Description:

Speaker: Tin Phan (Los Alamos National Laboratories)
Title: Mathematical modeling reveals that latently infected cells reactivated by AZD5582 differ substantially from productively infected cells
Zoom Link: https://illinois.zoom.us/j/84907159401?pwd=JboBtq30vntVuEpj8s3yYfAdwlb258.1
Abstract: AZD5582 (AZD) is a promising latency reversing agent to enable the “shock-and-kill” strategy in HIV-1 cure research, due to its potent ability to reactivate latently infected cells while maintaining high specificity by targeting the non-canonical NF-κB pathway. Previous studies in rhesus macaques have demonstrated that AZD can promote the reactivation of latently infected cells, which can lead to a viral load increase of 2-3 logs. However, the resulting reduction of the latent reservoir is less robust. Quantitative analysis of this phenomenon is difficult due to limited and fluctuating low amplitude longitudinal viral load data. To overcome this obstacle, we developed an ensemble of mechanistic models and fit it to a data set obtained from 23 macaques treated with AZD in combination with other therapies. The model ensemble recapitulates the reactivation patterns observed in SIV RNA, the change in SIV CA-DNA, and provides robust estimates of key parameters related to the reactivated cells. We find that the reactivated cells produce fewer viruses, are less susceptible to viral cytotoxicity, and do not interact strongly with the immune response compared to productively infected cells. Reactivated cells likely enter a temporary state that is refractory to drug effects, prior to their return to latency. This refractory phase causes a diminishing return effect on the effectiveness of AZD. Thus, introducing a waiting time in between treatment periods to bypass this refractory phase may enhance the overall effect of AZD. Altogether, our results suggest the difference between AZD-reactivated cells and productively infected cells as the underlying mechanism responsible for the lack of reservoir reduction.