Abstract

Human T-cell leukemia virus (HTLV-1) infects about 20 million individuals worldwide and is the etiological agent of an adult T-cell leukemia/lymphoma (ATLL), and can also result in an inflammatory disease syndrome called HTLV-1-associated myelopathy (HAM)/tropical spastic paraparesis (TSP). Prevalence rates for HTLV-1 infection in the general population are greater than 1% in the Caribbean Basin, Central Africa, and South Japan. HTLV-1 is notorious for being difficult to study in cell culture, which ha prohibited a rigorous analysis of how these viruses replicate in cells, including the steps involved in retrovirus assembly. The details for how retrovirus particle assembly occurs are poorly understood even for other more tractable retroviral systems. Using a tractable model system, state-of-the-art biophysical approaches, and an interdisciplinary research team, we have made novel observations that form the basis for this proposal. In this application, we propose to investigate questions related to HTLV-1 particle size, Gag stoichiometry in particles, and HTLV-1 Gag interactions in living cells using multiple experimental approaches. In particular, we will apply cryo-electron microscopy/tomography (cryo-EM/ET), total internal reflection fluorescence (TIRF) microscopy, and the novel single-molecule technology of fluorescence fluctuation spectroscopy (FFS) to investigate questions related to 1) particle size and Gag stoichiometry, 2) Gag targeting to membrane, and, 3) HTLV-1 particle biogenesis. The results from these proposed studies should provide further insight into fundamental aspects of HTLV-1 and retrovirus particle assembly, which may aid in developing therapeutics.

Public Health Relevance

Human T-cell leukemia virus type 1 (HTLV-1) is a cancer-causing human retrovirus that infects about 20 million individuals worldwide, with prevalence rates greater than 1% in certain regions. Fundamental studies of HTLV-1 assembly will lead to detailed information about these processes that will be useful for a better understanding of how these viruses replicate in cells. Such information may inform new therapeutic strategies.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM098550-04
Application #
8848386
Study Section
Virology - A Study Section (VIRA)
Program Officer
Sakalian, Michael
Project Start
2012-09-28
Project End
2016-05-31
Budget Start
2015-06-01
Budget End
2016-05-31
Support Year
4
Fiscal Year
2015
Total Cost
$282,647
Indirect Cost
$92,647

  Institution

Name
University of Minnesota Twin Cities
Department
Dentistry
Type
Schools of Dentistry
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455

  Publications

Zhang, Wei; Mendonça, Luiza; Mansky, Louis L (2018) The Retrovirus Capsid Core. Subcell Biochem 88:169-187
Martin, Jessica L; Mendonça, Luiza M; Marusinec, Rachel et al. (2018) Critical Role of the Human T-Cell Leukemia Virus Type 1 Capsid N-Terminal Domain for Gag-Gag Interactions and Virus Particle Assembly. J Virol 92:
Eichorst, John P; Chen, Yan; Mueller, Joachim D et al. (2018) Distinct Pathway of Human T-Cell Leukemia Virus Type 1 Gag Punctum Biogenesis Provides New Insights into Enveloped Virus Assembly. MBio 9:
Wu, Weixin; Hatterschide, Joshua; Syu, Yu-Ci et al. (2018) Human T-cell leukemia virus type 1 Gag domains have distinct RNA-binding specificities with implications for RNA packaging and dimerization. J Biol Chem 293:16261-16276
Martin, Jessica L; Mendonça, Luiza M; Angert, Isaac et al. (2017) Disparate Contributions of Human Retrovirus Capsid Subdomains to Gag-Gag Oligomerization, Virus Morphology, and Particle Biogenesis. J Virol 91:
Maldonado, José O; Angert, Isaac; Cao, Sheng et al. (2017) Perturbation of Human T-Cell Leukemia Virus Type 1 Particle Morphology by Differential Gag Co-Packaging. Viruses 9:
Meissner, Morgan E; Mendonça, Luiza M; Zhang, Wei et al. (2017) Polymorphic Nature of Human T-Cell Leukemia Virus Type 1 Particle Cores as Revealed through Characterization of a Chronically Infected Cell Line. J Virol 91:
Maldonado, José O; Cao, Sheng; Zhang, Wei et al. (2016) Distinct Morphology of Human T-Cell Leukemia Virus Type 1-Like Particles. Viruses 8:
Martin, Jessica L; Cao, Sheng; Maldonado, Jose O et al. (2016) Distinct Particle Morphologies Revealed through Comparative Parallel Analyses of Retrovirus-Like Particles. J Virol 90:8074-84
Martin, Jessica L; Maldonado, José O; Mueller, Joachim D et al. (2016) Molecular Studies of HTLV-1 Replication: An Update. Viruses 8:

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