RT Journal Article
SR Electronic
T1 Potentiation of drug toxicity through virus latency reversal promotes preferential elimination of HIV infected cells
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2022.01.12.476003
DO 10.1101/2022.01.12.476003
A1 Thanh Tung Truong
A1 Manuel Hayn
A1 Camilla Kaas Frich
A1 Lucy Kate Ladefoged
A1 Morten T. Jarlstad Olesen
A1 Josefine H. Jakobsen
A1 Cherie K. Lunabjerg
A1 Birgit Schiøtt
A1 Jan Münch
A1 Alexander N. Zelikin
YR 2022
UL http://biorxiv.org/content/early/2022/01/12/2022.01.12.476003.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.