipitation for human monocyte derived macrophages. Methods 70:89-96
Kochi, Naomi; Helikar, Tomáš; Allen, Laura et al. (2014) Sensitivity analysis of biological Boolean networks using information fusion based on nonadditive set functions. BMC Syst Biol 8:92
Haverland, Nicole A; Fox, Howard S; Ciborowski, Pawel (2014) Quantitative proteomics by SWATH-MS reveals altered expression of nucleic acid binding and regulatory proteins in HIV-1-infected macrophages. J Proteome Res 13:2109-19

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