Mechanisms of Reciprocal Interactions between HIV Associated Neuroinflammation and Central Nervous System (CNS) Persistence: Implications in HIV Neuropathogenesis and Cure

Presenter:

Jeymohan Joseph, Ph.D.
Division of AIDS Research

Goal:

The goal of this concept is to encourage research using novel CNS cell systems, organoid models, and single-cell technologies to examine mechanisms of reciprocal interactions between HIV-associated neuroinflammation and HIV persistence in the CNS despite effective anti-retroviral therapy (ART).

Rationale:

HIV cure research is a top priority for the NIH Office of AIDS Research (OAR) and NIMH Division of AIDS Research (DAR). NIMH is participating in cure research by supporting studies to eradicate or silence HIV from reservoirs in the CNS where the virus may evade detection and treatment. In addition to understanding HIV persistence despite effective ART, NIMH is interested in understanding the mechanisms of HIV-associated comorbidities, including CNS comorbidities (e.g., cognitive deficits and mental illnesses).

A critical gap exists in understanding the factors that drive ongoing neuroinflammation and HIV persistence in the setting of effective ART. HIV-infected individuals on effective ART may experience ongoing immune activation and neuroinflammation, which may result in HIV-associated co-morbidities. Neuroinflammation may be caused by defective HIV pro-viruses, viral RNA, and viral proteins that are derived from infected CNS cells (i.e., macrophages, microglia, and astrocytes). Residual levels of viral replication during ART are associated with persistently low levels of immune activation, which can promote the replenishment of the HIV reservoir in the CNS. Chronic inflammation might lead to HIV persistence by causing virus production, generating new target cells (cells targeted for viral infection), enabling infection of activated and resting target cells, altering the migration patterns of susceptible target cells, increasing the proliferation of infected cells, and preventing normal HIV-specific clearance mechanisms. A vicious cycle of HIV persistence and neuroinflammation may exist.

This concept aims to examine mechanisms of reciprocal interactions between HIV-associated neuroinflammation and CNS HIV persistence. This concept encourages the use of novel model systems such as brain organoids, iPSC- (induced pluripotent stem cell) derived microglia, astrocytes, and state-of-the-art single-cell methodologies to define:

• Mechanisms of neuroinflammation in CNS-derived cells driven by defective proviruses, viral proteins, and RNA;
• Mechanisms of the impact of neuroinflammation and immune dysfunction on HIV persistence in CNS;
• Mechanisms of the impact of latent/persistent viral HIV reservoirs on immune homeostasis in the CNS and the impact of these latent/persistent reservoirs on neurotransmitters, neuronal function, and neuronal plasticity; and
• Development of therapeutic strategies to alleviate the reciprocal impact of persistent virus and associated neuroinflammation in the CNS compartment.

Successful completion of these studies may advance our understanding of the mechanisms of HIV neuropathogenesis and persistence to help achieve an HIV cure.