HIV-1 cure strategies: why CRISPR?

ABSTRACT

Introduction

Antiretroviral therapy (ART) has transformed prognoses for HIV-1-infected individuals but requires lifelong adherence to prevent viral resurgence. Targeted elimination or permanent deactivation of the latently infected reservoir harboring integrated proviral DNA, which drives viral rebound, is a major focus of HIV-1 research.

Areas covered

This review covers the current approaches to developing curative strategies for HIV-1 that target the latent reservoir. Discussed herein are shock and kill, broadly neutralizing antibodies (bNAbs), block and lock, Chimeric antigen receptor (CAR) T cells, immune checkpoint modulation, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) coreceptor ablation, and CRISPR/Cas9 proviral excision. Emphasis is placed on CRISPR/Cas9 proviral excision/inactivation. Recent advances and future directions toward discovery and translation of HIV-1 therapeutics are discussed.

Expert opinion

CRISPR/Cas9 proviral targeting fills a niche amongst HIV-1 cure strategies by directly targeting the integrated provirus without the necessity of an innate or adaptive immune response. Each strategy discussed in this review has shown promising results with the potential to yield curative or adjuvant therapies. CRISPR/Cas9 is singular among these in that it addresses the root of the problem, integrated proviral DNA, with the capacity to permanently remove or deactivate the source of HIV-1 recrudescence.

KEYWORDS:

• HIV-1
• crispr/Cas9
• proviral excision
• shock and kill
• bNAbs
• car T
• block and lock
• immune blockade
• coreceptor
• ccr5
• off-target
• delivery

Article highlights

• HIV-1 curative strategies focus on elimination or deactivation of the latent viral reservoir.

• HIV-1 curative strategies include CRISPR/Cas9 proviral excision, CRISPR/Cas9 coreceptor ablation, shock and kill, bNAbs, CAR T cells, block and lock, and immune blockade.

• CRISPR/Cas9 proviral excision fills a unique niche among HIV-1 curative strategies by targeting proviral DNA directly.

• Proof-of-concept that HIV-1 viral elimination is possible using the CRISPR/Cas9 system has been demonstrated in a murine model.

• Problems surrounding the adaptive immune response, HIV-1 escape mutations, and delivery can all be solved for the CRISPR/Cas9 system as an HIV-1 therapy.

• Off-target proclivity of the CRISPR/Cas9 system targeting HIV-1 can be avoided with an appropriate design and screening paradigm.

This box summarizes key points contained in the article.

Declaration of interest

The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This work was supported by National Institute of Mental Health (NIMH) R01 MH110360 (Contact PI, BW), NIMH Comprehensive NeuroAIDS Center (CNAC) P30 MH092177 (Kamel Khalili, PI; Brian Wigdahl, PI of the Drexel subcontract involving the Clinical and Translational Research Support Core, Drexel Component PI, BW), NIMH T32 MH079785 (Drexel Component PI, BW) and the Ruth L. Kirschstein National Research Service Award T32 MH079785 (Dr. Brian Wigdahl, Principal Investigator of the Drexel University College of Medicine component and Drs. Olimpia Meucci and Michael Nonnemacher as Co-Directors). The contents of the paper were solely the responsibility of the authors and do not necessarily represent the official views of the NIH.