(360bd) CCR5-Eriously? Reexamining HIV-1 Tropism Switching with In Silico directed Evolution

The human immunodeficiency virus type 1 (HIV-1) hijacks the CD4 receptor on a plethora of immune cells to enable viral fusion and cellular entry. HIV-1’s envelope glycoprotein, Env, is comprised of the gp120 and gp41 subunits. Gp120 serves as the agonist for immune cell receptors and makes use of CD4, as well as one of two chemokine receptors, namely CCR5 or CXCR4. Which chemokine receptor gp120 utilizes defines a specific strain’s tropism: R5-tropic (able to utilize CCR5), X4-tropic (able to utilize CXCR4), or R5X4-tropic (able to utilize either receptor). Transmitted/founder (T/F) strains of HIV-1—strains which can seed new infections—are overwhelmingly, if not all, R5-tropic. In late-stage HIV-1 patients, tropism switching has been observed. This phenotypic change is associated with the fast depletion of CD4+ T Cells and the rapid onset of acquired immunodeficiency syndrome (AIDS). Herein we describe the development of a computational pipeline for exploring the evolutionary dynamics that drive HIV-1 tropism switching during disease progression. Specifically, we combine an in silico directed evolution model adapted from a previously published model of antibody evolution in response to HIV-1 vaccination, with established machine learning algorithms and physics-based simulations. We validate our results against existing experimental datasets relating HIV-1 sequence and tropism. Ultimately, our results provide new fundamental insights into viral/immune cell receptor interactions that drive HIV-1 pathogenesis and disease progression, which may enable the design of novel strategies for harnessing the immune system to combat HIV-1 infection.