Recent research has suggested that opioid administration alters susceptibility to a variety of infectious agents, including the Human Immunodeficiency Virus (HIV). It is estimated that a third of HIV-infected individuals in this country are intravenous opioid drug abuser. Little is known, however, about the influence of opioid drugs of abuse on HIV infection of the central nervous system (CNS), or associated neurological disorders including dementia. Current evidence indicates that initial transmission of the virus to the CNS involves trafficking of infected blood-derived monocytes during the acute phase of the infection. The traffic of monocytes to the CNS is a normal physiological process, but is augmented during inflammation and/or in association with infection of the brain. Evidence reported from our laboratory, as well as others, suggest that opioid drugs may promote the trafficking process that leads to migration of infected cells to the brain. Our hypothesis in this application is that opioids have a significant ability to alter the development of HIV encephalitis by altering the expression of critical chemokines and chemokine receptors. We believe that the opioid administration promotes the development of pro-inflammatory monocytes which possess an elevated capacity to both produce and respond to pro-inflammatory chemokines, and by virtue of greater trafficking capacity, accelerate the transit of virally infected cells into the brain. In this grant project, we will examine the effect of opioid administration on development of a proinflammatory monocyte phenotype. We will determine the molecular mechanism for mu and kappa opioid effects on the expression of the critical chemokine receptor CCR2, as well as the very important pro-inflammtory chemokine MCP-1. Our laboratory has shown that acute mu opioid administration induces the expression of the chemokine receptors CCR5 and CXCR4. We will extend these studies to determine the biochemical basis for these effects using cloned molecular constructs for the CCR2 and MCP-1 promoters. In contrast, our results suggest that kappa opioids inhibit HIV-1 coreceptor expression, and depress HIV susceptibility, and we propose studies to examine the molecular basis for this effect as well. We believe these studies will contribute significantly to our understanding of the molecular basis for the effects of opioids on the neuropathology associated with HIV infection.
It is estimated that a third of HIV-infected individuals in this country are intravenous opioid drug abuser. Little is known, however, about the influence of opioid drugs of abuse on HIV infection of the central nervous system (CNS), or associated neurological disorders including dementia. This project is intended to investigate the effect of opioid drugs on the mechanism responsible for the spread of the virus from the bloodstream to the brain.
|Bednar, Filip; Song, Changcheng; Bardi, Giuseppe et al. (2014) Cross-desensitization of CCR1, but not CCR2, following activation of the formyl peptide receptor FPR1. J Immunol 192:5305-13|
|Cornwell, William D; Lewis, Mark G; Fan, Xiaoxuan et al. (2013) Effect of chronic morphine administration on circulating T cell population dynamics in rhesus macaques. J Neuroimmunol 265:43-50|
|Rogers, Thomas J (2011) Immunology as it pertains to drugs of abuse, AIDS and the neuroimmune axis: mediators and traffic. J Neuroimmune Pharmacol 6:20-7|
|Song, Changcheng; Rahim, Rahil T; Davey, Penelope C et al. (2011) Protein kinase Czeta mediates micro-opioid receptor-induced cross-desensitization of chemokine receptor CCR5. J Biol Chem 286:20354-65|
|Happel, Christine; Kutzler, Michele; Rogers, Thomas J (2011) Opioid-induced chemokine expression requires NF-?B activity: the role of PKC?. J Leukoc Biol 89:301-9|
|Chertov, Oleg; Zhang, Ning; Chen, Xin et al. (2011) Novel peptides based on HIV-1 gp120 sequence with homology to chemokines inhibit HIV infection in cell culture. PLoS One 6:e14474|
|Finley, Matthew J; Steele, Amber; Cornwell, William D et al. (2011) Transcriptional regulation of the major HIV-1 coreceptor, CXCR4, by the kappa opioid receptor. J Leukoc Biol 90:111-21|