HIV-1 Preintegration Complex Preferentially Integrates the Viral DNA into Nucleosomes Containing Trimethylated Histone 3-Lysine 36 Modification and Flanking Linker DNA

Sapp, Nicklas; Burge, Nathaniel L.; Cox, Khan L.; Prakash, Prem; Muthukumar, B.; Thapa, Santosh; Christensen, Devin E.; Li, Min; Linderberger, Jared; Kvaratskhelia, Mamuka; Pandhare, Jui; Craigie, Robert; Poirier, Michael G.; Dash, Chandravanu

doi:10.1128/jvi.01011-22

Cited by 11 publications

(9 citation statements)

References 178 publications

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“…Studies of rare people with HIV (PWH) with nonsuppressible HIV-1 viremia (NSV) have shown that the integration sites of the intact producer provirus that are responsible for generating sequencing-matching plasma viruses in the circulation show significant enrichment of activating H3K36 methylation marks [ 34 ]. These findings align with a recent study showing that nucleosomes containing H3K36me3 are preferentially targeted by the HIV-1 preintegration complex [ 35 ]. H3K36 methylation is also found in microglial cells [ 36 ].…”

Section: Epigenetic Control Of Hiv-1 Latencysupporting

confidence: 92%

The sounds of silencing: dynamic epigenetic control of HIV latency

Nguyen,

Karn

2024

Current Opinion in HIV and AIDS

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Purpose of review This review highlights advances in understanding the epigenetic control mechanisms that regulate HIV-1 latency mechanisms in T-cells and microglial cells and describes the potential of current therapeutic approaches targeting the epigenetic machinery to eliminate or block the HIV-1 latent reservoir. Recent findings Large-scale unbiased CRISPR-Cas9 library-based screenings, coupled with biochemical studies, have comprehensively identified the epigenetic factors pivotal in regulating HIV-1 latency, paving the way for potential novel targets in therapeutic development. These studies also highlight how the bivalency observed at the HIV-1 5’LTR primes latent proviruses for rapid reactivation. Summary The HIV-1 latent is established very early during infection, and its persistence is the major obstacle to achieving an HIV-1 cure. Here, we present a succinct summary of the latest research findings, shedding light on the pivotal roles played by host epigenetic machinery in the control of HIV-1 latency. Newly uncovered mechanisms permitting rapid reversal of epigenetic restrictions upon viral reactivation highlight the formidable challenges of achieving enduring and irreversible epigenetic silencing of HIV-1.

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Section: Epigenetic Control Of Hiv-1 Latencysupporting

confidence: 92%

The sounds of silencing: dynamic epigenetic control of HIV latency

Nguyen,

Karn

2024

Current Opinion in HIV and AIDS

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“…While the exact inhibition mechanism in the infected cells remains to be fully described, our data show that the selected drugs are good candidates for new antiviral lead compounds and provide a new antiviral precept that may pave the way for further developments of such strategies targeting the integration step. Recent work showed that purified PIC may display distinct behavior that isolated intasome especially in their preference for histone-modified nucleosomes or naked DNA ( 26 ). Thus, testing the selected compounds on these purified complexes may provide additional clues in their action mechanism.…”

Section: Resultsmentioning

confidence: 99%

Modulation of the functional interfaces between retroviral intasomes and the human nucleosome

Mauro

Lapaillerie

Tumiotto

et al. 2023

mBio

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Infection by retroviruses as HIV-1 requires the stable integration of their genome into the host cells. This process needs the formation of integrase (IN)-viral DNA complexes, called intasomes, and their interaction with the target DNA wrapped around nucleosomes within cell chromatin. To provide new tools to analyze this association and select drugs, we applied the AlphaLISA technology to the complex formed between the prototype foamy virus (PFV) intasome and nucleosome reconstituted on 601 Widom sequence. This system allowed us to monitor the association between both partners and select small molecules that could modulate the intasome/nucleosome association. Using this approach, drugs acting either on the DNA topology within the nucleosome or on the IN/histone tail interactions have been selected. Within these compounds, doxorubicin and histone binders calixarenes were characterized using biochemical, in silico molecular simulations and cellular approaches. These drugs were shown to inhibit both PFV and HIV-1 integration in vitro . Treatment of HIV-1-infected PBMCs with the selected molecules induces a decrease in viral infectivity and blocks the integration process. Thus, in addition to providing new information about intasome-nucleosome interaction determinants, our work also paves the way for further unedited antiviral strategies that target the final step of intasome/chromatin anchoring. IMPORTANCE In this work, we report the first monitoring of retroviral intasome/nucleosome interaction by AlphaLISA. This is the first description of the AlphaLISA application for large nucleoprotein complexes (>200 kDa) proving that this technology is suitable for molecular characterization and bimolecular inhibitor screening assays using such large complexes. Using this system, we have identified new drugs disrupting or preventing the intasome/nucleosome complex and inhibiting HIV-1 integration both in vitro and in infected cells. This first monitoring of the retroviral/intasome complex should allow the development of multiple applications including the analyses of the influence of cellular partners, the study of additional retroviral intasomes, and the determination of specific interfaces. Our work also provides the technical bases for the screening of larger libraries of drugs targeting specifically these functional nucleoprotein complexes, or additional nucleosome-partner complexes, as well as for their characterization.

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“…Reports on the relationship between histone proteins and viral infections mainly focus on the roles of core histone H2A/B, H3, and H4 or their post-translational modification (PTM) in viral infections, such as Enterovirus 71 (EV71), influenza virus, and human immunodeficiency virus (HIV) [ 25 , 26 , 27 ]. However, there are a few reports on the involvement of linker histones (H1) with viral infection.…”

Section: Discussionmentioning

confidence: 99%

Histone H1.2 Inhibited EMCV Replication through Enhancing MDA5-Mediated IFN-β Signaling Pathway

Song,

Li,

Lian

et al. 2024

Viruses

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Histone H1.2 is a member of the linker histone family, which plays extensive and crucial roles not only in the regulation of chromatin dynamics, cell cycle, and cell apoptosis, but also in viral diseases and innate immunity response. Recently, it was discovered that H1.2 regulates interferon-β and inhibits influenza virus replication, whereas its role in other viral infections is poorly reported. Here, we first found the up-regulation of H1.2 during Encephalomyocarditis virus (EMCV) infection, implying that H1.2 was involved in EMCV infection. Overexpression of H1.2 inhibited EMCV proliferation, whereas knockdown of H1.2 showed a significant promotion of virus infection in HEK293T cells. Moreover, we demonstrated that overexpression of H1.2 remarkably enhanced the production of EMCV-induced type I interferon, which may be the crucial factor for H1.2 proliferation–inhibitory effects. We further found that H1.2 up-regulated the expression of the proteins of the MDA5 signaling pathway and interacted with MDA5 and IRF3 in EMCV infection. Further, we demonstrated that H1.2 facilitated EMCV-induced phosphorylation and nuclear translocation of IRF3. Briefly, our research uncovers the mechanism of H1.2 negatively regulating EMCV replication and provides new insight into antiviral targets for EMCV.

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HIV-1 Preintegration Complex Preferentially Integrates the Viral DNA into Nucleosomes Containing Trimethylated Histone 3-Lysine 36 Modification and Flanking Linker DNA

Abstract: HIV-1 infection is dependent on integration of the viral DNA into the host chromosomes. The preintegration complex (PIC) containing the viral DNA, the virally encoded integrase (IN) enzyme, and other viral/host factors carries out HIV-1 integration.

Cited by 11 publications

References 178 publications

The sounds of silencing: dynamic epigenetic control of HIV latency

The sounds of silencing: dynamic epigenetic control of HIV latency

Modulation of the functional interfaces between retroviral intasomes and the human nucleosome

Histone H1.2 Inhibited EMCV Replication through Enhancing MDA5-Mediated IFN-β Signaling Pathway

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