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Review
. 2021 Mar 18:12:636642.
doi: 10.3389/fmicb.2021.636642. eCollection 2021.

Towards a Functional Cure of HIV-1: Insight Into the Chromatin Landscape of the Provirus

Julie Janssens  1 , Anne Bruggemans  1 , Frauke Christ  1 , Zeger Debyser  1
Affiliations
Review

Towards a Functional Cure of HIV-1: Insight Into the Chromatin Landscape of the Provirus

Julie Janssens et al. Front Microbiol. .

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.

Keywords: HIV-1; HIV-1 reservoir; LEDGF/p75; block-and-lock; chromatin landscape; integration site selection; latency.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Determinants of HIV-1 integration site selection. The HIV-1 nuclear import pathway is linked to integration. The HIV-1 PIC engages NUPs, favoring integration in close proximity to the NPC (upper left part). Second, cellular cofactors affect the proviral integration site. LEDGF/p75 interacts with HIV-1 IN and targets integration toward active genes. The HIV-1 PIC interacts with other cellular cofactors that affect integration: TRN-SR2 and CPSF6 have been associated with integration in gene-dense regions. TRN-SR2 mediates nuclear import of SR proteins, such as CPSF6, and interacts with the viral IN. The exact mechanism by which these proteins affect nuclear import and integration is not completely understood yet (upper right part). Third, the nuclear architecture affects integration site selection. The heterochromatin condensed regions in the LADs are disfavored, while gene-rich and euchromatin regions in close association with the NPC are frequently targeted by HIV-1 (lower part). PIC, pre-integration complex; NUPs, nucleoporins; LEDGF/p75, lens-epithelium-derived growth factor; IN, integrase; TRN-SR2, transportin-SR2; CPSF6, cleavage and polyadenylation specificity factor 6; LAD, lamina-associated domains; figure created with BioRender.com.
FIGURE 2
FIGURE 2
LEDGIN-mediated retargeting provides a “block-and-lock” functional cure. LEDGF/p75 binds to the viral IN and targets the HIV-1 PIC to the chromatin via interaction with H3K36me3 (upper left part). LEDGINs inhibit the LEDGF/p75-IN interaction and retarget integration (upper right part). LEDGF/p75-independent integration in the presence of LEDGINs results in relatively more proviruses that are in a transcriptionally silent or latent state, compared to LEDGF/p75-dependent integration (middle part). After latency reversal, latently infected cells rebound, resulting in reactivation of HIV-1 gene expression (lower left part). In contrast, LEDGIN-mediated retargeting results in a cellular reservoir that is resistant to reactivation after latency reversal. LEDGIN-mediated retargeting provides a potential “block-and-lock” functional cure strategy. LEDGF/p75, lens-epithelium-derived growth factor; IN, integrase; PIC, pre-integration complex; figure created with BioRender.com.
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