Mechanism of Human LysRS/tRNALys Primer Recruitment and Packaging Into HIV-1

Ohio State University, Columbus OH

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Abstract

? DESCRIPTION (provided by applicant): While many aspects of the complex viral lifecycle of Human Immunodeficiency Virus Type-I (HIV-1), including host factor interactions are understood, many assembly mechanisms remain poorly characterized. The primer for reverse transcription in HIV-1, human tRNALys3, is selectively packaged into virions along with tRNALys1,2. Human lysyl-tRNA synthetase (LysRS), the only cellular factor known to interact specifically with all three tRNALys isoacceptors, is also packaged into HIV-1. Selective packaging of tRNALys depends on the ability of the tRNA to bind to LysRS and their combined presence is required for optimal viral infectivity. LysRS is normally part of a dynamic mammalian multisynthetase complex (MSC). In recent years, LysRS has been shown to be mobilized from the MSC and to function in a wide variety of non-translational pathways. Elucidating the detailed molecular mechanism for the alternative function of LysRS in HIV-1 infectivity is needed in order to develop effective therapeutics aimed at targeting the recruitment of this essential host cell factor. The concentration of free tRNA is tightly regulated within the cell and under normal conditions tRNAs are bound to components of the translational machinery, including LysRS. While some aspects of tRNA primer packaging into HIV-1 particles are now understood, the mechanism by which the LysRS:tRNA complex is diverted from its normal function in translation and recruited into particles through interaction with Gag is unclear. The aims addressed in this proposal proposal are: 1) To elucidate the effect of HIV-1 infection on localization of human LysRS, 2) To determine the location of vRNA, Gag and host LysRS/tRNAlys3 interactions.