Abstract

The autonomous parvoviruses are small, single-stranded DNA-containing viruses capable of inducing fetal demise and teratogenic effects during pregnancy and of interfering with both normal tissue turnover and the development of neoplastic disease in their adult host. The proposed research is aimed at understanding the mechanisms underlying the tissue-tropism exhibited by these agents during pathogenesis. Recombinant DNA techniques will be used in combination with viral and somatic cell genetics to analyse, at the molecular level, developmentally regulated host factors essential for viral growth, and the viral components with which the host factors interact - the combination of which determines virus strain-dependent target cell specificity. Viral determinants responsible for lethal viral gene expression in particular differentiated cells will be mapped by constructing and characterizing recombinants between strains of minute virus of mice (MVM) which differ in their ability to grow productively in fibroblasts and T-lymphocytes. Mutations allowing each parental virus to grow in an otherwise restrictive host cell will be mapped and sequenced. Host cell variants selected for resistance to the virus will be further characterized and exploited in cDNA cloning experiments designed to isolate the developmentally regulated host factors essential for viral, but not cellular, replication. The viral non-structural proteins will be studied to discover the role of each in pathogenesis. The two genes will be functionally separated by mutagenesis, and expressed in target cells, in order to assess their effects on cellular physiology. Bacterial reporter genes will be cloned under the control of each viral promoter, in concert with putative viral control elements, and their expression monitored in transfected cells, in order to explore both intra-viral genetic control circuits and the mechanisms of developmentally regulated control of viral gene expression. These approaches will also be used to develop in vitro systems in which to study the replication and hematotropism of the human parvovirus B19.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA029303-10
Application #
3168640
Study Section
Experimental Virology Study Section (EVR)
Project Start
1981-01-01
Project End
1991-12-31
Budget Start
1990-01-01
Budget End
1990-12-31
Support Year
10
Fiscal Year
1990
Total Cost
Indirect Cost

  Institution

Name
Yale University
Department
Type
Schools of Medicine
DUNS #
082359691
City
New Haven
State
CT
Country
United States
Zip Code
06520

  Publications

Forbes, Neil S; Coffin, Robert S; Deng, Liang et al. (2018) White paper on microbial anti-cancer therapy and prevention. J Immunother Cancer 6:78
Marr, Matthew; D'Abramo, Anthony; Pittman, Nikea et al. (2018) Optimizing the Targeting of Mouse Parvovirus 1 to Murine Melanoma Selects for Recombinant Genomes and Novel Mutations in the Viral Capsid Gene. Viruses 10:
Pittman, Nikéa; Misseldine, Adam; Geilen, Lorena et al. (2017) Atomic Resolution Structure of the Oncolytic Parvovirus LuIII by Electron Microscopy and 3D Image Reconstruction. Viruses 9:
Meir, Chen; Mincberg, Michal; Rostovsky, Irina et al. (2017) The MVMp P4 promoter is a host cell-type range determinant in vivo. Virology 506:141-151
Subramanian, Suriyasri; Organtini, Lindsey J; Grossman, Alec et al. (2017) Cryo-EM maps reveal five-fold channel structures and their modification by gatekeeper mutations in the parvovirus minute virus of mice (MVM) capsid. Virology 510:216-223
Nakaya, Yuki; Stavrou, Spyridon; Blouch, Kristin et al. (2016) In Vivo Examination of Mouse APOBEC3- and Human APOBEC3A- and APOBEC3G-Mediated Restriction of Parvovirus and Herpesvirus Infection in Mouse Models. J Virol 90:8005-12
Mihaylov, Ivailo S; Cotmore, Susan F; Tattersall, Peter (2014) Complementation for an essential ancillary non-structural protein function across parvovirus genera. Virology 468-470:226-37
Vollmers, Ellen M; D'Abramo Jr, Anthony; Cotmore, Susan F et al. (2014) Genome sequence of tumor virus x, a member of the genus protoparvovirus in the family parvoviridae. Genome Announc 2:
Halder, Sujata; Cotmore, Susan; Heimburg-Molinaro, Jamie et al. (2014) Profiling of glycan receptors for minute virus of mice in permissive cell lines towards understanding the mechanism of cell recognition. PLoS One 9:e86909
Cotmore, Susan F; Agbandje-McKenna, Mavis; Chiorini, John A et al. (2014) The family Parvoviridae. Arch Virol 159:1239-47

Showing the most recent 10 out of 64 publications