Contribution of PDZD8 to Stabilization of the Human Immunodeficiency Virus Type 1 Capsid

Guth, Charles Alexander; Sodroski, Joseph

doi:10.1128/jvi.02945-13

Cited by 29 publications

(28 citation statements)

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“…1). PDZD8 is a cytoskeleton-regulating protein which was recently shown to bind HIV-1 Gag, stabilizing capsid and enhancing HIV reverse transcription (Guth and Sodroski, 2014; Henning et al, 2010). HIV-1 is inserted in the intron of HELZ in a convergent orientation in the 11B10 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In both of these cell lines provirus was integrated in a convergent orientation and, although we did not explore the mechanism, it is possible that the HIV LTR in the converse orientation is altering the local chromatin environment to promote targeted host gene expression. PDZD8, a moesin-interacting protein that regulates cytoskeleton organization, has been shown to influence herpes simplex virus type 1 and HIV-1 infections (Guth and Sodroski, 2014; Henning et al, 2010). For HIV-1, PDZD8 enhances infection by interacting with Gag to stabilize HIV-1 capsid and modulating the uncoating process during reverse transcription (Guth and Sodroski, 2014; Henning et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

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RNAP II processivity is a limiting step for HIV-1 transcription independent of orientation to and activity of endogenous neighboring promoters

et al. 2015

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Since HIV-1 has a propensity to integrate into actively expressed genes, transcriptional interference from neighboring host promoters has been proposed to contribute to the establishment and maintenance HIV-1 latency. To gain insights into how endogenous promoters influence HIV-1 transcription we utilized a set of inducible T cell lines and characterized whether there were correlations between expression of endogenous genes, provirus and long terminal repeat architecture. We show that neighboring promoters are active but have minimal impact on HIV-1 transcription, in particular, expression of the endogenous gene did not prevent expression of HIV-1 following induction of latent provirus. We also demonstrate that releasing paused RNAP II by diminishing negative elongation factor (NELF) is sufficient to reactivate transcriptionally repressed HIV-1 provirus regardless of the integration site and orientation of the provirus suggesting that NELF-mediated RNAP II pausing is a common mechanism of maintaining HIV-1 latency.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

RNAP II processivity is a limiting step for HIV-1 transcription independent of orientation to and activity of endogenous neighboring promoters

et al. 2015

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“…Similarly, accumulated evidence suggests that cyclophilin A (CypA) and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (prolyl isomerase Pin1) proteins interact with HIV-1 capsid (CA) protein in target cells and facilitate the proper uncoating of HIV-1 (9,10). In addition, some other cellular factors with putative roles in HIV-1 reverse transcription and uncoating have been described in recent studies (11)(12)(13)(14). Although the exact mechanism(s) by which these cellular factors contribute to HIV-1 reverse transcription and/or uncoating is not very clear, the accumulated evidence so far clearly suggests a key role for cellular cofactors in HIV-1 uncoating and reverse transcription.…”

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confidence: 99%

Human Immunodeficiency Virus Type 1 Employs the Cellular Dynein Light Chain 1 Protein for Reverse Transcription through Interaction with Its Integrase Protein

Jayappa

Wang

et al. 2015

J Virol

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In this study, we examined the requirement for host dynein adapter proteins such as dynein light chain 1 (DYNLL1), dynein light chain Tctex-type 1 (DYNLT1), and p150Glued in early steps of human immunodeficiency virus type 1 (HIV-1) replication. We found that the knockdown (KD) of DYNLL1, but not DYNLT1 or p150 Glued T he steps of early stage human immunodeficiency virus type 1 (HIV-1) replication include virus entry, uncoating, reverse transcription, intracytoplasmic retrograde transportation (i.e., the migration of HIV from the cytoplasmic periphery to the perinuclear space), nuclear import, and genomic integration (reviewed in reference 1). Following HIV-1 entry into the cell, viral genomic RNA and associated proteins are released into the cytoplasm as a ribonucleoprotein complex referred as the reverse transcription complex (RTC). Within the RTC, HIV-1 genomic RNA is reverse transcribed into a cDNA, which then forms a highmolecular-weight preintegration complex (PIC). HIV-1 cDNA enters the nucleus as a part of PIC by active nuclear import and subsequently integrates into the host cell genome (reviewed in reference 2).HIV-1 utilizes various cellular proteins for replication mostly by interacting with its viral proteins. Genome-wide small interfering RNA (siRNA)/short hairpin RNA (shRNA) screening as well as other functional studies have uncovered a large number of host proteins with putative roles in HIV-1 replication (reviewed in references 3, 4, and 5). Additionally, functional studies from our laboratory, as well as from other groups, have uncovered key viral and cellular protein interactions that promote successful HIV-1 nuclear import and integration (reviewed in references 2 and 6). However, molecular events associated with HIV-1 reverse transcription, uncoating, or retrograde transport in the cytoplasm are not well understood. To date, evidence suggests that gem-associated protein 2 (Gemin2) interacts with HIV-1 integrase (IN) in target cells and contributes to reverse transcription by an unknown mechanism(s) (7,8). Similarly, accumulated evidence suggests that cyclophilin A (CypA) and peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (prolyl isomerase Pin1) proteins interact with HIV-1 capsid (CA) protein in target cells and facilitate the proper uncoating of HIV-1 (9, 10). In addition, some other cellular factors with putative roles in HIV-1 reverse transcription and uncoating have been described in recent studies (11)(12)(13)(14). Although the exact mechanism(s) by which these cellular factors contribute to HIV-1 reverse transcription and/or uncoating is not very clear, the accumulated evidence so far clearly suggests a key role for cellular cofactors in HIV-1 uncoating and reverse transcription.Dynein adapter proteins such as dynein light chain 1 (DYNLL1, LC8, DLC1), dynein light chain Tctex-type 1 (DYNLT1), and p150Glued have been implicated in cargo recruitment to the dynein complex during retrograde transport (15-18). The dynein complex is a microtubule (MT)-associated protein c...

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“…According to this model, certain lineages of SIVs found it advantageous to lose the glycine-proline motif that allows interaction with CypA. As CypA can promote capsid stability (18), these viruses may have had to evolve other means of stabilizing their capsids, such as a glutamine-rich helix 4-5 loop.…”

Section: Discussionmentioning

confidence: 99%

“…The import of the preintegration complex into the nucleus, which contributes to the ability of lentiviruses to infect resting cells, can also be affected by changes in capsid stability. Host proteins that bind CA and can stabilize the capsid include cyclophilin A (CypA), PDZD8, and cytoplasmically localized CPSF6 (12,(16)(17)(18). Other capsid-binding proteins, TRIM5␣ and TRIMCyp, prematurely accelerate uncoating and thus block reverse transcription and infection (19)(20)(21)(22).…”

mentioning

confidence: 99%

Contribution of Glutamine Residues in the Helix 4-5 Loop to Capsid-Capsid Interactions in Simian Immunodeficiency Virus of Macaques

Tipper¹,

Sodroski²

2014

J Virol

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Following retrovirus entry, the viral capsid (CA) disassembles into its component capsid proteins. The rate of this uncoating process, which is regulated by CA-CA interactions and by the association of the capsid with host cell factors like cyclophilin A (CypA), can influence the efficiency of reverse transcription. Inspection of the CA sequences of lentiviruses reveals that several species of simian immunodeficiency viruses (SIVs) have lost the glycine-proline motif in the helix 4-5 loop important for CypA binding; instead, the helix 4-5 loop in these SIVs exhibits an increase in the number of glutamine residues. In this study, we investigated the role of these glutamine residues in SIVmac239 replication. Changes in these residues, particularly glutamine 89 and glutamine 92, resulted in a decreased efficiency of core condensation, decreased stability of the capsids in infected cells, and blocks to reverse transcription. In some cases, coexpression of two different CA mutants produced chimeric virions that exhibited higher infectivity than either parental mutant virus. For this complementation of infectivity, glutamine 89 was apparently required on one of the complementing pair of mutants and glutamine 92 on the other. Modeling suggests that glutamines 89 and 92 are located on the distal face of hexameric capsid spokes and thus are well positioned to contribute to interhexamer interactions. Requirements to evade host restriction factors like TRIMCyp may drive some SIV lineages to evolve means other than CypA binding to stabilize the capsid. One solution used by several SIV strains consists of glutamine-based bonding. IMPORTANCEThe retroviral capsid is an assembly of individual capsid proteins that surrounds the viral RNA. After a retrovirus enters a cell, the capsid must disassemble, or uncoat, at a proper rate. The interactions among capsid proteins contribute to this rate of uncoating. We found that some simian immunodeficiency viruses use arrays of glutamine residues, which can form hydrogen bonds efficiently, to keep their capsids stable. This strategy may allow these viruses to forego the use of capsid-stabilizing factors from the host cell, some of which have antiviral activity.

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Contribution of PDZD8 to Stabilization of the Human Immunodeficiency Virus Type 1 Capsid

Abstract: Following human immunodeficiency virus type 1 (HIV-1

Cited by 29 publications

References 50 publications

RNAP II processivity is a limiting step for HIV-1 transcription independent of orientation to and activity of endogenous neighboring promoters

RNAP II processivity is a limiting step for HIV-1 transcription independent of orientation to and activity of endogenous neighboring promoters

Human Immunodeficiency Virus Type 1 Employs the Cellular Dynein Light Chain 1 Protein for Reverse Transcription through Interaction with Its Integrase Protein

Contribution of Glutamine Residues in the Helix 4-5 Loop to Capsid-Capsid Interactions in Simian Immunodeficiency Virus of Macaques

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