Histones Are Rapidly Loaded onto Unintegrated Retroviral DNAs Soon after Nuclear Entry

Wang, Gary Z.; Wang, Ying; Goff, Stephen P.

doi:10.1016/j.chom.2016.10.009

Cited by 41 publications

(54 citation statements)

References 67 publications

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“…Our data, and previous work from the Goff laboratory, are consistent with the hypothesis that proviral DNA integration allows escape from the epigenetic silencing that occurs if integration is blocked (17). However, this hypothesis does not preclude the possibility that integration also facilitates other aspects of retroviral replication.…”

Section: Discussionsupporting

confidence: 90%

“…These increases in viral DNA and protein expression were lost when a replication incompetent, env-deficient HIV-1 was analyzed, and hence must result from virus spread ( Fig. 2E and F Previously, it has been reported that unintegrated retroviral DNA is rapidly chromatinized after nuclear entry and then decorated with inhibitory epigenetic marks that are removed, by an unknown process, after integration occurs (16,17). Here, we demonstrate that Tax expression also reduces the deposition of inhibitory chromatin marks, and increases the deposition of activating marks, on unintegrated proviral DNA (Fig.…”

Section: Discussionmentioning

confidence: 92%

“…Conversely, we hypothesize that retroviruses avoid cellular restriction factors that recognize and silence extrachromosomal DNA by integrating their proviral DNA into the host genome, where it eludes detection. It is well established that unintegrated retroviral DNA is rapidly loaded with histones that are then decorated with repressive chromatin marks that induce epigenetic silencing (16,17). In the case of unintegrated murine leukemia virus (MLV) DNA, epigenetic silencing is mediated not by PML-NBs but rather by a DNA binding protein called NP220 acting in concert with the human silencing hub (HUSH) complex (18).…”

Section: Introductionmentioning

confidence: 99%

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Robust HIV-1 replication in the absence of integrase function

Irwan

Karnowski

Bogerd

et al. 2020

Preprint

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Integration of the proviral DNA intermediate into the host cell genome represents an essential step in the retroviral life cycle. While the reason(s) for this requirement remains unclear, it is known that unintegrated proviral DNA is epigenetically silenced. Here, we demonstrate that HIV-1 mutants lacking functional integrase can mount a robust, spreading infection in cells expressing the Tax transcription factor encoded by human T-cell leukemia virus 1. In these cells, HIV-1 forms episomal DNA circles, analogous to Hepatitis B virus covalently closed circular DNAs (cccDNAs), that are transcriptionally active and fully capable of supporting viral replication. This rescue correlates with the loss of inhibitory epigenetic marks, and the acquisition of activating marks, on histones bound to unintegrated HIV-1 DNA. Thus retroviral DNA integration may have evolved, at least in part, as a mechanism to avoid the epigenetic silencing of extrachromosomal viral DNA by host innate antiviral factors. SignificanceWhile retroviral DNA is synthesized normally after infection by integrase-deficient viruses, the resultant episomal DNA is then epigenetically silenced. Here, we show that expression of the Tax transcription factor encoded by a second human retrovirus, HTLV-1, prevents the epigenetic silencing of unintegrated HIV-1 DNA and instead induces the addition of activating epigenetic marks, and the recruitment of NF-kB/Rel proteins, to the HIV-1 LTR promoter. Moreover, in the presence of Tax, the HIV-1 DNA circles that form in the absence of integrase function are not only efficiently transcribed but also support a spreading, pathogenic IN-HIV-1 infection. Thus, retroviruses have the potential to replicate without integration, as is indeed seen with HBV.

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Section: Discussionsupporting

confidence: 90%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Robust HIV-1 replication in the absence of integrase function

Irwan

Karnowski

Bogerd

et al. 2020

Preprint

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show abstract

“…Like several other DNA viruses and retroviruses (e.g., herpes simplex virus, Kaposi's sarcoma-associated herpesvirus, simian virus 40, and murine leukemia virus), the HAdV DNA associates with cellular histones during specific stages of the virus life cycle (60)(61)(62). Modifications of these histones has very recently been shown to modulate HAdV gene expression (34), but many questions regarding the "chromatinization" and epigenetic regulation of the HAdV genome still remain unanswered.…”

Section: Discussionmentioning

confidence: 99%

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

Saha

Parks

2019

J Virol

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Human adenovirus (HAdV) causes minor illnesses in most patients but can lead to severe disease and death in pediatric, geriatric, and immunocompromised individuals. No approved antiviral therapy currently exists for the treatment of these severe HAdV-induced diseases. In this study, we show that the pan-histone deacetylase (HDAC) inhibitor SAHA reduces HAdV-5 gene expression and DNA replication in tissue culture, ultimately decreasing virus yield from infected cells. Importantly, SAHA also reduced gene expression from more virulent and clinically relevant serotypes, including HAdV-4 and HAdV-7. In addition to SAHA, several other HDAC inhibitors (e.g., trichostatin A, apicidin, and panobinostat) also affected HAdV gene expression. We determined that loss of class I HDAC activity, mainly HDAC2, impairs efficient expression of viral genes, and that E1A physically interacts with HDAC2. Our results suggest that HDAC activity is necessary for HAdV replication, which may represent a novel pharmacological target in HAdV-induced disease. IMPORTANCE Although human adenovirus (HAdV) can cause severe diseases that can be fatal in some populations, there are no effective treatments to combat HAdV infection. In this study, we determined that the pan-histone deacetylase (HDAC) inhibitor SAHA has inhibitory activity against several clinically relevant serotypes of HAdV. This U.S. Food and Drug Administration-approved compound affects various stages of the virus lifecycle and reduces virus yield even at low concentrations. We further report that class I HDAC activity, particularly HDAC2, is required for efficient expression of viral genes during lytic infection. Investigation of the mechanism underlying SAHA-mediated suppression of HAdV gene expression and replication will enhance current knowledge of virus-cell interaction and may aid in the development of more effective antivirals with lower toxicity for the treatment of HAdV infections.

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“…This strongly resembles freshly synthesized (linear) retroviral DNA that can either integrate (as desired by the virus) or be “repaired” to dead-end single long terminal repeat (LTR) circles via intramolecular homologous recombination of the two LTRs, and double LTR circles by non-homologous end-joining (NHEJ) [47,135]. …”

Section: Evidence For a Connection Between Hbv And The Host Dna Damentioning

confidence: 99%

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

Schreiner

Nassal

2017

Viruses

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Chronic hepatitis B virus (HBV) infection puts more than 250 million people at a greatly increased risk to develop end-stage liver disease. Like all hepadnaviruses, HBV replicates via protein-primed reverse transcription of a pregenomic (pg) RNA, yielding an unusually structured, viral polymerase-linked relaxed-circular (RC) DNA as genome in infectious particles. Upon infection, RC-DNA is converted into nuclear covalently closed circular (ccc) DNA. Associating with cellular proteins into an episomal minichromosome, cccDNA acts as template for new viral RNAs, ensuring formation of progeny virions. Hence, cccDNA represents the viral persistence reservoir that is not directly targeted by current anti-HBV therapeutics. Eliminating cccDNA will thus be at the heart of a cure for chronic hepatitis B. The low production of HBV cccDNA in most experimental models and the associated problems in reliable cccDNA quantitation have long hampered a deeper understanding of cccDNA molecular biology. Recent advancements including cccDNA-dependent cell culture systems have begun to identify select host DNA repair enzymes that HBV usurps for RC-DNA to cccDNA conversion. While this list is bound to grow, it may represent just one facet of a broader interaction with the cellular DNA damage response (DDR), a network of pathways that sense and repair aberrant DNA structures and in the process profoundly affect the cell cycle, up to inducing cell death if repair fails. Given the divergent interactions between other viruses and the DDR it will be intriguing to see how HBV copes with this multipronged host system.

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Histones Are Rapidly Loaded onto Unintegrated Retroviral DNAs Soon after Nuclear Entry

Cited by 41 publications

References 67 publications

Robust HIV-1 replication in the absence of integrase function

Robust HIV-1 replication in the absence of integrase function

Histone Deacetylase Inhibitor Suberoylanilide Hydroxamic Acid Suppresses Human Adenovirus Gene Expression and Replication

A Role for the Host DNA Damage Response in Hepatitis B Virus cccDNA Formation—and Beyond?

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