PT  - JOURNAL ARTICLE
AU  - Thanh Tung Truong
AU  - Manuel Hayn
AU  - Camilla Kaas Frich
AU  - Lucy Kate Ladefoged
AU  - Morten T. Jarlstad Olesen
AU  - Josefine H. Jakobsen
AU  - Cherie K. Lunabjerg
AU  - Birgit Schiøtt
AU  - Jan Münch
AU  - Alexander N. Zelikin
TI  - Potentiation of drug toxicity through virus latency reversal promotes preferential elimination of HIV infected cells
AID  - 10.1101/2022.01.12.476003
DP  - 2022 Jan 01
TA  - bioRxiv
PG  - 2022.01.12.476003
4099  - http://biorxiv.org/content/early/2022/01/12/2022.01.12.476003.short
4100  - http://biorxiv.org/content/early/2022/01/12/2022.01.12.476003.full
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.