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 experimental 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.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDA1-EXL-T (13))
Program Officer
Satterlee, John S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Nebraska Medical Center
Schools of Medicine
United States
Zip Code
Sathyanesan, Monica; Watt, Michael J; Haiar, Jacob M et al. (2018) Carbamoylated erythropoietin modulates cognitive outcomes of social defeat and differentially regulates gene expression in the dorsal and ventral hippocampus. Transl Psychiatry 8:113
DeBoer, Jason; Wojtkiewicz, Melinda S; Haverland, Nicole et al. (2018) Proteomic profiling of HIV-infected T-cells by SWATH mass spectrometry. Virology 516:246-257
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 62:157-168
Burns, Ariel; Ciborowski, Pawel (2016) Acute exposure to methamphetamine alters TLR9-mediated cytokine expression in human macrophage. Immunobiology 221:199-207
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
Helikar, Tomáš; Cutucache, Christine E; Dahlquist, Lauren M et al. (2015) Integrating interactive computational modeling in biology curricula. PLoS Comput Biol 11:e1004131
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
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

Showing the most recent 10 out of 24 publications