Grant Number: 5R01MH071151-02
Project Title: SIV Encephalitis and Disease Progression
PI Information: PROFESSOR CLAYTON A. WILEY, wileyca@upmc.edu

Abstract: DESCRIPTION (provided by applicant):
Approximately 1/4 of immunosuppressed AIDS patients develop a neurodegenerative disorder clinically characterized as HIV associated dementia complex. In our experience, autopsies of AIDS patients who had become demented for reasons other than opportunistic infection uniformly demonstrated HIV encephalitis. Why there is such an abundance of activated and infected macrophages in the CNS remains an enigma, however, we theorize that it may be due to increased trafficking of HIV-infected monocytes. Monocytes are activated upon leaving the blood stream and entering the CNS where they transform into macrophages and can initiate viral replication and a neuroinflammatory cascade. Tissue damage begins a cycle of astrocytic and microglial activation, providing susceptible targets for further HIV infection and destruction of synaptic connectivity. We propose to use SIV infection of Macaca nemestrina and Macaco mullata as models of HIV encephalitis to test several hypotheses related to our theory of lentiviral neuropathogenesis. While no animal disease model is perfect, numerous similarities between simian and human nervous systems, between SIV and HIV infection and the capacity to manipulate and monitor CNS damage, make the macaque models optimal for these studies. Our overarching hypothesis is: Progression of SIV infection leads to increased monocyte/macrophage infection and trafficking into the CNS with destruction of the synaptic matrix. For all 3 aims of the current proposal, we will study a group of 36 SIV infected macaques. At 2-week intervals we will measure; absolute CD4 and CD8 T-cell counts and viral loads in the CSF and serum of all animals. In Specific Aim 1 we will examine the relationship between peripheral SIV infection and the development of SIV encephalitis. These experiments will test the hypothesis that: with progression of immune suppression there is increased trafficking of SIV infected monocytes causing increased brain viral burden. In Specific Aim 2 we will assess activation of CNS macrophages using Positron Emission Tomography and the peripheral benzodiazepine receptor radioligand [11C]-DAA1106. We hypothesize that when animals begin to show disease progression (decline in CD4 T-cells, increase in viremia) they will show increased CSF virus and increased binding of DAA1106 consistent with activation of CNS macrophages. In Specific Aim 3 we will measure synaptic and extracellular matrix damage in autopsy brain tissues and compare them to the temporal course of peripheral and central viral loads, DAA1106 binding. In summary, the proposed specific aims will test a set of interconnected hypotheses helping define mechanisms of synaptic damage and therapeutic targets to arrest its development and progression.

Thesaurus Terms:
AIDS dementia complex, cell migration, host organism interaction, infectious encephalitis, monocyte, neuropathology, psychoneuroimmunology, simian immunodeficiency virus, virus cytopathogenic effect
cerebrospinal fluid, cytotoxic T lymphocyte, disease /disorder model, helper T lymphocyte, longitudinal animal study, virus load
Macaca mulatta, Macaca nemestrina, behavioral /social science research tag, benzodiazepine receptor, leukocyte count, positron emission tomography, radiotracer

Institution: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
350 THACKERAY HALL
PITTSBURGH, PA 15260
Fiscal Year: 2006
Department: PATHOLOGY
Project Start: 01-MAY-2005
Project End: 30-APR-2010
ICD: NATIONAL INSTITUTE OF MENTAL HEALTH
IRG: ZRG1

Am J Pathol. 2006 May; 168(5): 1553–1569.
Copyright © American Society for Investigative Pathology

Longitudinal Analysis of Monocyte/Macrophage Infection in Simian Immunodeficiency Virus-Infected, CD8+ T-Cell-Depleted Macaques that Develop Lentiviral Encephalitis

Stephanie J. Bissel,* Guoji Wang,† Anita M. Trichel,‡ Michael Murphey-Corb,‡ and Clayton A. Wiley†

From the Department of Infectious Diseases and Microbiology,* Graduate School of Public Health, and the Departments of Pathology† and Molecular Genetics and Biochemistry,‡ School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania

Animals
Rhesus macaques (Macaca mulatta) were housed and maintained according to American Association of Laboratory Animal Care standards. Macaque information is described in Table 1. Ten rhesus macaques were treated with CD8-depleting antibody17 at −3, 0, and 4 days after infection. Depletion of CD8+ T cells was confirmed by flow cytometry. At day 0, macaques were inoculated with SIVDeltaB670 viral swarm by intravenous injection. Macaques were observed daily for clinical signs of anorexia, weight loss, lethargy, or diarrhea. Two of the macaques were humanely sacrificed at 2 and 4 weeks after infection before onset of clinical signs. The eight remaining macaques were euthanized on development of AIDS. A macaque was considered to have AIDS when SIV infection had progressed to the end stage and was nonresponsive to treatment as determined by clinical observations (eg, increased body temperature, sustained weight loss of 20% or greater, anorexia, increased lymph node size and splenomegaly, changes in activity, diarrhea unresponsive to treatment, opportunistic infections, and changes in general condition), peripheral blood analysis (eg, complete blood cell counts/differentials), and T-cell subset changes. Animals moribund with AIDS were euthanized. Ages of the macaques ranged from 22 to 46 months (age at time of necropsy). Complete necropsies were performed after humane sacrifice.
Cell Counts