HIV Nanoheroes: novel CRISPR/Cas9-based CD4+ cell-specific HHV-7 vectors to cure HIV

01 November 2023 → 31 October 2027
Research Foundation - Flanders (FWO)
Research disciplines
  • Medical and health sciences
    • Clinical microbiology
    • Virology
    • Biopharmaceutics
    • Infectious diseases
viral vector HIV CRISPR-Cas9
Project description

Nearly 38 million people globally are living with HIV, the virus that causes AIDS by replicating in CD4+ immune cells. Current therapies can inhibit the virus from multiplying, but cannot eliminate viral DNA copies integrated in the genome of CD4+ long-living cells (viral reservoir). Genetic therapy would be a sophisticated way to treat HIV, but conventional vectors are still unable to target the HIV reservoir. Here, we aim to design herpesviral vectors that deliver CRISPR-Cas9 ribonucleoproteins targeting both ends of the viral genome (long terminal repeats) and the viral coreceptor CCR5. As such, our novel nanomedicine will selectively purge HIV reservoirs in CD4+ cells, while conferring healthy CD4+ cells resistant to HIV reinfection in case of remnant virus. In addition, off-target effects in non-target cells will remain minimal. To do so, a library of viral protein-Cas9 fusion HHV-7 mutants will be screened to obtain conditionally replicating HHV-7 vectors that can deliver cargo to CD4+ cells. HHV-7 naturally targets CD4+ T cells. Selected vectors will be further validated in vitro in primary human CD4+ cells and in vivo in a humanized mouse model of HIV infection. Together, the current proposal has a high potential to lay the foundation to make a final cure for HIV. Furthermore, the viral vector delivery platform has potential applications in gene therapies, autoimmune diseases, and oncology, which could bolster Flanders' biotech industry in viral delivery platforms.