Jay Rappaport, PhD
Professor and Associate Chair, Department of Neuroscience
Director of Graduate Programs, Department of Neuroscience
- Contact Information
- About Me
- Immuno-pathogenesis of HIV infection and the development of therapeutics for the treatment of AIDS.
- The role of altered monocyte/macrophage homeostasis in the immunopathogenesis of AIDS and the development of HIV associated dementia.
Our laboratory is interested in studying the role of certain cells of the innate immune system, monocyte/macrophages, in the pathogenesis of HIV infection. Studies are in progress to identify the role of altered monocyte/macrophage homeostasis in contributing to immune dysfunction in AIDS. Using a simian immunodeficiency virus infection model in non-human primates, we are investigating the molecular and cellular mechanisms involved in dysregulation of monocyte/macrophage homeostasis, immune dysfunction, and the role of altered monocyte/macrophage trafficking in the development of AIDS induced CNS disorders. We are also using this model to determine the effects of opioid drugs of abuse in disease pathogenesis in this model. We are further investigating the effects of opioids on the invasion of virus into the brain and the impact on the development of CNS disease. Studies are now in progress with the goal of developing novel, target-based approaches, to inhibit HIV infection in macrophages, destabilize HIV infected monocyte/macrophage reservoirs, and thereby restore immune function in the setting of AIDS.
Pathogenesis of HIV Associated Dementia Complex/HIV Encephalitis
HIV infection, particularly during the latter stages of disease (AIDS), is accompanied by an increase in the number of activated monocytes in circulation. These cells are often infected by HIV and can invade the CNS leading to neurological disorders. Our current studies are focused on defining the monocyte populations, which are infected by HIV in CNS, and aimed at determining mechanisms responsible for abnormal activation and increased trafficking into organ compartments. It is likely that the mechanisms leading to monocyte activation not only promote CNS disease, but also promote further increases in virus replication and potentially contribute to drug resistant reservoirs in HIV infected patients. Results of our studies in human tissues derived from autopsy specimens demonstrate that the perivascular macrophage is the major reservoir for productive HIV infection in the CNS in HIV encephalitis. In addition, cells with ramified microglial morphology in brain parenchyma are also productively infected. There is a large increase in both populations of macrophages/microglia in HIVE. Having ruled out proliferation as a mechanism for the increased number of these cells, our studies now focus on trafficking of monocyte/macrophages in HIVE. Indeed, other organs including kidney, liver, lymph node and spleen exhibit invasion of monocyte/macrophages in patients with HIVE. Viral genetic analysis of individual cell subsets is currently in progress to determine if HIV evolution is compartmentalized within the CNS or alternatively, if similar viral sequences are found in various organs and tissues.
In order to investigate if altered monocyte/macrophage trafficking is involved in the pathogenesis of HIVE, studies are in progress to investigate the time-course of accumulation, organ invasion and trafficking kinetics in an animal model for HIV induced CNS disease. We are currently investigating alterations in monocyte/ macrophage homeostasis in SIV infected macaques resulting in the expansion of an altered monocyte subset expressing the Fc receptor CD16. We are investigating the rate of production, clearance, as well as the consequent changes in immune polarization. In addition, we are using multiplex and bioinformatics approaches to study a number of candidate genes and biomarkers involved in this process. We are further exploring candidate compounds that may have the capacity to normalize monocyte/macrophage production, differentiation, and activation, with the goal of interfering with the harmful effects of macrophages on the immune system and CNS. This project is in collaboration with Tracy Fischer-Smith and Mark G. Lewis (Bioqual, Inc).
Effect of Drugs of Abuse in AIDS Pathogenesis:
In collaboration with Thomas Rogers, Tracy Fischer-Smith, Kamel Khalili, Toby Eisenstein, and Mark Lewis, we are investigating the effect of morphine on the pathogenesis of AIDS in non-human primates. This study should provide information regarding the impact of drugs of abuse on the development of AIDS and CNS disease in humans who are addicted to heroin. These studies involve virologic as well as biologic evaluations including immune and tissue based studies.
- Education, Training & Credentials
- PhD, Microbiology, University of Pennsylvania, Philadelphia, PA, 1986
- BA, Biology, University of Pennsylvania, Philadelphia, PA, 1979