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.
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.
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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.