Download or read book The Effect of Host MRNA Decay Proteins on HIV-1 Genomic RNA Metabolism and Viral Gene Expression written by Shringar Rao and published by . This book was released on 2018 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "mRNA surveillance pathways are host quality control mechanisms that degrade aberrant mRNA to prevent the accumulation of potentially toxic truncated or misfolded proteins. Substrates for mRNA surveillance include transcripts that have pre-termination codons, long 3’ untranslated regions (UTRs), retained introns or upstream open reading frames. The human immunodeficiency virus type 1 (HIV-1) genomic RNA (vRNA) also contains long 3’ UTRs. However, not only is the vRNA able to evade mRNA surveillance, HIV-1 has also been demonstrated to recruit the mRNA decay proteins to promote vRNA stability and ensure viral gene expression. UPF1 is an integral protein of the nonsense-mediated mRNA decay pathway and Staufen1 is also involved in the post-transcriptional events of mRNA decay, mRNA trafficking and translation. In this work, we further elucidated the roles of these host mRNA decay proteins on the post-transcriptional regulation of HIV-1 vRNA metabolism. The ability of HIV-1 to form a stable viral reservoir is the major obstacle to an HIV-1 cure. In our studies investigating HIV-1 latency, we characterised the roles of mRNA decay proteins on the maintenance of viral latency in a latently-infected model T cell line using fluorescence in situ hybridisation - Flow Cytometry (FISH-flow). We observed that UPF1 enhances vRNA stability, thus promoting viral gene expression at a post-transcriptional level. We also demonstrated that two other proteins involved in nonsense-mediated mRNA decay, UPF2 and SMG6, are negative regulators of proviral reactivation and reduce viral gene expression in the same model T cell line. In primary HIV-1-infected CD4+ T cells, UPF1 also enhanced vRNA stability and viral gene expression. UPF2 and SMG6 were also found to restrict HIV-1 gene expression in primary monocyte-derived macrophages, another viral reservoir of HIV-1 infection. In related studies investigating the host response to viral infection, we characterised a novel role for Staufen1 in the rescue of cellular mRNA translation and viral gene expression during HIV-1 nucleocapsid (NC)-induced stress granule assembly. Altogether, the host mRNA decay proteins UPF1, UPF2, SMG6 and Staufen1 affect various stages of vRNA metabolism and HIV-1 replication. These findings can be applied towards an HIV-1 cure using two strategies: the ‘kick and kill’ strategy to bolster the reactivation of the HIV-1 provirus and effectively decrease the size of the viral reservoir, or a ‘block and lock’ strategy to permanently silence the HIV-1 provirus"--