Human mmunodeficiency virus type 1 (HIV-1) causes the acquired immunodeficiency syndrome (AIDS). The lack of an HIV-1 vaccine, multi-drug resistance and complications from (and cost of) treatment emphasize a continuing need to identify new virus-host interfaces with the potential for targeting with antiviral strategies. We recently identified a species-specific attribute of the cellular CRM1 nuclear export receptor that suppresses the nucleocytoplasmic transport of HIV-1's intron-containing mRNAs (including gRNAs) in murine cells. CRM1 is remarkably well conserved among vertebrates and regulates the nuclear export of a broad range of cellular and viral proteins encoding hydrophobic peptides known as nuclear export signals (NESs). The HIV-1 Rev protein encodes a leucine-rich NES and recruits CRM1 to viral mRNAs that encode the cis- acting Rev response element (RRE) in order to facilitate their nuclear export. That CRM1's activities are species limited in the context of Rev leads to important questions regarding CRM1's protein evolution and cell- specific modes of action. First, what is human CRM1 (hCRM1) doing that murine CRM1 (mCRM1) is not? We have mapped the hCRM1 species-specific determinant that regulates Rev activity.
In Aim 1 we will study the role of this determinant in Rev/gRNA complex formation and determine if the mCRM1 block to HIV-1 Rev function can be made manifest in human cells. Second, why is HIV-1 Rev adapted to preferentially exploit hCRM1? In Aim 2, we will characterize newly identified HIV-1 Rev and gRNA mutants that rescue virion production in murine cells in the absence of hCRM1, and test if hCRM1 or these viral mutants can provide for active HIV-1 replication in murine cell culture. Finally, in Aim 3 we will establish a systems- based live cell imaging strategy to study how perturbations affecting HIV-1 gRNA nuclear export can influence the downstream stages of gRNA trafficking, Gag translation, gRNA packaging and efficient virus particle assembly.
Human immunodeficiency virus type 1 (HIV-1) infects more than 34 million people worldwide and causes ~2 million deaths each year. Treatments that perturb the late, productive stages of HIV-1 infection are lacking in large part due a lack of knowledge regarding the cellular factors and pathways that regulate these phases. In this application we propose to exploit murine-specific blocks that profoundly suppress HIV-1 mRNA nucleocytoplasmic transport, the translation of structural proteins and the efficiency of virus particle assembly to gain new insight into the regulation of HIV-1's post- transcriptional phases in human cells. These studies have relevance to the identification of new antiviral targets, better understanding of cell- and species-specific blocks to infection and the development of new cellular imaging strategies for studying HIV-1 infection.
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