Effects of RNA splicing and post-transcriptional regulation on HIV-1 growth: a quantitative and integrated perspective

Abstract

Despite major advances over the last two decades in our understanding of RNA splicing and (post-) transcriptional regulation in human immunodeficiency virus type-1 (HIV-1), debate continues on the mechanisms and effects of Rev protein on HIV-1 growth. Moreover, arguments that HIV-1 has been optimised for growth have been largely based on speculation. Here, we begin systematically to address these issues by developing a detailed kinetic model for HIV-1 intracellular development. The model accounts for transcription, successive steps in RNA splicing, nuclear export of mRNAs, translation and shuttling of Rev and Tat, Tat-mediated transactivation of transcription, thresholds on Rev in its effects on nuclear export of mRNA, and inhibitory effects of Rev on splicing. Using the model, we found that inefficient splicing of HIV-1 mRNA was generally beneficial for HIV-1 growth, but that an excessive reduction in the splicing efficiency could be detrimental, suggesting that there exists a splicing efficiency that optimises HIV-1 growth. Further, we identified two key contributors to splicing efficiency, the intrinsic splicing rate and the extent of Rev-mediated splicing inhibition, and we showed how these should be balanced for HIV-1 to optimise its growth. Finally, we found that HIV-1 growth is relatively insensitive to different levels of the Rev export threshold, and we suggest that this mechanism evolved to delay viral growth, perhaps to enable evasion of host defensive responses. In summary, our model provides a quantitative and qualitative framework for probing how constituent mechanisms contribute to the complex, yet logical, process of HIV-1 growth.