Despite the progress of antiviral therapy, a majority of HIV-infected patients ultimately suffer from a variety of comorbid psychiatric illnesses, particularly major depressive disorders. These disorders impact patients' well-being and decrease their compliance with therapy, which can further compromise their quality of life. The mechanisms underlying the high comorbidity between HIV-1 infection and psychiatric disorders are still elusive. We have already established that proinflammatory cytokines produced by activated macrophages and T lymphocytes act in the brain to induce neurochemical and behavioral signs of depression in mice. In this condition, depressive-like behavior is associated with increased expression of indoleamine 2,3 dioxygenase (IDO), a key enzyme that regulates degradation of the essential amino acid tryptophan, and blockade of this enzyme abrogates depressive-like behavior. We propose that a similar mechanism accounts for HIV-associated depression. HIV-1 does not act directly on neurons but acts indirectly via glial cells through the generation of neurotoxic intermediates, such as proinflammatory cytokines and reactive oxygen species. When exposed to both viral glycoproteins (e.g., gp120) and/or transactivator viral proteins (e.g., Tat), virally infected macrophages and microglial cells synthesize these neurotoxic metabolites. In partial support of this hypothesis, we have obtained preliminary results indicating that repeated intracerebral administration of the viral glycoprotein gp120 to naive mice induces both depressive-like behavior and enhanced expression of brain IDO at doses that do not cause any sign of acute sickness. Based on these findings, we propose that the neuroinflammation induced by HIV proteins culminates in alterations of serotoninergic and dopaminergic neurotransmission that are at the origin of HIV-associated major depressive disorders. This hypothesis will be tested in three complementary objectives: (1) Do HIV proteins injected into the brain cause behavioral phenotypes of depression? Are these phenotypes also observed in mice with an inducible overexpression of Tat in astrocytes? (2) What is the neurochemical basis of the depressive-like behavioral effects of HIV proteins? And (3) Does targeting of brain inflammation at the level of microglial or IDO activation attenuate the functional consequences of HIV proteins on behavior and neurochemistry? Although the prevalence of clinical depression is much higher in HIV-infected patients than in the general population, the biological mechanisms that are responsible for this decline in mental health remain unknown. The research carried out in this project is needed to define potentially important cellular and molecular mechanisms that are used by HIV that results in depression, to identify the vulnerable brain structures that are responsible for this comorbid condition and to determine whether new pharmacological agents that negatively impact the ability of HIV to replicate can also alleviate the symptoms of depression in HIV-infected patients. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH079829-02
Application #
7290360
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
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$352,838
Indirect Cost
Name
University of Illinois Urbana-Champaign
Department
Pathology
Type
Schools of Medicine
DUNS #
041544081
City
Champaign
State
IL
Country
United States
Zip Code
61820
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Dantzer, Robert (2012) Depression and inflammation: an intricate relationship. Biol Psychiatry 71:4-5
Fu, Xin; Lawson, Marcus A; Kelley, Keith W et al. (2011) HIV-1 Tat activates indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures in a p38 mitogen-activated protein kinase-dependent manner. J Neuroinflammation 8:88
Kelley, Keith W; Dantzer, Robert (2011) Alcoholism and inflammation: neuroimmunology of behavioral and mood disorders. Brain Behav Immun 25 Suppl 1:S13-20
Dantzer, Robert; O'Connor, Jason C; Lawson, Marcus A et al. (2011) Inflammation-associated depression: from serotonin to kynurenine. Psychoneuroendocrinology 36:426-36
Lawson, Marcus A; Kelley, Keith W; Dantzer, Robert (2011) Intracerebroventricular administration of HIV-1 Tat induces brain cytokine and indoleamine 2,3-dioxygenase expression: a possible mechanism for AIDS comorbid depression. Brain Behav Immun 25:1569-75
Fu, Xin; Zunich, Samantha M; O'Connor, Jason C et al. (2010) Central administration of lipopolysaccharide induces depressive-like behavior in vivo and activates brain indoleamine 2,3 dioxygenase in murine organotypic hippocampal slice cultures. J Neuroinflammation 7:43

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