Speaker
Description
To date, the only instances of HIV ‘cure’ were the result of transplantation with stem cells containing mutated genes for the CCR5 coreceptor, a cell-surface protein required by most HIV strains to enter and infect a cell. Thus, researchers are pursuing different gene therapy methods to reduce CCR5 expression without the need for a stem cell transplant, but it is unclear what fraction of target cells must be gene edited to achieve HIV cure or prevent transmission. To answer this question, 73 mice underwent human stem cell transplantation with varying mixtures of CCR5 intact and knock-out stem cells. Animals were subsequently inoculated weekly with HIV, and the time-to-infection was monitored.
The observed risk of infection per inoculation decreased from 28% to 0% in animals receiving only intact CCR5 vs. only CCR5 knock-out stem cells. To mechanistically characterize the effect of CCR5 knock-out on infection risk, we developed a probabilistic model of the expected number of infected cells as a function of the fraction of CCR5 knock-out cells. We then predicted the impact of editing rate on human HIV infection by shifting the parameters of this model to values relevant to the human context. We estimated that to sufficiently suppress replication to prevent transmission would require an editing rate of 88%. This rate is beyond the capabilities of current technologies, although rates of up to 80% have been reported in gene therapy clinical trials for other diseases.
