Project Details
Description
Project Summary/Abstract
The human retroviruses – i.e., human immunodeficiency virus type 1 (HIV-1) and human T-cell leukemia virus
type 1 (HTLV-1) – infect over 37 million and 15 million people worldwide, respectively. HIV-1 causes acquired
immunodeficiency syndrome (AIDS) and HTLV-1 infection causes fatal and debilitating diseases such as adult
T cell leukemia/lymphoma (ATLL) and a variety of chronic inflammatory syndromes, most notably HTLV-1
associated myelopathy/tropical spastic paraparesis (HAM/TSP). Differences in the basic mechanisms of HIV-1
and HTLV-1 replication can provide important insights into the molecular basis for viral pathogenicity and virus
spread. For instance, HIV-1 can more efficiently spread and infect cells by cell-free infection, while HTLV-1
spread is strongly reliant upon cell-to-cell transmission as a means for virus spread. Virus eradication of
lymphoid tissue has emphasized the importance of HIV-1 cell-to-cell transmission in HIV spread, which
emphasizes the importance of parallel analyses with HTLV-1. An important open question in the field is the
nature of retrovirus assembly in the context of cell-to-cell infection. This application proposes a comparative
investigation of the mechanism of Gag and genomic RNA (gRNA) translocation to the plasma membrane in the
context of non-polarized and polarized cells, which are implicated in cell-free and cell-to-cell virus spread,
respectively. Gag translocation will be explored by examining Gag punctum biogenesis and mobility and by
characterizing the dynamics of non-punctate Gag. Non-punctate Gag dynamics and Gag punctum biogenesis
will be observed using total internal reflection fluorescence (TIRF) and super-resolution microscopy of Gag
labeled with a photoconvertible fluorophore. Super-resolution microscopy will be used to investigate the
dynamics of HIV-1 and HTLV-1 gRNA translocation to the plasma membrane in the absence and presence of
wtGag or selected Gag mutants. Whether the translocation of gRNA to the VS occurs by directed movement in
polarized cells will be determined, and whether Gag expression or Gag-gRNA interactions are required. The
form of gRNA that is transported (i.e., monomer or dimer) will also be investigated. These studies will provide a
deeper understanding of virus assembly in polarized cells, and provide new insights into the mechanisms of
virus assembly at cell-cell contacts.
Status | Finished |
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Effective start/end date | 9/30/19 → 9/29/23 |
Funding
- National Institute of Allergy and Infectious Diseases: $32,385.00
- National Institute of Allergy and Infectious Diseases: $30,649.00
- National Institute of Allergy and Infectious Diseases: $31,669.00
- National Institute of Allergy and Infectious Diseases: $31,153.00
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