A recently described highly pathogenic variant of SIV from sooty mangabey monkeys (Cercocebus atys) termed SIVsmmPBj uniformly induces an acutely lethal disease in inoculated pig-tailed macaques (Macaca nemestrina). There are several hypotheses to be evaluated. The first is that a combination of specific changes in structural and regulatory genes of SIVsmmPBj, relative to its parent virus, SIVsmm9, are required for the altered pathogenesis of disease and result in the generation of an acutely lethal disease. The second is that specific genetic changes in env and the LTR (long terminal repeat) of SIVsmmPBj result in a modified cell tropism of the virus, ultimately contributing to the increased pathogenesis of this acutely lethal virus. Third, as a consequence of genetic changes and modified cell tropism, the replication of SIVsmmPBj in vivo is targeted to the gastrointestinal tract early during infection, in contrast to typical SIV infection of macaques. To evaluate the role of genetic change in the pathogenesis of SIVsmmPBj, chimeric molecular clones will be generated between SIVsmmPBj and SIVsmm9. These chimeric clones will be used to identify the specific changes that are responsible for the development of acute disease. Molecularly cloned PBj viruses (parental and chimeric) will be used to compare their abilities to replicate in primary lymphoid cells and cells from various sources. Finally, macaques inoculated with SIVsmmPBj or SIVsmm9 and analyzed in a serial time course study over the first six days after infection will allow a comparison of cell tropisms and dissemination of virus in vivo. Experiments using virus isolation and quantitation, quantitative PCR, in situ hybridization, and immunohistochemistry will permit an evaluation of the replication and tissue distribution of virus as a function of time.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA067364-04
Application #
2633904
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1995-01-01
Project End
1999-12-31
Budget Start
1998-01-01
Budget End
1999-12-31
Support Year
4
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Emory University
Department
Type
Other Domestic Higher Education
DUNS #
042250712
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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