Federico de América Perdomo Celis

This symposium summarized advances and challenges in gene editing tools for curing HIV. First, the status of gene editing in HIV was discussed. In addition, the first-in-human gene therapy study of CRISPR delivery in adults with HIV-1 was presented. Finally, recent advances of B cell engineering in HIV were discussed.

Dr. Ben Berkhout discussed how CRISPR-Cas is being used to attack HIV DNA. He highlighted the important success of gene therapies in diseases such as sickle disease and beta-thalassemia. However, contrary to those disorders, we need multiple editing rounds to tackle HIV, and during this process, potential unintended large chromosomal deletions may occur. These large deletions could have beneficial effects such as HIV inactivation but could also lead to loss of cellular function or protooncogene activation, which eventually might lead to malignant cell transformation. Dr. Rachel Presti presented EBT-101, the first in vivo gene therapy approach to excise the latent HIV proviral genome with AAV9 multiplex CRISPR-SaCas9. Six people with HIV under ART were included. This gene therapy was safe, and no off-target DNA damage was observed. One participant had a delay in viral rebound of 16 weeks during analytical treatment interruption, associated with a decrease in HIV viral reservoir. Dr. Tianling Ou presented applications derived from B cell engineering to express broadly neutralizing antibodies. These engineered B cells could be used for i) the design of novel in vivo vaccine models and immunogen design; ii) the study of antibody evolution; iii) the production of neutralizing sera for antiviral therapy.

Despite the significant progress in gene editing tools for HIV, there are still important challenges that need to be addressed. For example, the unintended large deletions that may occur during CRISPR-Cas gene editing require long-term follow-up in current and future clinical trials to detect potential off-target effects of gene therapies. Scalability of gene therapy and its limited efficacy are also major issues that need to be resolved. However, the development of new in vivo strategies for immunogen and antibody design through B cell engineering will help advance vaccine and antiviral therapy discovery.