Table 1.

Key knowledge gaps for understanding CNS reservoirs guiding current and future investigations

What are the cellular characteristics of the CNS reservoirs and how do they differ within the CNS (especially CSF vs brain tissue)?

What are the molecular mechanisms contributing to persistence of HIV reservoirs and resistance to intrinsic and extrinsic cytolytic stimuli? How do these mechanisms differ between cell types (e.g., microglia vs T-cells) and immunologic microenvironments?

Do CNS reservoirs in humans have replication-competent provirus capable of rebound and systemic spread (proven in non-human primates but not yet in humans)?

How can cure therapies target CNS reservoirs? Should the intervention target only replication-competent provirus or all HIV transcription and translation in order to protect the CNS from neurotoxic viral proteins?

What are the direct and indirect effects of cure interventions on CNS reservoirs, CNS inflammation, microglial activation, inflammasome upregulation, neuronal injury, neurocognitive function, and mental health?

What is the effect of long-term suppressive ART on all of the above?