Deficiencies in the innate immune response of HIV infected people and FIV infected cats are well documented. The defect often presents clinically as reduced competence in eliminating intracellular opportunistic pathogens. Not only is innate immunity responsible for the control and elimination of the majority of opportunistic infections, it is the innate response that initiates the type and strength of the adaptive immune response. The nature of the innate immune defect in HIV infection has been most convincingly associated with decreased macrophage function, natural killer (NK) cell function, cytokine dysregulation (decreased IFN-y, ILl 5, TNF-a, or elevated ILl 0) and immunosuppression by specific viral proteins (gp4l, gpl 20, and Tat). However, the majority of the data has been generated in vitro, thus the significance in vivo is largely unknown. The studies proposed here are designed: 1.) To define the cellular and cytokine defects associated with impaired innate immunity of Fl V-infected cats to a well-characterized intracellular opportunistic pathogen, L. monocytogenes; 2.) To modulate the innate response of FlV V-infected cats by introducing IFN-7, IL10 0, ILl 5, or TNF-.a into the milieu; 3.) To determine if lentivirus Tat or envelope glycoproteins are immunosuppressive in the absence of infection and; 4.) To determine whether suppression or modulation of the innate immune response impacts the adaptive immune response. As preliminary work, the investigators have developed the model of L. monocytogenes as an immune system probe in Fl V-infected cats and have performed initial characterization of the cellular and cytokine response. Completion of the specific aims proposed here will better define the innate immune defect, identify potential points for intervention/modulation, and validate an animal model for the future evaluation of immune-modulating compounds.ompounds.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI047707-04
Application #
6750693
Study Section
AIDS and Related Research 8 (AARR)
Program Officer
Voulgaropoulou, Frosso
Project Start
2001-07-01
Project End
2007-03-31
Budget Start
2004-07-01
Budget End
2007-03-31
Support Year
4
Fiscal Year
2004
Total Cost
$256,375
Indirect Cost
Name
North Carolina State University Raleigh
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042092122
City
Raleigh
State
NC
Country
United States
Zip Code
27695
Zhang, Lin; Reckling, Stacie; Dean, Gregg A (2015) Phenotypic and functional analysis of CD1a+ dendritic cells from cats chronically infected with feline immunodeficiency virus. Comp Immunol Microbiol Infect Dis 42:53-9
Simoes, Rita D; Howard, Kristina E; Dean, Gregg A (2012) In vivo assessment of natural killer cell responses during chronic feline immunodeficiency virus infection. PLoS One 7:e37606
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Dean, Gregg A; LaVoy, Alora; Yearley, Jennifer et al. (2006) Cytokine modulation of the innate immune response in feline immunodeficiency virus-infected cats. J Infect Dis 193:1520-7
Ignacio, Glicerio; Nordone, Shila; Howard, Kristina E et al. (2005) Toll-like receptor expression in feline lymphoid tissues. Vet Immunol Immunopathol 106:229-37
Sirriyah, Jamal; Dean, Gregg A; LaVoy, Alora et al. (2004) Assessment of CD4+ and CD8+ IFN-gamma producing cells by ELISPOT in naive and FIV-infected cats. Vet Immunol Immunopathol 102:77-84
Burkhard, Mary Jo; Dean, Gregg A (2003) Transmission and immunopathogenesis of FIV in cats as a model for HIV. Curr HIV Res 1:15-29