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.
