There is increasing evidence that chronic activation of the immune system may be a major factor leading to AIDS and paradoxically to its complete failure. From initial infection to late-stage HIV disease multiple signs of activation involving all lymphocyte subsets have been documented. To address problems associated with lentiviral disease, infection of macaques with the related simian immunodeficiency virus (SIV) is the most appropriate model system. Using a family of highly related SIV strains with defined biologic properties that induce a spectrum of disease in macaques, the investigators propose to identify: 1) signal transduction pathways activated in macaque lymphocytes after SIV infection; 2) the mechanism of apoptosis associated with SIV infection; 3) the roles of SIV Nef and Env proteins in cellular activation, apoptosis and disease progression; and 4) specific genes or regions of the SIV genome that influence viral pathogenesis during evolution of the quasispecies. A combination of in vitro and in vivo techniques, such as immunofluorescence, radioimmunoprecipitation, immunohistochemistry and in situ hybridization, to assess the expression of specific cellular genes during SIV infection will be used. Other studies include PCR-mediated analyses of mRNA expression of cellular proteins; transfection of cells with vectors expressing SIV Nef and Env proteins; sequence analysis of specific regions in SIV proviral DNA and genomic RNA in tissues obtained during persistent infection of macaques; evaluation of the effects of changes in regions of the SIV genome on pathogenesis. These studies will test the hypothesis that HIV/SIV and their antigens interfere with normal cellular signal transduction pathways, leading to uncontrolled immune system activation and ultimately to increased viral burden, pathogenicity, anergy and cell death.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI032377-07
Application #
2672111
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1992-04-01
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
7
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Microbiology/Immun/Virology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Fultz, P N; Vance, P J; Endres, M J et al. (2001) In vivo attenuation of simian immunodeficiency virus by disruption of a tyrosine-dependent sorting signal in the envelope glycoprotein cytoplasmic tail. J Virol 75:278-91
Chen, Z W; Shen, Y; Davis, I C et al. (2000) Down-regulation of macaque gammadelta + T cells in lymphoid compartments after rectal infection with SIVsmmPBj14. J Med Primatol 29:143-7
Tao, B; Fultz, P N (1999) Pathogenicity and comparative evolution in vivo of the transitional quasispecies SIVsmmPBj8. Virology 259:166-75
Thai, T H; Fultz, P N (1998) Down-modulation of the ZAP-70 protein tyrosine kinase in macaque T lymphocytes infected with SIVsmmPBj14. J Med Primatol 27:141-7
Schwiebert, R S; Fultz, P N (1998) Severe combined immunodeficient mice engrafted with macaque peripheral blood leukocytes support replication of SIVsmm. AIDS Res Hum Retroviruses 14:269-74
Schwiebert, R S; Tao, B; Fultz, P N (1997) Loss of the SIVsmmPBj14 phenotype and nef genotype during long-term survival of macaques infected by mucosal routes. Virology 230:82-92
Fultz, P N; Su, L; May, P et al. (1997) Isolation of sooty mangabey simian T-cell leukemia virus type I [STLV-I(sm)] and characterization of a mangabey T-cell line coinfected with STLV-I(sm) and simian immunodeficiency virus SIVsmmPBj14. Virology 235:271-85
Anderson, M J; Porter, D C; Fultz, P N et al. (1996) Poliovirus replicons that express the gag or the envelope surface protein of simian immunodeficiency virus SIV(smm) PBj14. Virology 219:140-9
Fultz, P N; Schwiebert, R; Stallworth, J (1995) AIDS-like disease following mucosal infection of pig-tailed macaques with SIVsmmPBj14. J Med Primatol 24:102-7
Fultz, P N; Schwiebert, R S; Su, L et al. (1995) Effects of total lymphoid irradiation on SIV-infected macaques. AIDS Res Hum Retroviruses 11:1517-27

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