The Highly Conserved Codon following the Slippery Sequence Supports -1 Frameshift Efficiency at the HIV-1 Frameshift Site

Mathew, Suneeth F.; Crowe-McAuliffe, Caillan; Graves, Ryan; Cardno, Tony S.; McKinney, Cushla; Poole, Elizabeth S.; Tate, Warren P.

By contrast to these clearly interpretable decoding experiments, the results from eRF1 knockdown by shRNAs were puzzling. First, levels of eRF1 were reduced with expected effects on readthrough at a test stop codon and +1 antizyme frameshifting with a specific shRNA targeting eRF1, but not with the control shRNA, as expected. However, translation of the HIV-1 frameshift element was affected differently from these other test systems. The control and test shRNAs both affected frameshifting with the native element (not containing a stop codon), and yet neither affected the element where GGG was substituted with UGA. We speculate that expression of shRNAs may have triggered the innate interferon response, activating the kinase PKR to decrease translation initiation efficiency by phosphorylation of eIF2α [56] [57] [58] . A slower translation rate increases frameshift efficiency in HIV-1 [28] . There is also evidence that the HIV-1 frameshift element is regulated by endogenous small RNAs [10] . Expressed shRNAs can compete with existing cellular small RNAs for the RNAi processing machinery [59] .