Site-specific anti-HIV gene thearpy

Colin Exline
University of Southern California
Basic Biomedical Sciences

Gene therapy engineering of human cells to be resistant to HIV is one approach that in the future could allow patients to fight off HIV infection without having to take daily doses of anti-HIV drugs. We have already shown that this is possible in a proof-of-principle study using a technology called zinc finger nucleases that can block expression of the essential CCR5 entry molecule. Although these results are exciting, CCR5 gene knockout will only protect against certain types of HIV-1 that use CCR5 to enter cells, and will not protect against other strains that use CXCR4 instead. To expand protection to these other strains of HIV-1, I am now developing a next generation therapy that simultaneously knocks out the CCR5 gene in human cells while also inserting an anti-HIV gene at the same site. In this proposed work, I will determine which of a panel of candidate anti-HIV genes is the most effective at protecting human cells from infection by both types of HIV-1. The first part of my proposal will be aimed at optimizing the tools and techniques to do this efficiently in human cells, and the second part will then investigate which of the candidate anti-HIV genes works the best. I will examine this using ‘humanized mice’, which both support the growth of engineered human cells and can be infected by HIV-1.