MR-guided focused ultrasound to eradicate CNS viral reservoirs and promote neurogenesis in the HIV-infected brain

Project Summary:
This DP1 application responds to PAR-20-221 “NIDA Avant-Garde Award Program for
HIV/AIDS and Substance Use Disorder Research”. The PI, Linda Chang, proposes to tackle a
major challenge in the treatment or cure for HIV, namely, the inability of current treatment
regimens to eradicate the viral reservoirs, especially those that are protected by the blood brain
barrier (BBB) in the central nervous system (CNS). HIV-infected persons who have substance
use disorders (SUDs) often have even higher viral loads and suffer from greater severity of HIV-
associated neurocognitive disorders (HAND). She proposes to use the emerging technology of
MR-guided focused ultrasound (MRgFUS) to safely and transiently open the BBB in order to
maximize the delivery of long-acting slow release antiretroviral therapy (LASER ART), and to
provide targeted delivery of CRISPR-Cas9 to eliminate the integrated HIV proviral DNA in the
CNS viral reservoirs. The combined approach of LASER ART, followed by AAV-CRISPR-Cas9
has shown early successes in subgroups of rodent models, but further optimal delivery of these
agents to the CNS is needed. First, HIV-humanized rodent models will be used to demonstrate
markedly improved delivery of these agents into the CNS, and the efficacy of eliminating the
virus without rebounds. Furthermore, since the same FUS energy and pulse patterns used for
BBB opening can also induce neurogenesis and activate microglia, these secondary effects will
be evaluated as well. Lastly, due to compelling early preclinical findings with neuromodulation
by others, low-intensity MRgFUS as a potential treatment for addiction will also be explored in
drug self-administration rodent models. The PI has assembled an outstanding team of
collaborators who are experts in each of the techniques and approaches required to ensure the
success of the proposed research. Furthermore, since MRgFUS, at higher intensities, is
currently being used in the clinical settings to successfully treat patients with essential tremors
or Parkinson’s disease, and at different parameters (e.g., pulsed high intensity, low intensity,
etc.) and hardware configurations in clinical trials of other neurological disorders, the proposed
research has a high potential for clinical translation. Given the available resources and expertise
at the University of Maryland, pilot clinical trials may start in years 3-5. In summary, the
proposed research to use MRgFUS to maximize the delivery of HIV elimination agents may
ultimately eradicate the HIV viral reservoirs, especially those in the CNS, and halt the
progression or prevent the development of HAND, particularly for those with SUDs.

Grant Number: 5DP1DA053719-04
NIH Institute/Center: NIH
Principal Investigator: LINDA CHANG