Trends in Immunology
Volume 38, Issue 3, March 2017, Pages 217-228
Journal home page for Trends in Immunology

Review
HIV Latency: Should We Shock or Lock?

https://doi.org/10.1016/j.it.2016.12.003Get rights and content

Trends

Reservoirs of latent HIV-1 are a major obstacle to viral eradication.

Understanding the molecular mechanisms involved in HIV-1 latency has allowed the development of therapeutic strategies that deliberately reactivate the expression of the latent provirus, and thereby expose latently infected cells to the host immune system and to antiretroviral therapy: the ‘shock and kill’ strategy.

The shock and kill strategy has produced unconvincing results so far. This strategy faces multiple barriers which prevent complete eradication of replication-competent viruses, and must therefore be optimized.

Other more recent and less-advanced strategies focus on suppressing residual levels of HIV-1 transcription to lock the virus in a deep latency state to prevent viral reactivation: the ‘lock’ strategy.

Combinatory antiretroviral therapy (cART) increases the survival and quality of life of HIV-1-infected patients. However, interruption of therapy almost invariably leads to the re-emergence of detectable viral replication because HIV-1 persists in viral latent reservoirs. Improved understanding of the molecular mechanisms involved in HIV-1 latency has paved the way for innovative strategies that attempt to purge latent virus. In this article we discuss the results of the broadly explored ‘shock and kill’ strategy, and also highlight the major hurdles facing this approach. Finally, we present recent innovative works suggesting that locking out latent proviruses could be a potential alternative therapeutic strategy.

Section snippets

HIV-1 As a Chronic Infection

The advent of improved cART allows clinicians to successfully manage HIV-infected patients and to decrease side effects. However, cART is not curative, and a new set of HIV-associated complications have emerged, resulting in a chronic disease that for many will span several decades of life.

Furthermore, cART interruption leads to the re-emergence of a detectable level of viremia because HIV-1 persists in viral reservoirs [1]. These reservoirs, defined as a cell type or anatomical site where the

Regulation of HIV-1 Transcription

Latently infected cells maintain a suboptimal cellular environment for HIV-1 expression via several mechanisms operating at the post-transcriptional level 13, 14 but predominantly at the transcriptional level.

The processes which cause the transcriptional inhibition are of interest given their potential to be manipulated to activate HIV-1 expression and hopefully allow latently infected cells to be eliminated, or, by contrast, to permanently silence HIV-1 transcription. HIV-1 latency results

The Shock and Kill Strategy

Recent cases (e.g., Timothy Brown [25], the Boston patients [26], the Mississippi child [27], the VISCONTI cohort [28], and the perinatally infected child who received treatment early [29]) have fueled hopes for HIV-1 cure or durable control. However, treatment interruption trials have revealed a correlation between total HIV-1 DNA levels and time to viral rebound following cART interruption 30, 31. At least partially, the HIV-1 reservoir size predicts the timing of viral rebound after cART

Concluding Remarks and Future Directions

Intensive efforts have been made by the scientific community to characterize HIV-1 latent reservoirs and to investigate the molecular mechanisms regulating HIV-1 latency. Improved knowledge of the mechanisms of persistence has paved the way for innovative strategies to decrease/eliminate latent HIV. One strategy for HIV-1 eradication consists of combinations of LRAs acting on several silencing molecular mechanisms to force viral expression at different levels. Coupled to immune interventions,

Acknowledgments

We acknowledge grant support from the ANRS (France Recherche Nord&Sud Sida - HIV Hépatites), the Belgian Fund for Scientific Research (FRS-FNRS), the Fondation Roi Baudouin, the NEAT program (Networking to Enhance the Use of Economics in Animal Health Education, Research, and Policy Making), the Walloon Region (Fonds de Maturation) and the University of Brussels [Action de Recherche Concertée (ARC) grant].

G.D. and C.V.L. are “Aspirant” and “Directeur de Recherches” of the FRS-FNRS (Belgium),

Glossary

Enhancer trapping
this phenomenon occurs when the enhancer located in the HIV-1 5’- long terminal repeat (LTR) is hijacked by a nearby promoter of a cellular gene and acts on the transcriptional activity of this cellular promoter, thereby preventing enhancer action on the viral promoter.
Ex vivo HIV-1 latency studies
assays performed using cultures of cells (mainly CD8+-depleted peripheral blood mononuclear cells or resting CD4+ T cells) isolated from the blood of HIV+ cART-treated individuals.
In

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