Role of T-Cells in HIV Central Nervous System Reservoir Seeding, Persistence, and Neuropathogenesis

Presenter

Jeymohan Joseph, Ph.D.
Division of AIDS Research

Goal

The goal of this concept is to encourage research to define the mechanisms and roles of T-cells in HIV/central nervous system (CNS) reservoir seeding, persistence and neuropathogenesis. This research will be critical for developing therapeutic strategies for targeting CNS reservoirs and ongoing neuroinflammation that drive CNS comorbidities.

Rationale

Eradicating latent reservoirs of HIV-1 within the body and achieving a sterilizing or functional cure have become priority areas in the AIDS field and NIH AIDS programs across many institutes and centers, including NIMH. In addition, understanding the mechanisms of HIV-associated comorbidities in the setting of effective anti-retroviral therapy (ART) is a major topic of interest. HIV-associated CNS comorbidities continue to exist despite excellent virologic control in this compartment. HIV persistence and neuroinflammation also continues to be observed in the CNS in the setting of ART.

HIV targets the CNS early in infection, and HIV-infected individuals can experience mild forms of neurological impairments even under ART. CD4+ T-cells and monocytes mediate HIV entry into the brain and constitute a source for HIV persistence and neuronal damage. CD8+ T-cells are also massively recruited in the CNS in acute infection to control viral replication. A significant amount of research has focused on the role of monocytes/macrophages in viral entry (Trojan horse theory) into the CNS. Much less attention has been given to the role of T-cells in CNS reservoir seeding and neuropathogenesis. Accumulating evidence supports the theory that CD4+ T-cells may be critical for HIV entry into the CNS during early infection. More recent data suggest that viral RNA/DNA detected in cerebrospinal fluid are T-cell derived and are linked with HIV neuropathogenesis.

Major gaps remain in understanding the mechanisms and roles of T-cells in CNS reservoir seeding, viral persistence, and neuropathogenesis. The role of HIV persistence in T-cells driving neuroinflammation is not fully understood. Strategies targeting T-cells neuroinvasion and HIV persistence are also an important research opportunity.

State-of-the art HIV virology, single cell technologies, and novel immunologic approaches are encouraged using animal models (e.g., humanized mice, non-human primates), human postmortem tissue, and clinical samples to:

• Define mechanisms of neuroinvasion of HIV-infected T-cells in acute and chronic phases of infection
• Address role of T-cells in CNS reservoir seeding and persistence
• Define T-cell contribution to CNS HIV clearance, neuroinflammation, and neuropathogenesis
• Develop therapeutic strategies to target T-cell neuroinvasion, reservoir maintenance, and neuropathogenesis

Closing the knowledge gaps in these areas may advance our understanding of the mechanisms of HIV neuropathogenesis and persistence to help achieve an HIV cure.