Our research interests revolve around many different subjects relevant to obtaining a better understanding of the interaction of retroviruses with their host cells and organisms. In our laboratory at Tufts University, we are engaged in studies using simple retroviruses (avian and murine viruses) to elucidate the nature of the retrovirus-receptor interaction; the mechanism and specificity of integration of viral DNA into host DNA; control of viral gene expression; mechanism of retroviral genetic variation; and evolution of the host-virus relationship, as revealed by the """"""""fossil"""""""" record provided by endogenous proviruses found in the normal DNA of all vertebrates and many other species. We have also been interested in the complex relationship between HIV and the infected host. Modeling of this interaction implies that virus and infected cells turn over very rapidly, at about one generation per day. Thus, large numbers of cells are infected and die every day, and their progeny viruses go on to infect another cell. This turnover has important implications for drug resistance. Together with the high mutation rate shared by all RNA viruses, it creates the means for accumulation of many viral variants, potentially including drug-resistant variants, even before the onset of drug treatment. Such preexisting mutants would be the principal cause of early treatment failure. The manner in which such mutants are expected to arise is strongly dependent on the structure of the HIV population in infected individuals -- its effective size and distribution among different sites of replication. Through the HIV Drug Resistance Program, we are initiating studies to follow in great detail the appearance, change in frequency, and linkage of mutations in virus present in plasma and tissue sites, in both untreated and drug-treated patients. We expect these studies to provide valuable insights into how resistance arises in patients, and possibly to provide clues to averting its appearance.

Agency
National Institute of Health (NIH)
Institute
Division of Basic Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010302-04
Application #
6559172
Study Section
(DRP)
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2001
Total Cost
Indirect Cost
Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Weidhaas, J B; Angelichio, E L; Fenner, S et al. (2000) Relationship between retroviral DNA integration and gene expression. J Virol 74:8382-9
Stoye, J P; Coffin, J M (2000) A provirus put to work. Nature 403:715, 717
Tomonaga, K; Coffin, J M (1999) Structures of endogenous nonecotropic murine leukemia virus (MLV) long terminal repeats in wild mice: implication for evolution of MLVs. J Virol 73:4327-40
Johnson, W E; Coffin, J M (1999) Constructing primate phylogenies from ancient retrovirus sequences. Proc Natl Acad Sci U S A 96:10254-60
Rouzine, I M; Coffin, J M (1999) Search for the mechanism of genetic variation in the pro gene of human immunodeficiency virus. J Virol 73:8167-78
Aschoff, J M; Foster, D; Coffin, J M (1999) Point mutations in the avian sarcoma/leukosis virus 3' untranslated region result in a packaging defect. J Virol 73:7421-9
Rouzine, I M; Coffin, J M (1999) Linkage disequilibrium test implies a large effective population number for HIV in vivo. Proc Natl Acad Sci U S A 96:10758-63
Coffin, John (1999) Proposed alternatives for the use of anti-HIV drugs: is it appropriate? Drug Resist Updat 2:71-72