Hitching a ride with a humanized retroelement

We have recently demonstrated that lentivirus-derived nanoparticles (LVNPs) generated from HIV-1 can provide transient ribonucleoprotein (RNP) delivery of genome editors to mammalian cells (Haldrup et al 2023; PMID:37678882). LVNP delivery addresses multiple long-standing disadvantages associated with lentiviral and AAV vector delivery of genome editing tools which both suffer from: (i) limited packaging capacity, (ii) unwanted genomic integration, and (iii) unnecessarily prolonged expression.

Importantly, as with conventional lentiviral vectors, LVNP cell tropism can be controlled via judicious selection of appropriate envelope proteins.

One potentially limiting factor that we have not addressed in our current LVNP designs is the potential for HIV-1 driven host immune responses to the LVNP platform. In this project, we hypothesise that host immunological responses to LVNPs can be modulated by replacing both the HIV-1 derived components and the pseudotyping envelope proteins with biologically active homologues rescued from the human genome.

Our source of these homologues will be endogenous retroviruses (ERVs), remnants of viral elements that have become passengers in the human genome. Amongst the ~5% of the human genome derived from ERV sequences are homologues of HIV-1 Gag/GagPol, a subset of which can self-assemble to form capsids that can deliver nucleic acid cargos to specific cell types.

Since ERVs are already present in the human genome, and have been inherited for millennia, they are anticipated to be immunologically inert and thus less likely to trigger host immune responses than HIV-1 derived viral vectors or LVNPs.

This project focuses on engineering a radical enhancement of our LVNP approach to generate an advanced genome editing platform suitable for the treatment of a wide array of both inherited and acquired human diseases using CRISPR technology.