Potentiation of drug toxicity through virus latency reversal promotes preferential elimination of HIV infected cells

Truong, T.; Hayn, M.; Kaas Frich, C.; Ladefoged, L. K.; Jarlstad Olesen, M.; Jakobsen, J.; Lunaberg, C.; Schiott, B.; Muench, J.; Zelikin, A. N.

doi:10.1101/2022.01.12.476003

bioRxiv · 10.1101/2022.01.12.476003

Potentiation of drug toxicity through virus latency reversal promotes preferential elimination of HIV infected cells

Truong, T.·Hayn, M.·Kaas Frich, C.·Ladefoged, L. K.·Jarlstad Olesen, M.·Jakobsen, J.·Lunaberg, C.·Schiott, B.·Muench, J.·Zelikin, A. N.

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Abstract

Eliminating latently infected cells is a highly challenging, indispensable step towards the overall cure for HIV/AIDS. We recognized that the unique HIV protease cut site (Phe-Pro) can be reconstructed using a potent toxin, monomethyl auristatin F (MMAF), which features Phe at its C-terminus. We hypothesized that this presents opportunities to design prodrugs that are specifically activated by the HIV protease. To investigate this, a series of MMAF derivatives was synthesized and evaluated in cell culture using latently HIV-infected cells. Cytotoxicity of compounds was enhanced upon latency reversal by up to 11-fold. In a mixed cell population, nanomolar concentrations of the lead compound depleted predominantly the HIV-infected cells and in doing so markedly enriched the pool with the uninfected cells. Despite expectation, mechanism of action of the synthesized toxins was not as HIV protease-specific prodrugs, but likely through the synergy of toxicities between the toxin and the reactivated virus.

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Truong, T., Hayn, M., Kaas Frich, C., Ladefoged, L. K., Jarlstad Olesen, M., Jakobsen, J., Lunaberg, C., Schiott, B., Muench, J., Zelikin, A. N.. 2022-01-12. Potentiation of drug toxicity through virus latency reversal promotes preferential elimination of HIV infected cells. https://doi.org/10.1101/2022.01.12.476003

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