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Yuri Persidsky, MD, PhD
Research Interests:
The research focus of the laboratory is studies of the functional
and structural alterations of the blood-brain barrier (BBB) during
HIV-1 infection. The hypothesis is that dysfunction of the BBB plays
a significant role in HIV-1 associated dementia (HAD) and that it
is related to the level of macrophage activation and infection. The
laboratory assesses structural (tight junctions, TJ) and functional
compromise (specific transport systems) of the BBB during the process
of macrophage trafficking to the brain in HIV-1 infection at the
cellular level utilizing the in vitro BBB model and a SCID mouse
model for HIV-1 encephalitis (HIVE) in vivo. The relationship between
neuropathologic changes, BBB alterations and behavior/motor impairment
is explored in the animal model of HIVE. The role of BBB transport
systems (multi-drug resistant proteins) in drug delivery during HIV-1
central nervous system (CNS) infection in order to improve penetration
of drugs across the BBB is also investigated. The potential synergistic
effects of alcohol and HIV-1 in BBB damage are currently under investigation.
We propose that alcohol abuse leads to direct alterations in monocyte
migration during HIVE and that alcohol alters CNS immune responses
through exacerbated BBB dysfunction.
Ongoing projects:
1. Effects of immune competent HIV-1 infected macrophages on BMVEC
TJ expression and function leading to BBB compromise:
Small dimeric
G-proteins, such as Rho, have been proposed to play a role in BMVEC
TJ assembly through activation of signaling pathways that regulate
cytoskeletal organization. Based on these findings, it is believed
that Rho represents a unique target for potential therapy in HIV-1
associated dementia (HAD) and TJ compromise is associated with Rho
activation and macrophage brain egress during HAD. The elucidation
of Rho activation mechanisms may provide clues about how TJ integrity
may be manipulated pharmacologically. Whether monocyte influence
BMVEC gene expression, morphology, and function through cell-cell
contacts and/or soluble-factor mechanisms is evaluated. The following
experimental systems are utilized for these studies (a) primary cell
models, (b) a functional BBB, and (c) a xenograft system for HIVE
in which human peripheral blood lymphocytes and monocytes have been
shown to migrate into brain parenchyma.
2. Expression of multi-drug resistant proteins on the BBB under
normal conditions, in HIV-1 CNS infection and their role in drug
delivery across the BBB:
The BBB restricts passage of a number of macromolecules, including
drugs, creating a sanctuary site for HIV-1 in the brain. A number
of transport proteins (including a membrane-associated ATP-dependent
efflux transporter, P-glycoprotein, multi-drug resistance-associated
proteins 1-6 and others) are expressed on BMVEC. They limit entry
into the brain of numerous xenobiotics, including anti-retroviral
drugs. How expression of transporters changes during HIV-1 infection
and what factors influence their expression/function are currently
under investigation. The ultimate goals of these studies are to develop
systems for improved drug delivery across BBB and to test them in
the relevant in vitro and in vivo models. This project is a collaborative
initiative involving the College of Pharmacy, UNMC and University
of Minnesota.
3. Role of alcohol in HIV-1 immune responses and BBB damage:
Although the CNS suffers the additive effects of alcohol abuse and
HIV infection, the specific effects of ethanol, as well as the
combined effects of alcohol abuse and HIV-1 infection on BBB function
and CNS immune responses are unclear. The laboratory proposes that
alcohol abuse leads to direct alterations in BBB function and exacerbates
monocyte infiltration into the brain in the context of HIVE. To
determine the specific cellular mechanisms underlying these phenomena,
the effects of ethanol on cytoskeleton and TJ proteins of BMVEC
in the BBB are explored. Also alterations in function of proteasomes
and immunoproteasomes in endothelial cells and macrophages, as
potential mechanisms for BBB dysfunction and altered immune dysfunction
seen in HIV-1 infection and alcohol abuse are studied. Alcohol-related
alterations in the BBB are studied in the BBB model in vitro and
in a murine animal model for HIVE. Therapeutic strategies will
be developed based on understanding of mechanisms underlying immune
dysfunction in alcohol abuse and HIV-1 infection.
4. Role of microglial deactivation in pathogenesis of HAD:
It is
proposed that inhibition of the kynurenine pathway in activated microglia
leads to a reduction in the neurotoxic potential of these cells and
results in cognitive improvement. To address this idea, the therapeutic
potential of drugs inhibiting a key enzyme of the kynurenine pathway,
indoleamine 2,3-dioxygenase (IDO) is being investigated. Study of
the mechanisms underlying these biochemical events and their effect
on clinical amelioration of HAD is underway in the laboratory. In
addition, other anti-inflammatory drugs to perform comparative analyses
are utilized. Integrated testing includes cognitive function, ex
vivo electrophysiology and neuropathology in a SCID mouse model of
HIVE.
Representative Publications (80 total):
Persidsky, Y., Limoges, J., McComb, R., Bock, P., Baldwin, T., Tyor,
W., Patil, A., Nottet, H. S. L. M., Epstein, L., Gelbard, H., Flanagan,
E., Reinhard, J., Pirruccello,
S.J. and Gendelman, H. E..: A quantitative analysis of brain immunopathology
in SCID mice with HIV-1 encephalitis. Am. J. Pathol. 149:1027-1053,
1996.
Persidsky, Y., Stins, M., Way, D., Witte, M. H., Weinand, M., Kim,
K. S., Bock, P.,
Gendelman, H. E., and Fiala, M.: A model for monocyte migration through
the blood-brain barrier during HIV-1 encephalitis. J. Immunol. 1997,
158:3499-3510.
Persidsky, Y., Ghorpade, A., Rasmussen, J., Limoges, J., Liu, X.J.,
Stins, M., Fiala,
M., Way, D., Kim, K.S., Witte, M. H., Weinand, M., Carhart, L., Gendelman,
H. E.
Microglial and Astrocyte Chemokines Regulate Monocyte Migration Through
the
Blood-Brain barrier in HIV-1 Encephalitis. Amer. J. Pathol. 1999;155:1599-1611.
Persidsky, Y., Limoges, J., Rasmussen, J., Zheng, J., Gearing, A.,
Gendelman, H.E.
Reduction in glial immunity and neurophathology by a PAF antagonist
and an MMP and TNFa inhibitor in SCID mice with HIV-1 encephalitis.
J. Neuroimm. 2001, 114:57-68.
Limoges J, Poluektova L, Ratanasuwan W, Rasmussen J, Zelivyanskaia
M, McClernon DR, Lanier ER, Gendelman HE, Persidsky Y: The efficacy
of potent anti-retroviral drug combination tested in a murine model
of HIV-1 encephalitis. Virology 2001, 281:21-34.
Poluektova L, Zelivyanskaya M, Swindells S, Gendelman HE and Persidsky
Y: The regulation of alpha chemokines during HIV-1 infection and
leukocyte activation: relevance for HIV-1-associated dementia. J.
Neuroimmunol. 2001, 120:112-128.
Zink WE, Anderson E, Boyle J, Rodriguez-Sierra J, Xiong H, Gendelman
HE, Persidsky Y: SCID Mice Inoculated with HIV-1 Infected Human
Macrophages Display Transient Dementia and Corollary Reductions
in Hippocampal Long Term Potentiation. J. Neuroscience. 2002, 22:2096-2105.
Poluektova, L., Munn, D., Persidsky, Y., Gendelman, H.E. Generation
of cytotoxic T cells against virus-infected human brain macrophages
in a murine model of HIV-1 encephalitis. J. Immunol. 2002, 168:3941-3949.
Anderson, E.R., Boyle, J., Zink, W.E., Persidsky, Y., Gendelman,
H.E., Xiong, H. Hippocampal synaptic dysfunction in a murine model
of HIV-1 encephalitis. Neuroscience 2003, 118:359-369.
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