The human immunodeficiency virus (HIV) is a retrovirus that progressively attacks the human immune system. The virus carries its own viral protein for its replication, Tat. Tat serves as a mediator, bringing host elongation protein P-TEFb onto the viral trans-activation response element (TAR) RNA for active transcription. Tat grabs onto the protein with one hand and the RNA with the other hand, so to speak. Thus, the two sides have long been the drug targets for removing Tat from the complex in order to inhibit HIV transcription. Two inhibitors were previously developed to attack these two sides of Tat, F07#13 and JB181 respectively. Here we probe the potential synergy of these inhibitors in removing Tat by pulling on RNA artificially via steered molecular dynamics simulations.

Against the backdrop of viruses representing the devastating HIV epidemic, the cover image for the December 7 issue of Biophysical Journal reveals to which part of the complex, P-TEFb in yellow and green or TAR RNA in blue, Tat (red) remains attached when in the presence of F07#13 (left bubble) or JB181 (right bubble), when TAR RNA is pulled away. Tat retains its residual attachment by adopting different and dynamic conformations in the presence of only one of the inhibitors, shown at the top and bottom corners. The simulations indicate a far more complete removal of Tat from the complex and thus, a more efficient disintegration of the complex.

The accelerated sampling techniques used in this study allow enhanced sample efficiency for elucidating molecular details in the complex disassociation that are otherwise difficult to obtain. Therefore, our computational work can aid new experimental approaches to exploit the synergetic effect of combined inhibitors in removing Tat from both sides, possibly creating more efficient Tat degradation, which can set HIV-infected cells into deep latency.

—Shangbo Ning, Chengwei Zeng, Chen Zeng, and Yunjie Zhao