Adapting Immunotherapy Strategies for Targeting HIV Reservoirs in the CNS: Potential Benefits and Risks

Presenter:

Jeymohan Joseph, Ph.D.
Division of AIDS Research

Goal:

The goal of this initiative is to adapt immunotherapy-based strategies to target viral reservoirs in the central nervous system (CNS) and to examine the potential risks of applying such technologies to the CNS.

Rationale:

Eradication of latent reservoirs of HIV-1 within the body and achieving a sterilizing or functional cure is a high priority for the NIH Office of AIDS Research. Anti-retroviral therapy (ART) can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in HIV-1-infected individuals but does not 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 “shock and kill” strategy is one of the commonly used approaches for targeting latent reservoirs in hopes to cure HIV-1. It is based on the concept of purposely inducing reactivation of latent reservoirs in cART (combination antiretroviral therapy)-treated individuals by using stimulatory agents. However, it has become increasingly evident that attempts at elimination of HIV-1 reservoirs through latency reactivating agents (LRA) -mediated reactivation alone may not be sufficient. One novel strategy is the development of immunotherapy to optimize the recognition and killing of reservoir cells such as resting CD4 T-cells. These  immunotherapy strategies include uses of therapeutic vaccines to enhance HIV-1-specific CTL (cytotoxic T-cell) response, broadly neutralizing antibodies, dual-affinity retargeting antibodies that not only bind to HIV-1 viral envelope antigen but also activate the CTL response, and immune modulators, such as anti-PD1 (programmed cell death protein-1) or anti-CTL4 antibodies, to relieve the immune dysfunction and exhaustion found in cART-treated individuals due to chronic inflammation. Another strategy is the development of chimeric antigen receptor T-cells (CAR-T cells) to target latently infected cells.

Extensive research efforts involving immunotherapy aim to achieve remission of HIV from cellular and anatomic reservoirs. Current immunotherapy-based HIV eradication strategies are focused on the periphery and it is important to target CNS reservoirs as well. The brain presents a unique challenge where access is difficult and innovative strategies are needed to overcome the blood brain barrier. It is also important to understand the potential CNS toxicity of immunotherapy-based approaches currently being tested in clinical trials. This initiative would encourage research on adapting immunotherapy strategies to target CNS reservoirs. The scope of research includes but is not limited to the following.

• Refine and adapt immunotherapy-based approaches to target myeloid and CNS reservoirs using in vitro and in vivo models. These approaches include:
  • CAR-T-cells;
  • NK (Natural Killer Cells) cells;
  • check point inhibitors;
  • therapeutic vaccines; and,
  • eCD4-Ig (enhanced CD-4-immunoglobulin) variants.
• Develop broadly neutralizing antibodies and bi/tri-specific dual affinity re-targeting (DART) molecules that can cross the blood brain barrier and eliminate the CNS viral reservoirs.
• Examine the potential risk of CNS toxicity of immunotherapy targeting the reservoirs both in the periphery as well as CNS.