Fusion inhibitors, a new class of antiretroviral drugs, prevent new infections of cells by HIV by blocking the fusion of viral and cell membranes and denying access of the cellular replication machinery to HIV. In clinical trials, enfuvirtide, the first fusion inhibitor approved for the treatment of HIV infection, has induced a decline in plamsa HIV-1 RNA levels in highly treatment-experienced patients, raising new hopes of improved HIV treatment. Rational strategies to exploit fusion inhibitor action, however, are precluded by the poor understanding of the mechanism of HIV fusion with target cells. Here, we propose to develop a mechanistic theory of HIV fusion with target cells and a model of HIV dynamics under fusion inhibitor therapy. A reaction kinetic approach will be developed to describe protein binding across virion and target cell surfaces that leads to the formation of fusogenic protein complexes. Membrane shape evolution driven in part by fusogenic protein complexes will be described using theories from interface science, which determine interbilayer interactions, and statistical mechanics, which quantify density fluctuations, to predict the time required for the formation of a fusion pore. Comparisons of model predictions with experiments will provide a detailed understanding of fusion kinetics. Knowledge of the lifetimes of various structural intermediates will serve to identify novel drug and antibody targets and estimate fusion inhibitor efficacy. Standard models of HIV dynamics will be adapted to incorporate fusion inhibitor action and, in combination with descriptions of fusion inhibitor pharmacokinetics, to predict viral load evolution in patients undergoing fusion inhibitor therapy. The model will build a framework for analysis of patient data, provide insights into HIV pathogenesis in vivo, and establish guidelines for the optimization of fusion inhibitor-based therapy. The new strategies to combat HIV infection to be explored here are of particular importance to developing countries where affordable alternatives to current therapies are crucial in controlling HIV-related morbidity and mortality. ? ?
