Rab5 and Rab7, but Not ARF6, Govern the Early Events of HIV-1 Infection in Polarized Human Placental Cells

Vidricaire, Gaël; Tremblay, Michel J.

doi:10.4049/jimmunol.175.10.6517

Cited by 54 publications

(61 citation statements)

References 67 publications

(91 reference statements)

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“…Also, the rapid increase in internalization upon warming from 4°C to 37°C is highly reminiscent of receptor-mediated internalization. HIV has been shown to travel through apical recycling endosomes to the basolateral pole (54,55). HBV appears to be transported from the apical plasma membrane in microtubule-dependent endosomes to a subapically located site in the cell that is also sensitive to monensin, likely the common endosome or SAC, described for other polarized epithelial cells as a sorting center for substrates.…”

Section: Discussionmentioning

confidence: 98%

Hepatitis B Virus Translocates across a Trophoblastic Barrier

Bhat

Anderson

2007

J Virol

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Mother-infant transmission of hepatitis B virus (HBV) accounts for up to 30% of worldwide chronic infections. The mechanism and high-risk period of HBV transmission from mother to infant are unknown. Although largely prevented by neonatal vaccination, significant transmission continues to occur in high-risk populations. It is unclear whether HBV can traverse an intact epithelial barrier to infect a new host. Transplacental transmission of a number of viruses relies on transcytotic pathways across placental cells. We wished to determine whether infectious HBV can traverse a polarized trophoblast monolayer. We used a human placenta-derived cell line, BeWo, cultured on membranes as polarized monolayers, to model the maternal-fetal barrier. We assessed the effects of placental maturity and maternal immunoglobulin on viral transport. Intracellular viral trafficking pathways were investigated by confocal microscopy. Free HBV (and infectious duck hepatitis B virus) transcytosed across trophoblastic cells at a rate of 5% in 30 min. Viral transport occurred in microtubule-dependent endosomal vesicles. Additionally, confocal microscopy showed that the internalized virus traverses a monensin-sensitive endosomal compartment. Differentiation of the cytotrophoblasts to syncytiotrophoblasts resulted in a 25% reduction in viral transcytosis, suggesting that placental maturity may protect the fetus. Virus translocation was also reduced in the presence of HBV immunoglobulin. We show for the first time that transcytosis of infectious hepadnavirus can occur across a trophoblastic barrier early in gestation, with the risk of transmission being reduced by placental maturity and specific maternal antibody. This study suggests a mechanism by which mother-infant transmission may occur.

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Section: Discussionmentioning

confidence: 98%

Hepatitis B Virus Translocates across a Trophoblastic Barrier

Bhat

Anderson

2007

J Virol

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“…Several Rab proteins have been previously implicated in the life cycles of other viruses (human polyomavirus [23], human immunodeficiency virus [32], influenza virus [28], and West Nile and dengue viruses [12]). Most of these reports linked Rab5 and Rab7 to early events of viral infection through inhibition of viral entry using dominant-negative Rab mutants.…”

Section: Discussionmentioning

confidence: 99%

A Rab-GAP TBC Domain Protein Binds Hepatitis C Virus NS5A and Mediates Viral Replication

Sklan

Staschke

Oakes

et al. 2007

J Virol

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Hepatitis C virus (HCV) is an important cause of liver disease worldwide. Current therapies are inadequate for most patients. Using a two-hybrid screen, we isolated a novel cellular binding partner interacting with the N terminus of HCV nonstructural protein NS5A. This partner contains a TBC Rab-GAP (GTPase-activating protein) homology domain found in all known Rab-activating proteins. As the first described interaction between such a Rab-GAP and a viral protein, this finding suggests a new mechanism whereby viruses may subvert host cell machinery for mediating the endocytosis, trafficking, and sorting of their own proteins. Moreover, depleting the expression of this partner severely impairs HCV RNA replication with no obvious effect on cell viability. These results suggest that pharmacologic disruption of this NS5A-interacting partner can be contemplated as a potential new antiviral strategy against a pathogen affecting nearly 3% of the world's population.HCV is a positive single-stranded RNA virus whose 9.6-kb genome encodes an ϳ3,000-amino-acid polyprotein that is proteolytically processed into structural proteins (components of the mature virus) and nonstructural proteins (involved in replicating the viral genome) (15,20). The nonstructural protein 5A (NS5A) is part of the intracellular membrane-associated viral replication complex (15). Mutations in NS5A affect the rate of HCV replication (3). NS5A has generated considerable interest because of a postulated role in determining the response to interferon (21). A variety of host proteins have been reported to interact with NS5A, although for most their precise relevance in the HCV life cycle awaits definition.Like that of all positive-strand RNA viruses, HCV replication occurs in intimate association with specific intracellular membrane structures, which for HCV has been termed the membranous web (8). What host machinery is exploited to establish these sites of viral replication is unknown. Rab GTPases are small GTP-binding proteins that regulate vesicular-membrane-trafficking pathways, behaving as membraneassociated molecular switches (22). Rab proteins have been previously implicated in the life cycles of various enveloped viruses and are utilized by these viruses for endocytosis, trafficking, and sorting of their proteins (see, for example, Vonderheit and Helenius [33]). Because NS5A has been implicated in the membrane-associated replication of HCV (10), we hypothesized that among the host cell factors that associate with NS5A might be components of host cell membrane-trafficking machinery. To test this hypothesis, we used the full-length NS5A from genotype 1b as bait to screen a human liver cDNA prey library in a GAL4-based yeast two-hybrid screen. We have identified a TBC protein family member, TBC1D20, as a binding partner of HCV NS5A. TBC domain proteins contain an ϳ200-amino-acid motif initially identified in the TRE2/BUB2/ CDC16 genes (25). Like all TBC family members, TBC1D20 contains a Rab-GTPase-activating protein (GAP) homology domain required fo...

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“…Recently, Rab5 and Rab7, vesicular traffic regulators involved in transports from early endosomes to lysosomes, were found to directly govern endocytosis of virions [18][19][20] . However, the mechanism of Rab8 involved in DV entry is not clear.…”

Section: Discussionmentioning

confidence: 99%

Rab8, a Vesicular Traffic Regulator, Is Involved in Dengue Virus Infection in HepG2 Cells

Chen²,

Zhang³

et al. 2008

Intervirology

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Objective: The pathogenesis of dengue virus (DV) has not been completely clarified. Rab8 regulates vesicular traffic from Golgi to plasma membrane where DV is matured and then delivered by exocytosis. In this study, involvement of Rab8 in DV serotype 2 (DV2) infection was investigated in HpeG2 cells. Methods: Distributions of Rab8 and DV2, and the number of infection cells were observed by immunostaining. HepG2^Rab8AM and HepG2^Rab8DN cells were constructed to stably express a constitutively active mutant of Rab8 and a dominant negative mutant, respectively, which were assessed by flow cytometry. Production of infectious virions and the amounts of DV2 entry were detected by standard plaque assay. Viral RNA replication was detected by real-time RT-PCR. Results: Rab8 showed high co-localization with DV2 in HpeG2 cells and the amount of DV antigen-positive cells decreased in HepG2^Rab8AM and HepG2^Rab8DN cells. Also, progeny virus released from those cells was drastically reduced. Infectious virions produced in cells were also significantly reduced, while the viral RNA replication was down-regulated by a different level. Furthermore, viral entry into those cells was reduced by about 80%. Conclusions: Our data suggest that the function of Rab8 is important for DV2 infection, and Rab8 may be involved in DV2 infection.

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Rab5 and Rab7, but Not ARF6, Govern the Early Events of HIV-1 Infection in Polarized Human Placental Cells

Cited by 54 publications

References 67 publications

Hepatitis B Virus Translocates across a Trophoblastic Barrier

Hepatitis B Virus Translocates across a Trophoblastic Barrier

A Rab-GAP TBC Domain Protein Binds Hepatitis C Virus NS5A and Mediates Viral Replication

Rab8, a Vesicular Traffic Regulator, Is Involved in Dengue Virus Infection in HepG2 Cells

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