Abstract
Despite potent combination antiretroviral therapy, HIV-1 infection persists due to irreversible integration of the virus in long-living cells of the immune system. The main focus of HIV-1 cure strategies has been on HIV-1 eradication, yet without great success so far. Therefore, HIV-1 remission or a functional cure, whereby the virus is silenced rather than eradicated, is considered as an alternative strategy. Elite controllers, individuals who spontaneously control HIV-1, may point us the way toward a functional HIV-1 cure. In order to achieve such a cure, a profound understanding of the mechanisms controlling HIV-1 expression and silencing is needed. In recent years, evidence has grown that the site of integration as well as the chromatin landscape surrounding the integration site affects the transcriptional state of the provirus. Still, at present, the impact of integration site selection on the establishment and maintenance of the HIV-1 reservoirs remains poorly understood. The discovery of LEDGF/p75 as a binding partner of HIV-1 integrase has led to a better understanding of integration site selection. LEDGF/p75 is one of the important determinants of integration site selection and targets integration toward active genes. In this review, we will provide an overview of the most important determinants of integration site selection. Secondly, we will discuss the chromatin landscape at the integration site and its implications on HIV-1 gene expression and silencing. Finally, we will discuss how interventions that affect integration site selection or modifications of the chromatin could yield a functional cure of HIV-1 infection.
Highlights
Integration of the HIV-1 DNA into the host genome is central in the replication and pathogenesis of HIV-1 infection
The majority of cells productively infected with HIV-1 are rapidly eliminated by the host’s immune system, some infected cells contain provirus that enters a silent mode
Combination antiretroviral therapy reduces plasma viremia below detectable levels, the virus inevitably rebounds after combination antiretroviral therapy (cART) is discontinued (Chun et al, 1997)
Summary
Integration of the HIV-1 DNA into the host genome is central in the replication and pathogenesis of HIV-1 infection. Latency-reversing agents (LRAs) are given to deliberately reactivate proviral transcription in latently infected cells The hypothesis behind this approach is that reactivated cells will express viral proteins, allowing them to be recognized and destroyed by the host immune system or die due to viral cytopathic effects. A functional cure could be achieved by durably silencing the latent provirus in infected cells and thereby preventing viral rebound by creating a cellular reservoir resistant to reactivation. To achieve such a functional cure, it will be necessary to broaden our understanding on the molecular mechanisms contributing to HIV-1 silencing. We will discuss how an increased understanding of integration site selection could open new perspectives on the road toward a functional cure for HIV-1 infection
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