Revealing the molecular mechanisms of the early and late stages of the HIV-1 infection cycle through the computational microscope.

Juan Perilla, University of Delaware

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Juan Perilla, Jodi Hadden, Chaoyi Xu, Jennifer Zuczek, Alexander Bryer, John Melkumov, Tyler Reddy, Marcus Jordan, Richard Bernard III, Deanna Greco, Chad Cronce, Dipak Sanap, Sruthi Murlidaran

In the present proposal we seek to elucidate mechanistic details relevant to the early and late stages of the human immunodeficiency virus type 1 (HIV-1) infection cycle. In particular, we seek to determine the interactions between human cellular factors and the HIV-1 capsid, as well as the elucidation of the physical and chemical properties of the lipid envelope that surrounds the virus during the late stages of infection. Human interferon-induced myxovirus resistance 2 (Mx2/MxB) is a potent inhibitor of HIV-1 infection and a potential agent for the treatment of HIV/AIDS. MxB interacts directly with the HIV-1 capsid and blocks nuclear import of pre-integration complexes and subsequent chromosomal integration of the viral cDNA. In the proposed work, we will determine the dynamic interactions between the human interferon-induced myxovirus resistance 2 (Mx2/MxB) protein and the HIV-1 capsid protein. The insights provided by the proposed work will shed light on numerous long-standing questions regarding the binding specificity and antiviral activity of MxB. In addition, the model of an authentic HIV-1 lipidome will pave the way to the construction of a realistic HIV-1 virion which will provide a unique platform to study a plethora of biological process which occur inside of the HIV-1 virion. Importantly, due to the multiple-scales inherent to the HIV-1 infection processes, the proposed work requires the unique capabilities of a petascale supercomputer like Blue Waters.