Central nervous system involvement during HIV-1 infection represents one of the most serious complications beyond the induction of immunodeficiency. The penetration of HIV into the brain not only carries the potential for the development of serious neurological disease but may lead to the establishment of unique viral reservoirs protected from antiretroviral therapies. This compartmentalization and neurotoxicity may depend on the emergence of brain-specific quasispecies over time. The proposed studies will use heteroduplex tracking assay (HTA) technology to provide a critical evaluation of the extent to which HIV-1 and SIVsm evolve in the context of systemic and CNS disease. Viral envelope gene sequences will be evaluated in matched postmortem samples of plasma, cerebrospinal fluid (CSF) and various brain regions from individuals with severe neurological disease and contrasted with samples taken from individuals with comparable systemic disease but no neurological complications. A longitudinal analysis of SIVsm evolution in plasma and CSF will be used to provide an indication of co-evolution or divergent evolution within these compartments over time. Viral species that emerge within plasma and CSF will then be contrasted with sequences in brain and lymph nodes at autopsy. Full-length envelope genes unique to various regions of encephalitic brains will then be cloned, identified using envelope-specific HTA, evaluated for co-receptor use in PBMCs and macrophages and used to prepare full length, recombinant gp120. The purified gp120 will then be tested for neurotoxic properties in primary cortical and microglial cultures using assays of cell death, measures of neuronal calcium destabilization and quantification of the secretion of cytokines, chemokines and putative neurotoxins. After identifying envelope sequences that are neuropathogenic, gene array technology will be used to determine the profile of gene expression that is unique to the stimulation of microglia/macrophages by those sequences. SIVsm with an envelope gene representing a unique, compartmentalized neuropathogenic species will then be used to infect three macaques and the course of infection monitored in plasma and CSF. Results from these experiments will identify the nature of lentiviral envelope sequences that allow the development of unique viral reservoirs within the brain and will begin to answer how such sequences provoke toxic inflammatory reactions and neuropathogenesis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
5R01MH067751-04
Application #
7002644
Study Section
Special Emphasis Panel (ZMH1-BRB-P (03))
Program Officer
Joseph, Jeymohan
Project Start
2003-01-01
Project End
2008-12-31
Budget Start
2007-01-11
Budget End
2007-12-31
Support Year
4
Fiscal Year
2007
Total Cost
$395,193
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Biochemistry
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Grund, Birgit; Wright, Edwina J; Brew, Bruce J et al. (2013) Improved neurocognitive test performance in both arms of the SMART study: impact of practice effect. J Neurovirol 19:383-92
Schnell, Gretja; Joseph, Sarah; Spudich, Serena et al. (2011) HIV-1 replication in the central nervous system occurs in two distinct cell types. PLoS Pathog 7:e1002286
Robertson, K R; Su, Z; Margolis, D M et al. (2010) Neurocognitive effects of treatment interruption in stable HIV-positive patients in an observational cohort. Neurology 74:1260-6
Schnell, Gretja; Price, Richard W; Swanstrom, Ronald et al. (2010) Compartmentalization and clonal amplification of HIV-1 variants in the cerebrospinal fluid during primary infection. J Virol 84:2395-407
Schnell, Gretja; Spudich, Serena; Harrington, Patrick et al. (2009) Compartmentalized human immunodeficiency virus type 1 originates from long-lived cells in some subjects with HIV-1-associated dementia. PLoS Pathog 5:e1000395
Harrington, Patrick R; Schnell, Gretja; Letendre, Scott L et al. (2009) Cross-sectional characterization of HIV-1 env compartmentalization in cerebrospinal fluid over the full disease course. AIDS 23:907-15
Robertson, Kevin R; Smurzynski, Marlene; Parsons, Thomas D et al. (2007) The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 21:1915-21
Harrington, Patrick R; Connell, Mary J; Meeker, Rick B et al. (2007) Dynamics of simian immunodeficiency virus populations in blood and cerebrospinal fluid over the full course of infection. J Infect Dis 196:1058-67
Van Rie, Annelies; Harrington, Patrick R; Dow, Anna et al. (2007) Neurologic and neurodevelopmental manifestations of pediatric HIV/AIDS: a global perspective. Eur J Paediatr Neurol 11:1-9
Harrington, Patrick R; Haas, David W; Ritola, Kimberly et al. (2005) Compartmentalized human immunodeficiency virus type 1 present in cerebrospinal fluid is produced by short-lived cells. J Virol 79:7959-66

Showing the most recent 10 out of 12 publications