CCR5 Targeted Cell Therapy for HIV and Prevention of Viral Escape

Abstract

Allogeneic transplantation with CCR5-delta 32 (CCR5-d32) homozygous stem cells in an HIV infected individual in 2008, led to a sustained virus control and probably eradication of HIV. Since then there has been a high degree of interest to translate this approach to a wider population. There are two cellular ways to do this. The first one is to use a CCR5 negative cell source e.g., hematopoietic stem cells (HSC) to copy the initial finding. However, a recent case of a second allogeneic transplantation with CCR5-d32 homozygous stem cells suffered from viral escape of CXCR4 quasi-species. The second way is to knock down CCR5 expression by gene therapy. Currently, there are five promising techniques, three of which are presently being tested clinically. These techniques include zinc finger nucleases (ZFN), clustered regularly interspaced palindromic repeats/CRISPR-associated protein 9 nuclease (CRISPR/Cas9), transcription activator-like effectors nuclease (TALEN), short hairpin RNA (shRNA), and a ribozyme. While there are multiple gene therapy strategies being tested, in this review we reflect on our current knowledge of inhibition of CCR5 specifically and whether this approach allows for consequent viral escape.

Hematopoietic stem cell transplantation for HIV cure

“…Two newer approaches to gene editing include transcription activator-like effectors nucleases (TALENs) and engineered clustered regularly interspaced palindromic repeats (CRISPR) coupled to a CRISPR-associated (Cas) nuclease (e.g., Cas9) (49,50). Like zinc-finger nucleases, TALENs use protein-mediated recognition of specific DNA sequences to direct the FokI nuclease to disrupt the targeted gene at the desired location.…”

Recent advances in RNAi-based strategies for therapy and prevention of HIV-1/AIDS

“…Within 3 years of discovery, this technology has been used to knock out genes, create multiple gene knockout mice and monkeys, as well as knock in specific DNA sequences in a variety of systems (reviewed in [42, 43]). Many groups have successfully disrupted CCR5 using nucleases in various cell lines, primary T cells, HSPCs, as well as in humanized mice [2, 3, 44]. Notably, CCR5 modified (with ZFN) T cells has recently been tested in a clinical trial using a small cohort of 12 individuals [45].…”

Stem cell-based therapies for HIV/AIDS

“…Development of anti-HIV genes against chemokine receptor CCR5 has become a main focus in anti-HIV HSPC gene therapy research [12,13] CCR5 serves as a major co-receptor for HIV. After HIV binds to the CD4, the primary receptor, subsequent binding to CCR5 is essential for a successful HIV infection.…”