The therapeutic landscape of HIV-1 via genome editing

Abstract

Current treatment for HIV-1 largely relies on chemotherapy through the administration of antiretroviral drugs. While the search for anti-HIV-1 vaccine remain elusive, the use of highly active antiretroviral therapies (HAART) have been far-reaching and has changed HIV-1 into a manageable chronic infection. There is compelling evidence, including several side-effects of ARTs, suggesting that eradication of HIV-1 cannot depend solely on antiretrovirals. Gene therapy, an expanding treatment strategy, using RNA interference (RNAi) and programmable nucleases such as meganuclease, zinc finger nuclease (ZFN), transcription activator-like effector nuclease (TALEN), and clustered regularly interspaced short palindromic repeats/CRISPR-associated proteins (CRISPR–Cas9) are transforming the therapeutic landscape of HIV-1. TALENS and ZFNS are structurally similar modular systems, which consist of a FokI endonuclease fused to custom-designed effector proteins but have been largely limited, particularly ZFNs, due to their complexity and cost of protein engineering. However, the newly developed CRISPR–Cas9 system, consists of a single guide RNA (sgRNA), which directs a Cas9 endonuclease to complementary target sites, and serves as a superior alternative to the previous protein-based systems. The techniques have been successfully applied to the development of better HIV-1 models, generation of protective mutations in endogenous/host cells, disruption of HIV-1 genomes and even reactivating latent viruses for better detection and clearance by host immune response. Here, we focus on gene editing-based HIV-1 treatment and research in addition to providing perspectives for refining these techniques.

Targeted Chromatinization and Repression of HIV-1 Provirus Transcription with Repurposed CRISPR/Cas9

“…With the development of versatile genome editing tools such as zinc finger nucleases, TAL effector nucleases, and RNA-guided CRISPR/Cas9 systems, it is possible to directly target and modify the HIV-1 genome [ 24 , 25 , 26 ]. Furthermore, these tools have been used to make cells resistant to HIV-1 infection by modifying HIV-1 receptors, CCR5, and/or CXCR4 [ 27 , 28 , 29 , 30 ].…”

Genome-Editing and Biomedical Cell Products: Current State, Safety and Efficacy

“…Анализ предварительных данных некоторых КИ позволяет предположить возможность скорой регистрации таких препаратов. Так, компанией Sangamo Therapeutics (США) были продемонстрированы значимые результаты возможности применения технологии ZFN при лечении ВИЧ [20]. В ходе КИ NCT00842634 (открытое нерандамизированное неконтролируемое) 12 ВИЧ-положительным пациентам, получавшим высокоактивную антиретровирусную терапию (ВААРТ), однократно вводились аутологичные CD4 + -лимфоциты с «редактированным» геном CCR5.…”

Targeting reservoirs of HIV replication in lymphoid follicles with cellular therapies to cure HIV

“…Many innovative and promising HIV functional cure strategies are currently being developed. These include broadly neutralizing antibodies, bi‐ and tri‐specific antibodies, BIKES, and TRIKES; inactivating HIV in latently infected cells; activating latently infected cells for clearance; creating T cells and macrophages that are resistant to infection; and cellular immunotherapies that target HIV‐replicating cells . Whilst detailed discussion of all of these and other exciting current HIV‐cure strategies are beyond the scope of this mini‐review, here I will focus on the three cell therapy approaches and discuss them in the context of targeting lymphoid follicle reservoirs of HIV replication.…”