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.
Highlights
Combination antiretroviral therapy allows clinicians to successfully manage the majority of human immunodeficiency virus (HIV) infected patients, to prevent the development of AIDS and to drastically reduce the risk of virus transmission
A lot remains to be done to unravel the mechanisms leading to the establishment and maintenance of these epigenetic factors, several reports recently showed that an human immunodeficiency virus type 1 (HIV-1) antisense transcript expressed from the 30 long-terminal repeat (LTR) promotes proviral latency through the recruitment of DNMT3a, enhancer of Zeste homolog 2 (EZH2) and HDAC1 to the HIV-1 50 LTR promoter region [55,56,57]
The “shock and kill” strategy for purging latent viral reservoirs is one of the most explored approaches in reaching a cure for HIV. This approach is based on HIV reactivation in latently-infected cells, followed by the death of these virus-producing cells
Summary
Combination antiretroviral therapy (cART) allows clinicians to successfully manage the majority of human immunodeficiency virus (HIV) infected patients, to prevent the development of AIDS and to drastically reduce the risk of virus transmission. Viruses 2018, 10, 157 virus can persist, at least longer than the pool of HIV in the blood that rapidly turns over [9,10] This definition restricts the HIV reservoirs to proviruses capable of causing viral rebound following cART interruption and which constitute the fraction of proviruses sometimes called the “true reservoir” [11]. We discuss how the popular clustered regularly interspaced palindromic repeats (CRISPR) tool can be harnessed to reactivate viral gene expression from latency in a gene therapy setting, and we will review the benefits and drawbacks of each option 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-Cas can be used to inactivate the HIV-1 proviral reservoir by excision or hypermutation
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