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Eradication of HIV-1 from Central Nervous System Reservoirs

NAMHC Concept Clearance

Presenter:

Jeymohan Joseph, Ph.D.
Division of AIDS Research

Goal:

The goal of this initiative is to study mechanisms of HIV-1 persistence and eradication strategies specifically focused on the central nervous system in the context of viral suppression.

Rationale:

Antiretroviral therapy (ART) can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in HIV-1-infected individuals, but it fails to eliminate the virus due to the presence of latent reservoirs. There is now a major push in the field of HIV research to target latent reservoirs to achieve sustained virologic remission. The question of whether the brain is a reservoir for replication competent HIV is currently an area of great interest. The long-lived cells in the central nervous system (CNS), including astrocytes, perivascular macrophages and microglia, have been shown to support both HIV infection and variable levels of replication. There is also evidence of compartmentalized viral evolution in the brain, suggesting that independent HIV replication can occur in the CNS and these variants can potentially reseed the periphery. Therefore, it is critical to study the role of CNS resident cells as potential cellular viral reservoirs, and how persistently infected cells in the CNS tend to persist despite ART. The molecular mechanisms involved in the establishment, maintenance, and resurgence of CNS-based HIV reservoirs in relationship to the effects and timing of ART represents a major gap in the field.

There is also a critical need for rapid development of innovative therapeutic interventions to eradicate HIV-1 from the brain. In addition to the ongoing HIV eradication efforts targeting the periphery, research is needed to specifically target viral reservoirs in the CNS sanctuary because of unique anatomic features in the brain, such as the blood-brain barrier and enclosure within the restricted skull cavity. One of the key challenges for eradication of HIV reservoirs is the development of strategies and approaches that can penetrate the blood-brain barrier. The currently popular strategies for HIV eradication in the periphery such as immunotherapy may also exhibit detrimental effects in the CNS due to neuronal toxicity and inflammatory sequelae. Therefore, there is a need for discovery research focused solely on expanding our knowledge base of CNS HIV-1 latency and eradication strategies tailored directly for the brain compartment. These may include approaches to target latent CNS infection using novel approaches like gene editing, viral silencing and broadly neutralizing antibodies.

To address the above research gaps, this initiative encourages applications in the following areas:

  • Basic and clinical studies to identify all potential cellular reservoirs of latent HIV within the CNS;
  • Discover the molecular mechanisms involved in establishment, maintenance, and resurgence of CNS-based HIV reservoirs in relationship to the effects and timing of ART;
  • Elucidate how persistently infected CNS cells escape the immune response and persist despite ART;
  • Develop physiologically relevant CNS-cell based assays that recapitulate HIV persistence in the presence of effective antiretroviral therapy, latency, and viral resurgence upon removal of ART;
  • Develop innovative strategies to selectively identify and eliminate latently infected CNS-derived cells;
  • Refine neuroimaging or microscopic tools to detect latent/persistent and reactivated CNS virus;
  • Assess current HIV eradication strategies for CNS toxicity, neuroinflammation, and neurocognitive outcomes;
  • Refine and adapt immunotherapy-based therapeutic strategies to target CNS reservoirs using approaches such as CAR-T-cells, NK cells, check point inhibitors, therapeutic vaccines and broadly neutralizing antibodies;
  • Develop novel eradication strategies with improved penetration through the blood-brain barrier to target and eliminate latent CNS reservoir;
  • Develop innovative strategies including gene editing based approaches, to selectively identify and eliminate virus and the latently infected cells without reactivation of provirus.