HIV Proteomic Center for Host-Viral Response Characterization
EMSL Project ID
33700
Abstract
A Pilot Proteomics Center has been established at PNNL that will apply powerful new proteomics technologies to broadly investigate changes in protein abundances resulting from the pathologic events associated with concomitant lentiviral infection and substance abuse as well as from pharmacologic interventions designed to treat these pathologies. These complex interactions will be studied in the context of longitudinal and cross-sectional studies of human immunodeficiency virus, type 1 (HIV)-infected and -uninfected subjects, treated or not with exogenous opioids as well as in well-defined nonhuman primate models of lentiviral pathogenesis induced by the simian immunodeficiency virus (SIV). In so doing, we aim to identify the quantitative proteomic biosignatures and profiles that define and predict the impact of opioids on lentiviral disease progression, with particular emphasis on the neurological sequelae that accompany the acquired immune deficiency syndrome (AIDS). These efforts will benefit from execution in a manner that benefits from the extensive experience of the investigators, existing sample sets, comparison of human and non-human primate responses, and the extensive use of complementary data and techniques (e.g. immunologic and microarray assays). Given previous studies indicating (a) that acute and long-term administration of exogenous opioids can have inhibitory effects on antibody and cellular immune responses, natural killer (NK) cell activity, and cytokine expression(1); (b) that antiretroviral drugs (and, in particular protease inhibitors) can exert significant immunomodulatory effects(2); and (c) that chronic immune activation is a major driving force of lentiviral disease progression(3-5), our overarching hypotheses that we plan to test using proteomics are as follows:1. Immunosuppression will be the dominant effect of exogenous opioid administration in the lentiviral-infected host.
2. Opioid-induced immunosuppression in the context of chronic lentiviral infection will foster viral replication and spread and, hence, cause disease progression.
3. The provision of antiretroviral drugs (and, in particular, protease inhibitors) to HIV-infected subjects on opioids may impact upon opioid-induced immunosuppression.
4. The combined application of proteomic, immunologic, and functional genomic assays will lead to the discovery of novel proteins, proteomic biosignatures or profiles (i.e. sets of proteins) that will be useful in the definition and prediction of disease progression, in understanding pathogenesis, and in describing drug-drug interactions in the context of opioid abuse and addiction in the lentiviral-infected host.
Project Details
Start Date
2009-03-18
End Date
2012-03-18
Status
Closed
Released Data Link
Team
Principal Investigator
Team Members
Related Publications
Brown JN, GM Ortiz, TE Angel, JM Jacobs, MA Gritsenko, EY Chan, DE Purdy, RD Murnane, K Larsen, RE Palermo, AK Shukla, TRW Clauss, MG Katze, JM McCune, and RD Smith. 2012. "Morphine Produces Immunosuppressive Effects in Non-human Primates at the Proteomic and Cellular Levels." Molecular & Cellular Proteomics. MCP. doi:10.1074/mcp.M111.016121
Dominy S, JN Brown, MI Ryder, MA Gritsenko, JM Jacobs, and RD Smith. 2014. "Proteomic Analysis of Saliva in HIV-positive Heroin Addicts Reveals Proteins Correlated with Cognition." PLoS One 9(4):e89366. doi:10.1371/journal.pne.089366
Price RW, J Peterson, D Fuchs, TE Angel, H Zetterberg, L Hagberg, SS Spudich, RD Smith, JM Jacobs, JN Brown, and M Gisslen. 2013. "Approach to Cerebrospinal Fluid (CSF) Biomarker Discovery and Evaluation in HIV Infection." Journal of Neuroimmune Pharmacology 8(5):1147-1158. doi:10.1007/s11481-013-9491-3