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Complex determinants of macrophage tropism in env of simian immunodeficiency virus
K Mori1, D J Ringler, T Kodama
1Division of Microbiology, New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772-9102.
Abstract:
Macrophage-tropic virus variants evolved during the course of infection of individual rhesus monkeys with cloned, non-macrophagetropic simian immunodeficiency virus. Specific changes in the envelope gene (env) were found to be primarily responsible for the dramatic increase in the ability of the virus to replicate in macrophages. Cloned viruses differing at nine amino acid positions in env exhibited a more than 100-fold difference in replicative capacity for primary cultures of rhesus monkey alveolar macrophages. At least five of the nine amino acid changes contributed to macrophage tropism. These determinants were distributed across the full length of env, including both the gp120 and gp41 products of the env gene. Furthermore, the emergence of macrophagetropic variants in vivo was associated with specific pathologic manifestations in which the macrophage is the major infected cell type. Thus, major determinants of macrophage tropism reside in env, they can be complex in nature, and the presence of macrophage-tropic virus variants in vivo can influence the disease course and disease manifestations.
Insights
Specific changes in the simian immunodeficiency virus envelope gene (env) drive increased replication in macrophages. These genetic alterations influence viral tropism and disease progression in rhesus monkeys.
Area of Science:
- Virology
- Immunology
- Genetics
Background:
- Simian immunodeficiency virus (SIV) infection in rhesus monkeys serves as a model for human immunodeficiency virus (HIV) pathogenesis.
- Understanding viral evolution and adaptation is crucial for developing effective interventions.
Purpose of the Study:
- To investigate the genetic basis of macrophage tropism in SIV.
- To determine how viral evolution impacts disease manifestations.
Main Methods:
- Infection of rhesus monkeys with cloned, non-macrophage-tropic SIV.
- Analysis of envelope gene (env) mutations in evolved macrophage-tropic variants.
- Assessment of viral replicative capacity in primary macrophages.
Main Results:
- Macrophage-tropic SIV variants emerged during infection.
- Specific amino acid changes in the env gene were responsible for increased macrophage replication.
- At least five of nine identified amino acid changes contributed to macrophage tropism.
- Emergence of these variants correlated with specific disease manifestations.
Conclusions:
- The SIV envelope gene (env) contains major determinants of macrophage tropism.
- These determinants can be complex and distributed throughout the env gene.
- Macrophage-tropic SIV variants can influence disease course and pathology.