Even though highly potent antiretroviral therapy (ART) has the ability to reduce viral replication to undetectable levels in the plasma in simian immunodeficiency virus (SIV) infected monkeys, our recently developed viral env directed immunoPET/CT imaging technology has been able to detect foyers of continued SIV signals even after prolonged ART. However, the ability of this non-invasive technique to map SIV signal in the CNS have thus far been elusive. In this application we propose to focus on the development of probes and strategies to specifically address SIV signals in the CNS, by optimizing the technology to enable SIV specific PET probes to cross the blood brain barrier and mark cells expressing SIV env in vivo. Towards this goal we will use the pigtailed macaque model infected with SIVsmB670/SIVmac239-17E-Fred developed and validated by the team of Dr. Clements as one of the most reliable models of neuroHIV. Leveraging the strength and technological advances available at the New Iberia Research Center and Georgia Tech, we will map the seeding of reservoirs in the CNS during acute infection and monitor the kinetic of viral signals post-acute infection using a combination of immunoPET/CT, light-sheet and confocal imaging techniques, as well as sorting of infected cells to document the nature and function of cells remaining active in the early chronic phase of CNS SIV infection. Next we will document the dynamics of viral kinetics in the CNS relative to total body upon ART initiation, as well as post- ART interruption. Data generated from these highly detailed analyses will delineate which cells retain persistent viral replication under ART (if any) and more importantly evaluate the contribution of CNS viral reservoirs to the early viral rebound in vivo. The in depth analysis of this data will also provide important steps towards the development of cure strategies that include the CNS.

Public Health Relevance

The central nervous system is readily infected by HIV upon systemic infection but represents a separate compartment which only select antiretroviral drugs penetrate, and in which virus evolves independently from the remainder of the body. It also appears that infected cells in the brain contribute to the durable viral reservoir under antiretroviral therapy yet investigating viral dynamics in the brain is almost impossible. Using a macaque model of simian immunodeficiency virus (SIV) that leads to neurological symptoms, we propose to develop new strategies to image SIV in the brain, in real-time, to monitor viral reservoir seeding, persistence and reactivation upon antiretroviral therapy interruption, paving the way for new interventions to minimize neurological damage due to HIV.

Agency
National Institute of Health (NIH)
Institute
National Institute of Mental Health (NIMH)
Type
Research Project (R01)
Project #
1R01MH125395-01
Application #
10126353
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Joseph, Jeymohan
Project Start
2020-09-19
Project End
2025-07-31
Budget Start
2020-09-19
Budget End
2021-07-31
Support Year
1
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Louisiana at Lafayette
Department
Type
Primate Centers
DUNS #
799451273
City
Lafayette
State
LA
Country
United States
Zip Code
70503