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HIV-1 has developed novel strategies to overcome or degrade multiple host restriction factors (APOBEC3G, UNG2, BST2 etc) which ensures its unhindered growth. HIV-1 accessory proteins (Nef, Vpu, Vif, Vpr) have profound effects on HIV-1 pathogenesis. While Nef degrades p53, Vpu stabilizes p53 in a B-TrCP dependent manner. This stabilization correlates with the extent of apoptosis in human T-cells. Natural Vpu variants were genetically and functionally characterized and a natural B-TrCP mutant was described that was functionally compromised in Indian patient. Thus p53 levels are down in the early stages but high during the late stage of virus replication – a situation favourable for the virus. We recently reported that Vpr is a global inhibitor of host cell ubiquitination and that it redirects the ubiquitination machinery for selectively destroying HIV-1 host-restriction factors. The role of P53-sensitive miRNA, 34a, its target PNUTS, was investigated in detail during HIV-1 infection. Recently, several viral mechanisms for escaping antiviral RNAi has been discovered which includes suppression of RNAi, mutational escape from RNAi and modulation of the cell’s microRNA (miRNA) profile. Similar to plant and insect viruses, several mammalian viruses encoding RNAi silencing suppressors (RSS) have been described. We have explored in detail whether HIV-1 infection-specific outcomes could be influenced by RNAi-mediated effects. Arginine Rich Motif (ARM) of HIV-1 Tat and Rev are extensively studied linear motifs (LMs) that are essential for HIV-1 gene expression. Our work explores the role of HIV-1 ARM as a uniquely evolved viral motif to combat Dicer-dependent RNAi. We report that Rev is endowed with powerful RNAi-suppressor function. We also observed that NS4B of Dengue virus is a powerful RNAi-suppressor and in this case also ARM motif is sufficient to confer that property. Our model argues that HIV-1 suppresses the processing of siRNAs through inhibition of Dicer while at the same time manipulates the RNAi machinery to process miRNA involved in HIV-1 replication from Dicer independent pathways. HIV-1 thus can reshape host cell microRNA profile to its own advantage. The mechanistic elucidation of HIV-host microRNA interplay will help in further understanding of host pathogen interactions and might help in developing novel biomarkers and therapeutics. |