Abstract

zed in the question Why is the low infectivity of human T-cell leukemia virus type 1 (HTLV-1) advantageous for the virus? The answer to this question is important for developing strategies to deal with HTLV-1-associated pathologies, which include adult T-cell leukemia and degenerative neurological disorders. We believe that these strategies will be revealed in studies that examine the HTLV-1 infectious cycle with respect to 1) events surrounding the assembly and transmission of virus particles; 2) reverse transcription; and 3) virus interactions with cellular restriction factors. Our understanding of the HTLV-1 infectious cycle lags behind that of HIV-1 because HTLV-1 does not spread in established T-cell lines like HIV-1. More than a decade ago, we constructed one of the first infectious molecular clones of HTLV-1, and later we developed vectors and cell culture methods that made it possible to analyze HTLV-1 replication in vitro. These tools are now an essential complement to biochemical and molecular methods that are used to study HTLV-1 infection and replication. We have begun to construct analogous vectors for bovine leukemia virus (BLV) and HTLV-2, -3, and -4 to take advantage of the biological and genetic diversity among the deltaretroviruses for comparative analyses. The experiments that are planned here to examine molecular mechanisms of HTLV-1 infection and replication address several questions of current general interest in our field. These include mechanisms of Gag targeting to specific membrane domains via interactions between the matrix domain of Gag and lipid and/or protein components of the membrane; pathways of assembly and release for viruses that use a PPXY late domain; mechanisms that coordinate Gag and Env assembly; and mechanisms of retroviral inhibition by, and resistance to, cellular restriction factors belonging to the APOBEC family of cytidine deaminases. [Corresponds to Derse Project 1 in the April 2007 site visit report of the HIV Drug Resistance Program]

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Intramural Research (Z01)
Project #
1Z01BC010003-12
Application #
7592615
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
2007
Total Cost
$1,081,407
Indirect Cost

  Institution

Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

LaRue, Rebecca S; Andresdottir, Valgerdur; Blanchard, Yannick et al. (2009) Guidelines for naming nonprimate APOBEC3 genes and proteins. J Virol 83:494-7
Mitchell, Michael S; Bodine, Ellen T; Hill, Shawn et al. (2007) Phenotypic and genotypic comparisons of human T-cell leukemia virus type 1 reverse transcriptases from infected T-cell lines and patient samples. J Virol 81:4422-8
Derse, David; Hill, Shawn A; Princler, Gerald et al. (2007) Resistance of human T cell leukemia virus type 1 to APOBEC3G restriction is mediated by elements in nucleocapsid. Proc Natl Acad Sci U S A 104:2915-20
Wencker, Melanie; Sausse, Celine; Derse, David et al. (2007) Human T-cell leukemia virus type 1 Tax protein down-regulates pre-T-cell receptor alpha gene transcription in human immature thymocytes. J Virol 81:301-8
Heidecker, Gisela; Lloyd, Patricia A; Soheilian, Ferri et al. (2007) The role of WWP1-Gag interaction and Gag ubiquitination in assembly and release of human T-cell leukemia virus type 1. J Virol 81:9769-77
Mazurov, Dmitriy; Heidecker, Gisela; Derse, David (2007) The inner loop of tetraspanins CD82 and CD81 mediates interactions with human T cell lymphotrophic virus type 1 Gag protein. J Biol Chem 282:3896-903
Mitchell, Michael S; Tozser, Jozsef; Princler, Gerald et al. (2006) Synthesis, processing, and composition of the virion-associated HTLV-1 reverse transcriptase. J Biol Chem 281:3964-71
Heidecker, Gisela; Lloyd, Patricia A; Fox, Kristi et al. (2004) Late assembly motifs of human T-cell leukemia virus type 1 and their relative roles in particle release. J Virol 78:6636-48
Liao, Huey-Jane; Baker, Carl C; Princler, Gerald L et al. (2004) cis-Acting and trans-acting modulation of equine infectious anemia virus alternative RNA splicing. Virology 323:131-40
Nicot, Christophe; Dundr, Miroslav; Johnson, Julie M et al. (2004) HTLV-1-encoded p30II is a post-transcriptional negative regulator of viral replication. Nat Med 10:197-201

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