The central and peripheral nervous system and the immune system are primary targets for human immunodeficiency virus type 1 (HIV-1) infection in individuals with acquired immunodeficiency syndrome (AIDS). The pathogenesis of the peripheral neuropathy has not been elucidated. The structural features of the peripheral sensory system offers the possibility to determine the exact mechanism by which neuronal damage is produced by HIV-1, dissecting out the relevant roles of macrophage/monocytes, HIV-1 infection-of macrophage/monocytes, cytokines production, and opportunistic viral infections. We will test the hypotheses that the distal progressive sensory neuropathy of AIDS is 1) A dying back disorder and 2) that humoral factors or cytokines secreted by macrophages are the likely cause. We will use immunohistochemistry, PCR techniques and in situ hybridization to identify cytokine-producing cells in peripheral nervous tissue from AIDS patients to confirm the identity of the HIV-1 infected cells, and the presence of opportunistic viruses. Cytokine production will be correlated with inflammation, neuronal loss, and replication of HIV-1. Biopsied sural nerve and post-mortem tissues of patients dying with AIDS and acute death controls will include the sural, tibial and sciatic nerves, the corresponding L5 and Sl dorsal root ganglia, and the whole spinal cord. Morphometric analyses will be performed to decide if this is a true dying back neuropathy or due to the cumulative effects of multiple peripheral nerve lesions. This proposal capitalizes on the high incidence of neuropathy among subjects dying with AIDS and will result in determination whether the incidence and progression of neuropathy among the AIDS subjects may result from cytokine production by macrophage/monocytes in situ in DRGs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS031488-03
Application #
2269406
Study Section
AIDS and Related Research Study Section 7 (ARRG)
Project Start
1993-02-01
Project End
1997-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
3
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Neurology
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Shapshak, Paul; Stewart, Renee V; Rodriguez de la Vega, Pura et al. (2002) Brain macrophage surface marker expression with HIV-1 infection and drug abuse: a preliminary study. J NeuroAIDS 2:37-50
Minagar, Alireza; Shapshak, Paul; Fujimura, Robert et al. (2002) The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 202:13-23
Shapshak, P; Segal, D M; Crandall, K A et al. (1999) Independent evolution of HIV type 1 in different brain regions. AIDS Res Hum Retroviruses 15:811-20
Bradley, W G; Shapshak, P; Delgado, S et al. (1998) Morphometric analysis of the peripheral neuropathy of AIDS. Muscle Nerve 21:1188-95
Delgado, S; Shapshak, P; Stewart, R et al. (1998) Heterogeneity of macrophage and T cell subpopulations in peripheral nerves from HIV infected individuals: A preliminary study. J NeuroAIDS 2:79-97
Segal, D M; Shapshak, P; Zhang, B T et al. (1997) Novel tetrameric tip motifs (APGK and VPGK) in the V3 loop of HIV type 1 envelope sequences in blood and brain from two injection drug users in Miami, Florida. AIDS Res Hum Retroviruses 13:1643-6
Bradley, W G; Verma, A (1996) Painful vasculitic neuropathy in HIV-1 infection: relief of pain with prednisone therapy. Neurology 47:1446-51
Nagano, I; Shapshak, P; Yoshioka, M et al. (1996) Parvalbumin and calbindin D-28 k immunoreactivity in dorsal root ganglia in acquired immunodeficiency syndrome. Neuropathol Appl Neurobiol 22:293-301
Nagano, I; Shapshak, P; Yoshioka, M et al. (1996) Increased NADPH-diaphorase reactivity and cytokine expression in dorsal root ganglia in acquired immunodeficiency syndrome. J Neurol Sci 136:117-28
Fiala, M; Rhodes, R H; Shapshak, P et al. (1996) Regulation of HIV-1 infection in astrocytes: expression of Nef, TNF-alpha and IL-6 is enhanced in coculture of astrocytes with macrophages. J Neurovirol 2:158-66

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