Closing the Door with CRISPR: Genome Editing of CCR5 and CXCR4 as a Potential Curative Solution for HIV

Abstract

Human immunodeficiency virus (HIV) infection can be controlled by anti-retroviral therapy. Suppressing viral replication relies on life-long medication, but anti-retroviral therapy is not without risks to the patient. Therefore, it is important that permanent cures for HIV infection are developed. Three patients have been described to be completely cured from HIV infection in recent years. In all cases, patients received a hematopoietic stem cell (HSC) transplantation due to a hematological malignancy. The HSCs were sourced from autologous donors that expressed a homozygous mutation in the CCR5 gene. This mutation results in a non-functional receptor, and confers resistance to CCR5-tropic HIV strains that rely on CCR5 to enter host cells. The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/CRISPR-associated (Cas) system is one of the methods of choice for gene editing, and the CRISPR/Cas system has been employed to target loci of interest in the context of HIV. Here, the current literature regarding CRISPR-mediated genome editing to render cells resistant to HIV (re)-infection by knocking out the co-receptors CCR5 and CXCR4 is summarized, and an outlook is provided regarding future (research) directions.

JAK/STAT signaling pathway affects CCR5 expression in human CD4 + T cells

“…CCR5 is the major gene target for the handful of R5-tropic HIV cures in humans ( 32 ). We and others reported that HIV Elite controllers and Viremic controllers (ECs/VCs) had lower CCR5 expression levels ( 33 , 34 ).…”

The chemokine receptor CCR5: multi-faceted hook for HIV-1

“…In addition, the treatments options remain limited for some patients with multiclass resistance and must be taken for life as they do not target the integrated proviral genome and fail to eradicate the virus in so called viral reservoirs. From this point of view, recent advances in genome editing offer encouraging prospects not only for blocking viral entry by modifying CCR5, but also for excising HIV sequences integrated into the genome [ 204 ]. One can hope that the combination of all these new therapeutic approaches will bring us closer to the development of an effective antiviral treatment against HIV that will be affordable for the broadest possible populations.…”

“…CCR5 gene editing —Recent advances in genome editing offers unprecedented possibilities for gene therapy, as it is now possible to replace one or more bases in any gene of interest, at any location [ 203 , 204 ]. The CRISPR/Cas9 system or the use of zinc finger nucleases (ZFN) are methods of choice for such gene editing [ 205 , 206 ].…”

Hematopoietic Stem Cell Transplantation As A Potential Cure For HIV-1

“…The authors suggest that transplantation of CRISPR gene edited allogeneic hematopoietic stem cells may be a safe and an effective tool for HIV resistance. The most effective, long-term solution would be a successful bone marrow transplantation with CRISPR/Cas9 CCR5 edited hematopoietic stem cells [27,28]. However, further exploration and precision of CRISPR/Cas9 technology is needed prior to clinical trials (Figure 3).…”