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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Virology - A Study Section (VIRA)
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Sakalian, Michael
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University of Minnesota Twin Cities
Schools of Dentistry
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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:
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; 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:
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:
Zhang, Wei; Cao, Sheng; Martin, Jessica L et al. (2015) Morphology and ultrastructure of retrovirus particles. AIMS Biophys 2:343-369
Cao, Sheng; Maldonado, José O; Grigsby, Iwen F et al. (2015) Analysis of human T-cell leukemia virus type 1 particles by using cryo-electron tomography. J Virol 89:2430-5
Smith, Elizabeth M; Hennen, Jared; Chen, Yan et al. (2015) Z-scan fluorescence profile deconvolution of cytosolic and membrane-associated protein populations. Anal Biochem 480:11-20
Smith, Elizabeth M; Hennen, Jared; Chen, Yan et al. (2015) In situ quantification of protein binding to the plasma membrane. Biophys J 108:2648-57

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