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.

Keywords: CRISPR-Cas system; CRISPR-dCas9; HIV latency; cure; latency-reversing agents; reservoirs; shock strategy.

Figure 1

Pharmacological versus clustered regularly interspaced palindromic repeats (CRISPR)-based anti-human immunodeficiency virus (HIV) strategies. (A) Latency-reversing agents (LRAs) or dCas9-activators can be used to reverse HIV-1 latency (the “shock”) by activating transcription (+). This step leads to cytotoxic T lymphocytes (CTL)-mediated killing of the virus-producing cells (“the kill”); (B) Latency-strengthening agents (LSAs) or dCas9-repressors can be used to reinforce latency by suppressing transcription (−). This strategy should prevent viral rebound following treatment interruption; (C) CRISPR-Cas9 can be used to inactivate the HIV-1 proviral reservoir by excision or hypermutation.