September 23, 2011
Eradication of HIV-1 from CNS Reservoirs: Implications for Therapeutics
NAMHC Concept Clearance
Jeymohan Joseph, Ph.D.
Chief, HIV Pathogenesis, Neuropsychiatry and Treatment Branch
Division of AIDS Research (DAR)
The goal of this initiative is to foster discovery research to define and characterize the sources of HIV-1 persistence in the central nervous system (CNS) for people on suppressive anti-retroviral therapy, and to foster translational research to enable therapeutic eradication of HIV-1 from the brain.
Highly active anti-retroviral therapy (HAART) is able to suppress HIV-1 replication to low levels (1-50 viral copies per ml), without completely eliminating virus. This limitation is due to latent sequestered virus found in cellular reservoirs, including memory T cells, monocyte-derived macrophages, hematopoietic cells, and cells within the gastrointestinal tract, genitourinary tract, and brain. The NIH has placed a high priority on the goal of eradicating HIV-1 from persistent reservoirs, and a number of eradication strategies are currently being tested. However, many of the therapeutic strategies under consideration may not be optimal for targeting the HIV-1 cellular reservoirs within the CNS, and could potentially have devastating consequences on the brain.
Additional research is needed to 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 challenges for eradication of CNS-specific HIV-1 reservoirs includes developing anti-HIV-1 therapeutics that can traverse the blood-brain barrier. Another challenge is that the current eradication strategies being tested may have detrimental effects in the CNS, due to neuronal toxicity of reactivated virus and other inflammatory sequelae. Therefore, we need discovery research focused solely on expanding our knowledge base of CNS HIV-1 latency and eradication strategies, tailored directly for the brain compartment.
The discovery research areas that are pertinent to this concept include, but are not limited to:
- Identify all potential cellular reservoirs of latent HIV-1 within the CNS (macrophages, microglia, astrocytes, T-cells);
- Discover the molecular mechanisms involved in establishment, maintenance, and resurgence of CNS-based HIV reservoirs in relationship to the effects and timing of HAART;
- Elucidate how latently infected cells of the CNS escape the immune response, and persist despite HAART;
- Adapt or refine existing animal models to study persistence or to test virus eradication strategies, with particular emphasis on the SIV model;
- Develop physiologically relevant CNS-based cell assays that recapitulate HIV persistence in the presence of effective antiretroviral therapy, HIV latency, and HIV resurgence upon removal of ART;
- Develop or refine high throughput assays of physiologically relevant primary cells for use in identifying drug candidates;
- Develop novel therapeutic strategies to target, eliminate, or permanently inactivate integrated provirus in latent CNS reservoirs; and,
- Identify novel strategies to prevent viral resurgence in the CNS upon cessation of HAART.