| The RNA of human immunodeficiency virus type-1 (HIV-1) undergoes a series of alternative splicing and (post-) transcriptional regulation steps, producing complicated spatial and temporal patterns of its mRNAs and proteins. Despite many detailed mechanistic studies about the splicing and regulation processes over the last 20 years, debate continues over potential roles that these processes play. Some studies have suggested that HIV-1 has evolved these processes to achieve a balanced expression of each viral component and to optimize the production of progeny virions. However, these arguments have been largely based on speculation. Here, we begin to systematically 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 there exists a splicing efficiency that optimizes HIV-1 growth. We identified two key contributors to the splicing efficiency, the intrinsic splicing rate and the extent of Rev-mediated splicing inhibition, and we showed how these should be balanced in order for HIV-1 to optimize its growth. Moreover, we found that the expression of Rev and Tat should also be balanced for optimal growth. Further, we simulated how HIV-1 would respond to many potentially detrimental variations in essential viral and cellular functions, and found that HIV-1 buffers the effects of these variations. This robust HIV-1 growth can be credited, at least in part, to its intrinsic regulatory structure: the coupling of a Rev-mediated negative feedback and a Tat-mediated positive feedback. Finally, we showed how targeting therapeutics against molecular components of the viral positive-feedback loop open new possibilities and potential in the effective treatment of HIV-1. 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. |
