Novel Strategies for Targeting HIV-CNS Reservoirs without Reactivation
Jeymohan Joseph, Ph.D.
Division of AIDS Research
The goal of this initiative is to stimulate research to identify latently infected cells in the central nervous system (CNS) and developing strategies for viral silencing without pro-viral reactivation.
Eradication of HIV from the CNS has become a major goal for NeuroAIDS researchers. The strategy most widely investigated and favored for the total eradication of HIV/AIDS is first activating HIV pro-viral reservoirs and then establishing control of HIV-1 replication through the use of potent highly active anti-retroviral therapy (HAART) or enhanced immune surveillance: a ‘shock and kill’ approach. The cells with the ‘reawakened’ productive infection would be targeted and eliminated, while new infection of neighboring cells would be prevented by HAART.
The potential benefits of this shock-and-kill approach come at a cost, as there are potential risks of reactivation of virus in the brain: paradoxically increased brain infection, virally mediated CNS damage, and immune-related CNS damage. Increased spread of the virus in the CNS may ensue if infectious virus is released from latently infected cells in the absence of effective enhanced immune surveillance or an efficacious HAART regimen. Virally mediated damage may occur as a result of reactivation, where productive infection is inhibited by effective HAART but some viral products are still released (rather than whole, intact viral particles). One such example is the transcriptional transactivator HIV-1 Tat, which has been demonstrated to be neurotoxic. The presence of replication-defective virus is often dismissed in non-neurological tissue, but this dismissal may not be appropriate for the brain. Immune-related damage may occur if there is an increased burden of viral products, again as a result of reactivation. These components may not be directly neurotoxic but the immune response that they trigger may lead to brain damage. There is a precedent for this scenario, with the original active immunization trial against amyloid for Alzheimer’s disease; a sizeable number of patients developed immune-mediated encephalitis, leading to death in a significant number of the patients.
Given the risks associated with reactivation of HIV in the brain, other approaches are needed to target the latent virus in the CNS. One of the approaches could be to silence HIV-1 infected cells using RNA interference. However, delivery of these agents to tissues can be difficult and newer technologies – such as liposomal delivery vehicles and adeno-associated virus gene delivery – need to be developed to target brain reservoirs. Another approach could be to develop markers to identify CNS cells that harbor latent pro-virus and then target these cells for destruction. In addition, it may be necessary to develop a novel class of anti-HIV drugs that inhibit viral production from stable reservoirs and residual viremia during HAART. Finally, the use of novel gene-editing techniques may be useful to target latent virus in the CNS.
This initiative would encourage research in the following areas:
- Innovative strategies to selectively identify and eliminate latently infected CNS-derived cells (e.g., microglia, astrocytes) without reactivation of pro-virus;
- Novel approaches for viral silencing, including siRNA targeting of HIV-infected CNS derived cells;
- Development of unique classes of HIV drugs that inhibit viral production from stable reservoirs and reduce residual viral presence in the blood; and,
- Use of novel gene-editing technologies, such as RNA-directed gene editing and Cas9/guide RNA (gRNA), for targeting HIV pro-virus within cells of the CNS compartment.