Noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging

Noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging

Bibliographic Details
Main Author: Duchon, Alice
Language:English
Published: The Ohio State University / OhioLINK 2017
Subjects:
Biochemistry
Virology
cellular translational machinery
human immunodeficiency virus
Online Access:http://rave.ohiolink.edu/etdc/view?acc_num=osu1500551765261649
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spelling ndltd-OhioLink-oai-etd.ohiolink.edu-osu15005517652616492021-08-03T07:03:35Z Noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging Duchon, Alice Biochemistry Virology cellular translational machinery human immunodeficiency virus The hallmark of a retrovirus is the necessity to reverse transcribe the single-stranded genomic RNA (gRNA) into a double-stranded DNA that is incorporated into the host cell genome. After integration, host transcription and translation machinery produces viral RNA and proteins, including one main component of the viral lifecycle, Gag. The HIV-1 Gag polyprotein, is composed of 3 primary domains: matrix (MA), capsid (CA), and nucleocapsid (NC), which play critical roles in almost every aspect of the retroviral lifecycle, including reverse transcription, selection of gRNA and assembly of new virions. HIV-1 MA targets assembly to the phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2)-enriched plasma membrane (PM) through residues in its highly basic region (HBR) and anchors multimers of Gag to the PM with a myristic acid moiety. CA is able to form protein-protein interactions that facilitate Gag assembly and form the capsid core of the virion. Finally, NC selects gRNA from the large cytoplasmic pool of host RNAs. Intriguingly, host tRNAs and host translational machinery have been found to regulate several aspects of the HIV-1 lifecycle examined here. Along with viral proteins and gRNA, several host factors are selectively packaged into HIV-1 virions. Human tRNALys3 acts as the primer for reverse transcription in HIV-1, during which the 3’ 18-nt are unwound and annealed to a complementary sequence in the 5’UTR of the genome known as the primer binding site (PBS). A stem-loop directly 3’ to the PBS mimics tRNALys and efficiently binds the aminoacyl-tRNA synthetase responsible for aminoacylating tRNALys isoacceptors, lysyl-tRNA synthetase (LysRS). LysRS is known to interact with and be packaged by HIV-1 Gag, facilitating the incorporation of tRNALys3 and correct placement of the tRNA onto the PBS. Under homeostatic conditions, LysRS is sequestered in a multi-aminoacyl-tRNA synthetase complex (MSC). Here, we show that HIV-1 infection results in a free pool of uncharged tRNALys-bound LysRS that can be incorporated into newly assembling virions. Recent studies show that HIV-1 MA binds almost exclusively to cellular tRNAs within the cytoplasm of infected cells. We have found that certain species of human tRNA are able to bind HIV-1 Gag and modulate the protein’s ability to discriminate between liposomes containing or lacking PI(4,5)P2. Additionally, the annealing of tRNALys3 to the gRNA has been proposed to cause a conformational switch within the 5’UTR favoring gRNA packaging over translation. In an ongoing microscopy study we are examining the cellular location of LysRS:tRNALys3 packaging initiation and the site of primer annealing. Identifying the areas of viral and host component interaction will contribute to our understanding of the mechanism of viral assembly. Taken together, the results of these studies will provide new information that can be used in the development of specific and effective therapeutics targeting these host cell factors. In conclusion, these studies provide evidence of noncanonical functions of human translational machinery that effect HIV-1 assembly and primer recruitment. 2017 English text The Ohio State University / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=osu1500551765261649 http://rave.ohiolink.edu/etdc/view?acc_num=osu1500551765261649 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws.
collection NDLTD
language English
sources NDLTD
topic Biochemistry
Virology
cellular translational machinery
human immunodeficiency virus
spellingShingle Biochemistry
Virology
cellular translational machinery
human immunodeficiency virus
Duchon, Alice
Noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging
author Duchon, Alice
author_facet Duchon, Alice
author_sort Duchon, Alice
title Noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging
title_short Noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging
title_full Noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging
title_fullStr Noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging
title_full_unstemmed Noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging
title_sort noncanonical function of cellular translational machinery in human immunodeficiency virus type-1 assembly and primer packaging
publisher The Ohio State University / OhioLINK
publishDate 2017
url http://rave.ohiolink.edu/etdc/view?acc_num=osu1500551765261649
work_keys_str_mv AT duchonalice noncanonicalfunctionofcellulartranslationalmachineryinhumanimmunodeficiencyvirustype1assemblyandprimerpackaging
_version_ 1719452800785580032

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