Fig 9. Different immune interventions may be required depending on timing of ART initiation and the duration of treatment.

One approach to long-term, ART-free control of HIV is to boost immune responsiveness to infection during ART. However, different therapeutic interventions may be effective depending on the timing of ART initiation. For example, for animals treated at an early stage of infection (red shaded area), increased priming of the response or measures to boost immunity may be effective. However, for animals treated later in infection (green shaded area), it may be necessary to reverse immune exhaustion to improve post-rebound setpoint viral levels. The mechanisms that lead to increase of post-rebound setpoint after a prolonged treatment (blue shaded area) are unclear and can be explained by either declining levels of immune memory or prolonged exposure to low levels of viral antigen that drives immune exhaustion. Thus, the interventions for boosting immune control may differ, depending on the underlying mechanisms. The surface depicted here is the best-fit of Eq (3) to the data used in this study. See Fig G in S1 Text for overlay of data points on this best-fit curve.