Roles of HIV-1 capsid in viral replication and immune evasion

Sage, Valerie Le; Mouland, Andrew J.; Valiente-Echeverría, Fernando

doi:10.1016/j.virusres.2014.07.010

Cited by 51 publications

(48 citation statements)

References 252 publications

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“…Considering that the large amounts of viral rcDNA, the precursor of cccDNA formation, exist in the cytoplasm and relatively small numbers of cccDNA accumulate in the nucleus, mature nucleocapsid uncoating and cccDNA formation must be tightly controlled by host and/or viral factors. In addition, because untimely uncoating and release of viral DNA in the cytoplasm may result in recognition of HBV infection by host cellular innate immune sensors to induce an antiviral response (Rasaiyaah et al, 2013), deliberating control of HBV genome uncoating is not only important for cccDNA formation, but also critical for the virus to evade host restriction (Le Sage et al, 2014). …”

Section: Regulation Of Cccdna Formation By Viral and Host Factorsmentioning

confidence: 99%

Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics

2015

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Persistent hepatitis B virus (HBV) infection relies on the stable maintenance and proper functioning of a nuclear episomal form of the viral genome called covalently closed circular (ccc) DNA. One of the major reasons for the failure of currently available antiviral therapeutics to achieve a cure of chronic HBV infection is their inability to eradicate or inactivate cccDNA. In this review article, we summarize our current understanding of cccDNA metabolism in hepatocytes and the modulation of cccDNA by host pathophysiological and immunological cues. Perspectives on the future investigation of cccDNA biology, as well as strategies and progress in therapeutic elimination and/or transcriptional silencing of cccDNA through rational design and phenotypic screenings, are also discussed. This article forms part of a symposium in Antiviral Research on “An unfinished story: from the discovery of the Australia antigen to the development of new curative therapies for hepatitis B.”

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Section: Regulation Of Cccdna Formation By Viral and Host Factorsmentioning

confidence: 99%

Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics

2015

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“…Given the size of the viral core, the capsid (CA) shell has to disassemble or “uncoat” to allow the genome to pass through nuclear pores (Campbell and Hope, 2015). Although some CA can be detected in the nucleus and functions in processes after nuclear entry (Chen et al, 2016; Hulme et al, 2015; Koh et al, 2013; Peng et al, 2014; Schaller et al, 2011; Stultz et al, 2017), whether reverse transcription and uncoating occur during transport along MTs in the cytoplasm or at nuclear pores remains a matter of debate (Arhel et al, 2007; Fassati and Goff, 2001; Le Sage et al, 2014; McDonald et al, 2002; Miller et al, 1997; Rasaiyaah et al, 2013; Zhou et al, 2011). However, recent live cell imaging supports the notion that uncoating begins in the cytoplasm (Francis et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

Localized Phosphorylation of a Kinesin-1 Adaptor by a Capsid-Associated Kinase Regulates HIV-1 Motility and Uncoating

Malikov

Naghavi

2017

Cell Reports

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Summary Although microtubule motors mediate intracellular virus transport, the underlying interactions and control mechanisms remain poorly defined. This is particularly true for HIV-1 cores, which undergo complex, interconnected processes of cytosolic transport, reverse transcription and uncoating of the capsid shell. Although kinesins have been implicated in regulating these events, curiously there are no direct kinesin-core interactions. We recently showed that the capsid-associated kinesin-1 adaptor protein, fasciculation and elongation protein zeta-1 (FEZ1) regulates HIV-1 trafficking. Here, we show that FEZ1 and kinesin-1 heavy, but not light chains regulate not only HIV-1 transport, but also uncoating. This required FEZ1 phosphorylation, which controls its interaction with kinesin-1. HIV-1 did not stimulate widespread FEZ1 phosphorylation, but instead bound MT affinity-regulating kinase 2 (MARK2) to stimulate FEZ1 phosphorylation on viral cores. Our findings reveal that HIV-1 binds a regulatory kinase to locally control kinesin-1 adaptor function on viral cores, thereby regulating both particle motility and uncoating.

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“…This is released into the cytoplasm upon HIV-1 infection and the viral RNA is reverse transcribed by HIV-1 reverse transcriptase (RT) into double stranded DNA that is integrated into the host cell genome. As the outer face of the core, CA is likely involved in trafficking the core to the nucleus [4] and protecting the viral nucleic acid from cytosolic sensors [5, 6]. However, the CA lattice can be recognised by cellular restriction factors that inhibit replication [7].…”

Section: Introductionmentioning

confidence: 99%

“…Regardless of timing, these findings concur that uncoating is a regulated process requiring a trigger. Indeed, perturbing uncoating is detrimental to viral infectivity [5, 15, 16] and therefore may represent a novel therapeutic target. Identifying what initiates uncoating is critical to understanding the role of CA and uncoating in HIV-1 replication.…”

Section: Introductionmentioning

confidence: 99%

HIV-1 capsid uncoating initiates after the first strand transfer of reverse transcription

2016

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BackgroundCorrect disassembly of the HIV-1 capsid shell, called uncoating, is increasingly recognised as central for multiple steps during retroviral replication. However, the timing, localisation and mechanism of uncoating are poorly understood and progress in this area is hampered by difficulties in measuring the process. Previous work suggested that uncoating occurs soon after entry of the viral core into the cell, but recent studies report later uncoating, at or in the nucleus. Furthermore, inhibiting reverse transcription delays uncoating, linking these processes. ResultsHere, we have used a combined approach of experimental interrogation of viral mutants and mathematical modelling to investigate the timing of uncoating with respect to reverse transcription. By developing a minimal, testable, model and employing multiple uncoating assays to overcome the disadvantages of each single assay, we find that uncoating is not concomitant with the initiation of reverse transcription. Instead, uncoating appears to be triggered once reverse transcription reaches a certain stage, namely shortly after first strand transfer.ConclusionsUsing multiple approaches, we have identified a point during reverse transcription that induces uncoating of the HIV-1 CA shell. We propose that uncoating initiates after the first strand transfer of reverse transcription.Electronic supplementary materialThe online version of this article (doi:10.1186/s12977-016-0292-7) contains supplementary material, which is available to authorized users.

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Roles of HIV-1 capsid in viral replication and immune evasion

Cited by 51 publications

References 252 publications

Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics

Metabolism and function of hepatitis B virus cccDNA: Implications for the development of cccDNA-targeting antiviral therapeutics

Localized Phosphorylation of a Kinesin-1 Adaptor by a Capsid-Associated Kinase Regulates HIV-1 Motility and Uncoating

HIV-1 capsid uncoating initiates after the first strand transfer of reverse transcription

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