The overall goal of the proposed research is to determine the relationship of both specific gene variants and epigenetic modification of genes of the opioidergic, stress response, serotonergic, and dopaminergic systems in the brain of HIV-1 infected subjects with the progression of HIV-1 disease. Many individuals infected with HIV-1 suffer from comorbid psychiatric illnesses, including depression, anxiety, and impulsive behaviors. Host genetic factors-can modify HIV-1 infection and have been shown to affect the vulnerability to develop psychiatric illnesses. Opioids promote HIV-1 replication in immune and glial cells in vitro, presumably by increasing levels of the chemokine CCR5 (one of the coreceptors for HIV-1 entry into the cell) and by the suppression of host HIV-protective factors. The relationship between the genotype and expression patterns of the mu-opioid receptor gene, OPRM1, and CCR5 in brain samples obtained from the National NeuroAIDS Tissue Consortium will be investigated. Comorbid depression, anxiety, atypical stress responsivity, impulsivity, and risk-taking behaviors, of which drug abuse/addiction may be a manifestation, will be examined. To identify peripheral markers for the progression of HIV-1 infection, the role of epigenetic factors in both brain and lymphocytes from individuals characterized as to psychiatric comorbidity and abuse/addiction, which may modulate key genes related to infectivity and risk-taking, will be examined. In a large study using samples from the Women's Interagency HIV Study repository, we will investigate the relationship between polymorphisms in genes of the serotonergic, dopaminergic and opioidergic systems with HIV-1 infection progression. The relationship of these variants with impulsivity and risk-taking to HIV-1 disease progression will be examined. Clarifying the functional relevance of polymorphisms associated with susceptibility to complex disorders such as psychiatric illnesses and abuse/addiction may provide the foundation for future clinical studies. Also, these studies may identify the role of genetic variants and epigenetic mechanisms in the progression of HIV- 1 infection and may point to targets for pharmacotherapy in HIV-1 disease with psychiatric comorbidity. The information gained from this research should help to alleviate the suffering of HIV-1 infection with comorbid psychiatric diseases. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH079880-03
Application #
7456454
Study Section
Special Emphasis Panel (ZMH1-ERB-S (07))
Program Officer
Joseph, Jeymohan
Project Start
2006-09-25
Project End
2011-07-31
Budget Start
2008-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2008
Total Cost
$605,946
Indirect Cost
Name
Rockefeller University
Department
Biology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Butelman, Eduardo Roque; Bacciardi, Silvia; Maremmani, Angelo Giovanni Icro et al. (2017) Can a rapid measure of self-exposure to drugs of abuse provide dimensional information on depression comorbidity? Am J Addict 26:632-639
Arnoldussen, Ilse A C; Kiliaan, Amanda J; Gustafson, Deborah R (2014) Obesity and dementia: adipokines interact with the brain. Eur Neuropsychopharmacol 24:1982-99
Proudnikov, Dmitri; Randesi, Matthew; Levran, Orna et al. (2013) Polymorphisms of the kappa opioid receptor and prodynorphin genes: HIV risk and HIV natural history. J Acquir Immune Defic Syndr 63:17-26
Gustafson, Deborah R; Mielke, Michelle M; Tien, Phyllis C et al. (2013) Anthropometric measures and cognition in middle-aged HIV-infected and uninfected women. The Women's Interagency HIV Study. J Neurovirol 19:574-85
Lawhorn, Collene; Yuferov, Vadim; Randesi, Matthew et al. (2013) Genetic diversity and linkage disequilibrium in the chemokine receptor CCR2-CCR5 region among individuals and populations. Cytokine 64:571-6
Proudnikov, Dmitri; Randesi, Matthew; Levran, Orna et al. (2012) Association of polymorphisms of the mu opioid receptor gene with the severity of HIV infection and response to HIV treatment. J Infect Dis 205:1745-56
Levran, Orna; Yuferov, Vadim; Kreek, Mary Jeanne (2012) The genetics of the opioid system and specific drug addictions. Hum Genet 131:823-42
Crystal, Howard A; Hamon, Sara; Randesi, Matthew et al. (2012) A C17T polymorphism in the mu opiate receptor is associated with quantitative measures of drug use in African American women. Addict Biol 17:181-91
Yuferov, Vadim; Nielsen, David A; Levran, Orna et al. (2011) Tissue-specific DNA methylation of the human prodynorphin gene in post-mortem brain tissues and PBMCs. Pharmacogenet Genomics 21:185-96
Rouault, Morgane; Nielsen, David A; Ho, Ann et al. (2011) Cell-specific effects of variants of the 68-base pair tandem repeat on prodynorphin gene promoter activity. Addict Biol 16:334-46

Showing the most recent 10 out of 24 publications