eprintid: 10248 rev_number: 4 userid: 6 dir: disk0/00/01/02/48 datestamp: 2011-11-10 20:09:53 lastmod: 2016-11-15 13:54:05 status_changed: 2011-11-10 20:09:53 type: thesis_degree metadata_visibility: show contact_email: sjbissel@mac.com item_issues_count: 0 eprint_status: archive creators_name: Bissel, Stephanie Jane creators_email: sjbissel@mac.com title: RELATIONSHIP BETWEEN SYSTEMIC AND CENTRAL NERVOUS SYSTEM MONOCYTE/MACROPHAGE INFECTION IN SIMIAN IMMUNODEFICIENCY VIRUS ENCEPHALITIS ispublished: unpub divisions: sch_gsph_infectiousdiseasesmicrobiology full_text_status: public keywords: brain; central nervous system; encephalitis; human immunodeficiency virus; macrophage; monocyte; pathology; simian immunodeficiency virus abstract: Approximately ΒΌ of AIDS patients develop HIVE, the pathologic entity associated with cognitive, motor, and behavioral deficits attributed to synaptic damage and neuronal loss. It still remains unclear why only a subset of HIV-infected individuals develops abundant central nervous system (CNS) macrophage/microglia infection that characterizes HIVE. The overarching hypothesis of this body of work is that simian immunodeficiency virus (SIV) encephalitis (SIVE) is the CNS manifestation of a systemic increase in SIV infection and activation of monocyte/macrophage elements. Specifically, we examined the relationship of infected and activated monocyte/macrophage elements outside of the CNS during the evolution of lentiviral encephalitis to the presence of infected macrophages in the CNS. We studied three models of SIV infection: SIV-infection of rhesus and pigtailed macaques and SIV-infection of CD8+ T cell depleted macaques. Antibody-mediated CD8+ T cell depletion did not increase the incidence of SIVE in infected rhesus macaques. In SIV-infected rhesus macaques, we examined whether presence of activated macrophages or SIV-infected macrophages is associated with the presence of neuronal damage. The presence of abundant infected macrophages in the CNS is related to postsynaptic neuronal damage in macaques with SIVE. At the same time cerebrospinal fluid viral load increased in SIV-infected CD8-depleted rhesus and non-depleted pigtailed macaques that developed encephalitis, monocyte-derived macrophages produced more virus ex vivo than macaques that did not develop encephalitis. Compared to pigtailed macaques that did not develop SIVE, the monocyte associated SIV-DNA load of monocytes was elevated in macaques that developed SIVE. Pigtailed macaques with SIVE had more infected macrophages in peripheral organs, with the exception of lymph nodes, than macaques without SIVE. Longitudinal analysis of phenotypic markers of monocyte activation show that increases in proportion of CD14+/CD16+ monocytes is associated with chronic disease. Brains with SIVE have greater numbers of T cells with cytotoxic potential. In conclusion, these findings suggest that inherent differences in host macrophage viral production or immune response to macrophage infection are associated with development of encephalitis. Further understanding of the differential role monocyte/macrophages have in the development of lentiviral encephalitis will identify therapeutic targets to halt this public health epidemic. date: 2006-02-03 date_type: completed institution: University of Pittsburgh refereed: TRUE etdcommittee_type: committee_chair etdcommittee_type: committee_cochair etdcommittee_type: committee_member etdcommittee_type: committee_member etdcommittee_name: Wiley, Clayton A etdcommittee_name: Barratt-Boyes, Simon etdcommittee_name: Murphey-Corb, Michael etdcommittee_name: Montelaro, Ronald C etdcommittee_email: claytonwiley@comcast.net etdcommittee_email: smbb@pitt.edu etdcommittee_email: mcorb@pitt.edu etdcommittee_email: rmont@pitt.edu etdcommittee_id: etdcommittee_id: SMBB etdcommittee_id: MCORB etdcommittee_id: RMONT etd_defense_date: 2005-11-29 etd_approval_date: 2006-02-03 etd_submission_date: 2005-12-09 etd_access_restriction: immediate etd_patent_pending: FALSE assigned_doi: doi:10.5195/pitt.etd.2011.10248 thesis_type: dissertation degree: PhD committee: Clayton A. Wiley (claytonwiley@comcast.net) - Committee Chair committee: Simon Barratt-Boyes (smbb@pitt.edu) - Committee Co-Chair committee: Michael Murphey-Corb (mcorb@pitt.edu) - Committee Member committee: Ronald C. Montelaro (rmont@pitt.edu) - Committee Member etdurn: etd-12092005-145928 other_id: http://etd.library.pitt.edu/ETD/available/etd-12092005-145928/ other_id: etd-12092005-145928 citation: Bissel, Stephanie Jane (2006) RELATIONSHIP BETWEEN SYSTEMIC AND CENTRAL NERVOUS SYSTEM MONOCYTE/MACROPHAGE INFECTION IN SIMIAN IMMUNODEFICIENCY VIRUS ENCEPHALITIS. Doctoral Dissertation, University of Pittsburgh. (Unpublished) document_url: http://d-scholarship-dev.library.pitt.edu/10248/1/bisselsj_etd2005-4.pdf