Advances in HIV Gene Therapy

Abstract

Early gene therapy studies held great promise for the cure of heritable diseases, but the occurrence of various genotoxic events led to a pause in clinical trials and a more guarded approach to progress. Recent advances in genetic engineering technologies have reignited interest, leading to the approval of the first gene therapy product targeting genetic mutations in 2017. Gene therapy (GT) can be delivered either in vivo or ex vivo. An ex vivo approach to gene therapy is advantageous, as it allows for the characterization of the gene-modified cells and the selection of desired properties before patient administration. Autologous cells can also be used during this process which eliminates the possibility of immune rejection. This review highlights the various stages of ex vivo gene therapy, current research developments that have increased the efficiency and safety of this process, and a comprehensive summary of Human Immunodeficiency Virus (HIV) gene therapy studies, the majority of which have employed the ex vivo approach.

Keywords: HIV; ex vivo; gene therapy; stem cells; vector.

Figure 1

Ex vivo delivery of gene of interest. Created with Biorender.com.

Figure 2

Cure strategies for HIV. CRISPR—Clustered Regularly Interspaced Short Palindromic Repeats; ZFN—Zinc Finger Nuclease; TALEN—Transcription activator-like effector nucleases. Created with Biorender.

Figure 3

Hierarchical structure for hematopoietic stem cell development. Ref [71]. NK-natural killer cell; DC-dendritic cell. Created with BioRender.com.

Figure 4

Advances in lentiviral vector generation. The first-generation construct comprises the transgene construct, a pseudotyped envelope (often VSV-G) and a packaging construct with gag, pol and all regulatory and accessory genes. The second-generation vector are similar to first-generation vectors, except that the accessory genes have been removed. Third-generation vectors are self-inactivating lentiviral vectors with 400 bp deletion in the U3 region. Fourth-generation lentiviral vectors has the 5′LTR removed and the RNA signals (PBS-Y-RRE) placed downstream of the 3′LTR. RRE: Rev responsive element; PM: cell derived or other promoter; cPPT: central poly purine tract; VSV-G: vesicular stomatitis virus type G; WPRE: Woodchunk hepatitis post-transcriptional regulatory element; Y: packaging signal. Ch5′: Chimeric 5′LTR; PAS: Primer Activation Signal.