Tackling HIV Persistence: Pharmacological versus CRISPR-Based Shock Strategies

Abstract

Jan Svoboda studied aspects of viral latency, in particular with respect to disease induction by avian RNA tumor viruses, which were later renamed as part of the extended retrovirus family. The course of retroviral pathogenesis is intrinsically linked to their unique property of integrating the DNA copy of the retroviral genome into that of the host cell, thus forming the provirus. Retroviral latency has recently become of major clinical interest to allow a better understanding of why we can effectively block the human immunodeficiency virus type 1 (HIV-1) in infected individuals with antiviral drugs, yet never reach a cure. We will discuss HIV-1 latency and its direct consequence—the formation of long-lasting HIV-1 reservoirs. We next focus on one of the most explored strategies in tackling HIV-1 reservoirs—the “shock and kill” strategy—which describes the broadly explored pharmacological way of kicking the latent provirus, with subsequent killing of the virus-producing cell by the immune system. We furthermore present how the clustered regularly interspaced palindromic repeats (CRISPR) and associated protein (Cas) system can be harnessed to reach the same objective by reactivating HIV-1 gene expression from latency. We will review the benefits and drawbacks of these different cure strategies.

Application of CRISPR/Cas9-Based Gene Editing in HIV-1/AIDS Therapy

“…Latency reversing agents (LRAs) have been used to reverse HIV-1 latency. However, the lack of specificity and the heterogeneous and dynamic nature of these drugs make this pharmacologic strategy less safe and inefficient (Darcis et al, 2018). CRISPR-based shock strategy with the characteristic of sequence specificity have advantages over pharmacological, but its potential drawbacks need to be evaluated, such as off-target effect and less efficient delivery method.…”

The role of exosomal transport of viral agents in persistent HIV pathogenesis

“…This fact underscores the need for novel treatment stratagems to combat this portion of the HIV life cycle. The ideal solution would be the discovery of the elusive functional cure for HIV infection, be it by “shock and kill” [144] or “block and lock” [137] approaches, by targeted gene editing to eliminate functional proviral DNA [145]. However, until such time as a safe and effective cure is found, alternative antiretroviral drugs are needed.…”

Clinical pharmacology in HIV cure research – what impact have we seen?

“…Several PKC agonists have been considered for purging the reservoirs of latent HIV-1 [56]. First of all, prostratin is a unique phorbol esterthat it induces potent T cell activation signals and is not tumorigenic.…”