To gain a better understanding of the pathogenesis of human immunodeficiency virus (HIV), the investigator proposes to use infection of macaques with a closely related simian virus isolated from sooty mangabey monkeys (SIVsmm). Dr. Fultz has identified a unique system for dissecting the evolution of an acutely lethal virus, SIVsmmPBj14, which was isolated from a pig-tailed macaque 14 months after inoculation with SIVsmm9, a prototype virus that induces AIDS-like disease. The applicant will use sequential isolates obtained at regular intervals between inoculation of SIVsmm9 and recovery of SIVsmmPBj14. The investigator will then attempt to define, at the biological and molecular levels, the evolution of the acutely lethal prototype and eight in vitro biologic properties that differ between SIVsmm9 and SIVsmmPBj14. This will be accomplished by characterization of the sequential SIVsmmPBj14 isolates for pathogenicity in pig-tailed macaques and for each of the eight biologic properties. In addition, some sequential isolates will be molecularly cloned to generate infectious viruses that reproduce all the phenotypes of the isolate from which they were generated. Because of distinct differences between SIVsmm9 and SIVsmmPBj14 in the LTR (long terminal repeat) and env (specifies viral membrane glycoproteins) and nef (negative regulatory factor [formerly 3' ORF]) genes, the applicant proposes to amplify relevant areas of the genome from all isolates by polymerase chain reaction (PCR). She will then sequence these to correlate acquisition of specific biologic properties with changes in specific regions of the genome. This should be possible since some of the unique properties of SIVsmmPBj14 are known to segregate. The in vivo relevance of the genomic quasispecies will be assessed using PCR and sequence analysis directly on DNA isolated from tissues of infected animals. Finally, to gain insight into virus-lymphocyte interactions as they relate to disease, the investigator proposes to determine whether SIVsmmPBj14 replicates in resting lymphocytes and to define the mechanism(s) by which this variant activates and induces lymphocytes to proliferate. Dr. Fultz will attempt to detect infection of lymphocytes at the single cell level, to assess the role of cytokines and the effects of metabolic inhibitors and to determine the specificity of induction of proliferation through the use of blocking agents and enriched cell populations.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI032377-01A1
Application #
3147412
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1992-04-01
Project End
1996-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
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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