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Morphine Induction of HIV Co-receptors and its Role in HIV Disease Progression
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Reported by Jules Levin
CROI 2012 March 5-8 Seattle WA
Irina Grishina1, Istvan Adany2, Shannon Callen3, Ramakrishna Hegde2, William Hu1, Paul Cheney2, Shilpa Buch2,3, and Satya Dandekar1
Departments of Medical Microbiology & Immunology1, University of California, Davis, CA; Department of Molecular & Integrative Physiology 2, University of Kansas, Kansas City , KS;
Department of Pharmacology and Experimental Neuroscience3, University of Nebraska, Omaha, NE
Changes induced by SIV infection alone caused significant changes in the expression of genes associated with neurological disorders..... In SIV+ RM the BG (Basal Ganglia) profile had many inflammatory processes upregulated, as well as increased cell growth/proliferation and neurological dysfunction...... there was an overrepresentation of genes in the functional categories of cell death and cell movement within the morphine group.....morphine treatment also increased the number genes related to inflammatory response. (c, d) In both jejunum and BG, SIV+ RM exceed the SIV+ M group in the number of genes being altered in the cell death, cell movement and inflammatory/infectious responses functional categories........ Apoptosis, Inflammatory Cell Chemotaxis and Immune Activation are Stimulated by Morphine Conditioning and SIV Disease Progression: In BG increased expression of interferon gamma inducible, T-cell attractant chemokines was observed in morphine conditioned groups. In the SIV+ RM this was also accompanied by upregulation of another group of leukocyte chemokines (CCL2, CCL3, and CCL5) which are associated with a breach of the blood-brain barrier. (d.) The subunits of NADPH oxidase, a key player in oxidative stress, are consistently upregulated in SIV+ RM in both tissue compartments..... Morphine Conditioning Induces HIV Co-receptor Expression in Gut but not in Basal Ganglia: In contrast, mild changes in the levels of HIV co-receptor expression was observed in BG of all experimental groups, compared to uninfected controls
Abstract
Background: An ongoing problem in the post-HAART era is the dependence of many HIV-infected patients on drugs of abuse such as opiates. Opiate use has been shown to lead to high viral loads and increased disease progression, though the interplay of opiate-HIV infection is not well understood. Two organ systems of interest for judging this interplay are the gut and brain. Using the SIV model of HIV infection we tested the hypothesis that morphine use induced alternate SIV co-receptor expression thus increasing available SIV targets, resulting in increased viral replication and progression to SAIDS.
Methods: SIVmac R71/17E infected (n=9) and uninfected (n=3) animals were utilized for this study. Of the infected animals: 3 were saline-treated, while 6 were morphine conditioned. 3 of the 6 rapidly progressed to SAIDS within the first 12 weeks of infection while the other three were necropsied at 53 weeks post infection. Virologic assessment was performed on blood plasma and CSF throughout infection and on intestinal tissue at necropsy. Microarray and real- time PCR analysis was utilized to determine gene expression changes in jejunum and basal ganglia (BG).
Objectives: Utilize a multi-compartment analysis to further understand the interplay between opiate use and HIV disease progression.
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