Bharadwaj Vemparala

Virus suppressive capacity of the early CD8 T cell response is predictive of natural control of SIV infection

Efforts to design therapies that elicit long-term remission of HIV are motivated by studies on natural controllers, a small set of individuals who spontaneously control the infection. Although a superior CD8 T cell response has been implicated in natural control, the underlying mechanisms are yet to be determined. In this study, we developed a mathematical model of virus dynamics that explicitly accounted for CD8 T cell dynamics and their cytotoxic effect on infected cells. We applied it to analyze virus dynamics in 16 SIV-infected macaques and elucidate the role of CD8 T cells in natural control. The model, for the first time, enabled simultaneous analysis of the canonical in vivo measurements like viremia and plasma SIV DNA together with a longitudinal quantitative marker of CD8 T cell responses, namely their viral suppressive capacity obtained by ex vivo measurements. Our model fit the data well and estimated that the recruitment rate and/or maximal killing rate of CD8 T cells was up to 2-fold higher in controllers than non-controllers (p=0.013). Importantly, the cumulative suppressive capacity of CD8 T-cells over the first 4-6 weeks of infection was associated with set-point viremia (Spearman’s rho=-0.51; p=0.05). Thus, our analysis identified the early cumulative suppressive capacity of CD8 T cells as a predictor of natural control. Furthermore, our model quantified the minimum capacity of this early CD8 T cell response necessary for long-term control. Our study presents new, quantitative insights into the role of CD8 T cells in the natural control of HIV infection. This framework can be extended to evaluating the role of CD8 T cell responses in post-treatment control.