RNA interference approaches for treatment of HIV-1 infection

Abstract

HIV/AIDS is a chronic and debilitating disease that cannot be cured with current antiretroviral drugs. While combinatorial antiretroviral therapy (cART) can potently suppress HIV-1 replication and delay the onset of AIDS, viral mutagenesis often leads to viral escape from multiple drugs. In addition to the pharmacological agents that comprise cART drug cocktails, new biological therapeutics are reaching the clinic. These include gene-based therapies that utilize RNA interference (RNAi) to silence the expression of viral or host mRNA targets that are required for HIV-1 infection and/or replication. RNAi allows sequence-specific design to compensate for viral mutants and natural variants, thereby drastically expanding the number of therapeutic targets beyond the capabilities of cART. Recent advances in clinical and preclinical studies have demonstrated the promise of RNAi therapeutics, reinforcing the concept that RNAi-based agents might offer a safe, effective, and more durable approach for the treatment of HIV/AIDS. Nevertheless, there are challenges that must be overcome in order for RNAi therapeutics to reach their clinical potential. These include the refinement of strategies for delivery and to reduce the risk of mutational escape. In this review, we provide an overview of RNAi-based therapies for HIV-1, examine a variety of combinatorial RNAi strategies, and discuss approaches for ex vivo delivery and in vivo delivery.

Gene Editing Approaches against Viral Infections and Strategy to Prevent Occurrence of Viral Escape

“…CRISPR/Cas9 targeting of HIV-1 generated mutant viruses able to escape and replicate [39–42], as observed earlier with RNAi approaches [43–45]. One report described a mutant HIV-1 generated after ZFN therapy [39], and other reports indicated CRISPR/Cas9 gave profound suppression of HIV replication, but escape mutations were rapidly and consistently generated [40–42].…”

“…RNAi approaches exist for a number of viruses, including HIV-1 [43, 79], HBV [80], HCV [81], HPV [82, 83], JCV [84], and HSV [85]. For example, RNAi against HIV-1 is already reaching the clinic [43, 79]. Delivery and the production of escape mutants are a problem, but combination of RNAi and CRISPR/Cas9 may address these problems.…”

A directed evolution approach to select for novel Adeno-associated virus capsids on an HIV-1 producer T cell line

“…Using AAV to target HIV-1-infected cells offers a potential research tool or gene therapy approach aimed at delivering an anti-HIV-1 therapeutic molecule, such as a small interfering RNA molecule or a genome editing system (Bobbin, Burnett, and Rossi, 2015; Limsirichai, Gaj, and Schaffer, 2016; Yin et al, 2017). Alternatively, isolation of an AAV variant that is better able to transduce non-HIV-1 infected T cells could be used potentially to protect them from HIV-1 infection as part of a prophylactic strategy.…”

Achieving HIV-1 Control through RNA-Directed Gene Regulation

“…Currently the dominant delivery method for therapeutics in clinical trials is large-scale apheresis followed by autologous re-infusion of ex vivo modified hematopoietic stem cells (HSC) and/or CD4+ T cells transduced with a viral vector, usually a lentivirus, adenovirus, or adeno-associated virus (AAV) [100] (Figure 3). However, alternates to this are being explored, particularly the challenging goal of in vivo delivery, which will also be discussed below.…”