(342ag) Molecular Dynamics Simulations of the Inhibition of HIV and Host Cell Machinery By Antiretroviral Drugs

It is estimated that around 1.2 million people in the U.S. are living with HIV today, for which there is no known cure¹. A large fraction of the ageing HIV population is currently experiencing some loss of neurocognitive function, a hallmark symptom of HIV-Associated Neurocognitive Disorder, or HAND, due to the virus’ attack on the central nervous system². Antiretroviral (ARV) drugs are commonly used to treat the non-neurological symptoms of HIV infection, but an accumulating body of evidence points to the ability of many types of ARVs to promote or even mediate neurocognitive decline in the patients that take them. For example, protease inhibitors (PIs) are one of the most widely prescribed types of ARVs, which act to inhibit the protease of HIV, thus preventing the virus from fully maturing to be able to multiply and infect other cells³. However, numerous experimental studies have now shown that PIs also inadvertently inhibit the proteasome in multiple human cell types, including neurons, causing activation of a stress response pathway called the unfolded protein response (UPR) and ultimately leading to cell death⁴. Yet, the precise molecular details of how PIs inhibit the proteasome and how this mechanism may differ from that employed by PIs to inhibit HIV protease remain unclear.

To this end, we performed molecular dynamics (MD) simulations to investigate the inhibitory interactions between a wide range of PIs and both the protease of HIV and the human 20S proteasome. Molecular docking simulations were first employed to identify initial binding locations and conformations of each PI on the two proteins, followed by MD and subsequent binding free energy calculations using the molecular mechanics Poisson-Boltzmann surface area (MM-PBSA) method. We observe consistent differences in the calculated binding free energies and molecular-level interactions that govern PI-protease versus PI-proteasome binding, across the many PIs studied. Our results suggest that exploiting these differences during the immunotherapeutic design process may be a promising pathway towards the development of new PIs that still robustly inhibit HIV machinery while leaving host machinery intact.

1. Centers for Disease Control and Prevention. HIV Surveillance Report, 2018 (Updated); vol. 31 (2020).
2. Clifford, D. B.; Ances, B. M. HIV-Associated Neurocognitive Disorder. Lancet Infect. Dis.2013, 13 (11), 976–986.
3. Gulnik, S.; Erickson, J. W.; Xie, D. HIV Protease: Enzyme Function and Drug Resistance. In Vitamins & Hormones; Elsevier: San Diego, CA, 2000; Vol. 58, pp 213–256.
4. Pajonk, F.; Himmelsbach, J.; Riess, K.; Sommer, A.; McBride, W. H. The Human Immunodeficiency Virus (HIV)-1 Protease Inhibitor Saquinavir Inhibits Proteasome Function and Causes Apoptosis and Radiosensitization in Non-HIV-Associated Human Cancer Cells. Cancer Res.2002, 62 (18), 5230–5235.