Fig. 4: Strategies for gene therapy.

Examples of ex vivo (left) and in vivo (right) gene therapy approaches that have been tested in people with HIV on ART. Ex vivo strategies include gene editing to either delete or inactivate CCR5 or HIV provirus in CD4⁺-enriched T cells using gene-editing tools such as zinc finger nucelases (ZFN) or CRISPR–Cas9. Alternatively, autologous T cells can be modified to express a CAR that can recognize HIV envelope, and this can then be reinfused into the participant. In vivo strategies, on the other hand, do not require external manipulation of cells; nanoparticles or viral vectors (such as adeno-associated virus (AAV)), which encapsulate mRNA or DNA, respectively, for the relevant gene to be expressed are administered directly to the patient. These approaches have recently been successful using lipid nanoparticles that contain mRNA encoding CRISPR–Cas9¹³⁵ or for expression of anti-HIV broadly neutralizing antibodies such as PG9 or VRC07 (ref. ¹²⁵). PBMCs, peripheral blood mononuclear cells; PLWH, person living with HIV.