Object-Oriented Simulation of HIV- and HIV/CNS-Infection. Acquired Immune Deficiency Syndrome (AIDS) is the ultimate consequence of a multi-faceted disease process caused by infection with the Human immunodeficiency Virus (HIV). HIV uses the cluster designation 4 (CD4) molecule as a receptor, which can be expressed by immune and nervous system cells. Besides CD4, numerous receptors and signals (hormones, cytokines, transmitters) are shared between the systems. Consequently, disease caused by HIV affects both the nervous and the immune system. Previous clinical studies have indicated that at least four critical events are involved in the pathogenesis of AIDS. The first is viral infection of helper T cells and monocytes early in the course of the disease, the second is the contribution of inductive signals from both cell types to disease progression, the third is massive HIV strain diversification and defective particle production, and the fourth is the transport of HIV into the brain by infected macrophages. Our previous computer-simulations showed that AIDS can be viewed as an immunoregulatory disease, where HIV together with secondary infections causes cascades of regulatory disruption. Here, we propose to extend our studies to neuro-immunologic regulatory networks. Specifically, we pose two questions: (1) in which way does HIV-infection alter cellular communication within and between the major sensory systems: the hardwired nervous system, the stationary endocrine transmitting glands and, the mobile neuroendocrine network called the immune system? and, (2) how are localized changes at the cellular level related to slowly emerging paralysis or loss of subsystems and subsystem functions, in particular cognitive impairment in learning and memory? We will approach these questions by studying the interaction between lymphoid and myeloid cells, hypothalamic-pituitary neurons, adrenal cells, and glial cells, with emphasis on the resulting hormone, peptide, and transmitter production. We will specifically evaluate the production of interleukin 1 (IL-l), IL-2, IL-4, IL-5, IL-6, interferon (IFN) and tumor necrosis factor (TNF), Substance P and Substance K, corticotropic releasing factor (CRF), adrenocorticotropic hormone (ACTH), cortisone, and nerve growth factor (NGF) associated with a single infection, multiple viral infections and neurological stressors. Using a computer-experimental system that allows the prediction of long-term behavior in the normal and diseased nervous-endocrine-immune system, we expect to identify models of HIV-induced immuno- and neuro-pathogenesis which can be applied in the testing of treatment with combined neuro-immuno-tropic factors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
2R01MH045688-04
Application #
2246726
Study Section
Psychobiological, Biological, and Neurosciences Subcommittee (MHAI)
Project Start
1989-07-01
Project End
1995-07-31
Budget Start
1992-08-01
Budget End
1993-07-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Diego
Department
Psychiatry
Type
Schools of Medicine
DUNS #
077758407
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Weinrich, J D; Atkinson Jr, J H; McCutchan, J A et al. (1995) Is gender dysphoria dysphoric? Elevated depression and anxiety in gender dysphoric and nondysphoric homosexual and bisexual men in an HIV sample. HNRC Group. Arch Sex Behav 24:55-72
Heaton, R K; Velin, R A; McCutchan, J A et al. (1994) Neuropsychological impairment in human immunodeficiency virus-infection: implications for employment. HNRC Group. HIV Neurobehavioral Research Center. Psychosom Med 56:8-17
Peavy, G; Jacobs, D; Salmon, D P et al. (1994) Verbal memory performance of patients with human immunodeficiency virus infection: evidence of subcortical dysfunction. The HNRC Group. J Clin Exp Neuropsychol 16:508-23
Sewell, D D; Jeste, D V; McAdams, L A et al. (1994) Neuroleptic treatment of HIV-associated psychosis. HNRC group. Neuropsychopharmacology 10:223-9
Gulevich, S J; McCutchan, J A; Thal, L J et al. (1993) Effect of antiretroviral therapy on the cerebrospinal fluid of patients seropositive for the human immunodeficiency virus. J Acquir Immune Defic Syndr 6:1002-7
Gulevich, S J; Kalmijn, J A; Thal, L J et al. (1992) Sensory testing in human immunodeficiency virus type 1-infected men. HIV Neurobehavioral Research Center Group. Arch Neurol 49:1281-4