Speaker
Description
Persistence of HIV in people living with HIV (PWH) on suppressive antiretroviral therapy (ART) has been linked to physiological mechanisms of CD4+ T cells. We summarize this concept with the “passenger hypothesis”, that most persistence of the HIV reservoir during ART is due to cellular vs viral mechanisms. In order to determine which mechanisms are most important for persistence, and thus ideal targets for rational curative interventions, we studied HIV DNA dynamics in PWH and combined data that quantified CD4 cell kinetics. We developed a parsimonious mechanistic model that could explain longitudinal HIV DNA data derived from 37 PWH on long-term ART in 5 CD4 subsets: naïve (TN), stem-cell- (TSCM), central- (TCM), transitional- (TTM), and effector-memory (TEM). We integrated deuterium labeling data from these participants to estimate both the proliferation rates and differentiation rates of each subset. We could therefore estimate the mechanistic contributions to HIV persistence, finding that cellular proliferation was the dominant mechanism, but that differentiation, particularly outward from TCM , could be a meaningful factor in HIV persistence. Accordingly, we show via simulation that antiproliferative therapy blocking T cell proliferation and/or a therapy that enhances T cell differentiation could reduce HIV DNA by 1-2 logs over 3 years. Recently published clinical data from patients taking dasatinib support this proposal. We will show results from a new model that demonstrate antiproliferative therapy could be particularly powerful during acute HIV infection to avoid HIV reservoir creation, and how deuterium labeling studies could be performed ideally to estimate proliferative reductions.
| Expedited Notification | No thanks, I do not require Expedited Notification |
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