Dynamic Disruptions in Nuclear Envelope Architecture and Integrity Induced by HIV-1 Vpr

Noronha, Carlos M. C. de; Sherman, Michael P.; Lin, Harrison W.; Cavrois, Marielle; Moir, Robert D.; Goldman, Robert D.; Greene, Warner C.

doi:10.1126/science.1063957

Cited by 258 publications

(236 citation statements)

References 43 publications

Supporting

Mentioning

220

Contrasting

Unclassified

Order By: Relevance

“…It is thus reasonable to think that other signals other than actual DNA damage triggers DNA damage-like cellular responses. These cellular responses could include the nuclear herniation caused by Vpr [53] or cellular stress responses to vpr gene expression [54][55][56]. Since ATR and CHK1 have primary roles in the responses to changes in DNA replication, an alternative possibility is that Vpr may interfere with DNA replication.…”

Section: Cell Cycle G2/m Arrest Induced By Hiv-1 Vprmentioning

confidence: 99%

Viral infections and cell cycle G2/M regulation

Zhao

Elder

2005

Cell Res

View full text Add to dashboard Cite

Progression of cells from G2 phase of the cell cycle to mitosis is a tightly regulated cellular process that requires activation of the Cdc2 kinase, which determines onset of mitosis in all eukaryotic cells. In both human and fission yeast (Schizosaccharomyces pombe) cells, the activity of Cdc2 is regulated in part by the phosphorylation status of tyrosine 15 (Tyr15) on Cdc2, which is phosphorylated by Wee1 kinase during late G2 and is rapidly dephosphorylated by the Cdc25 tyrosine phosphatase to trigger entry into mitosis. These Cdc2 regulators are the downstream targets of two wellcharacterized G2/M checkpoint pathways which prevent cells from entering mitosis when cellular DNA is damaged or when DNA replication is inhibited. Increasing evidence suggests that Cdc2 is also commonly targeted by viral proteins, which modulate host cell cycle machinery to benefit viral survival or replication. In this review, we describe the effect of viral protein R (Vpr) encoded by human immunodeficiency virus type 1 (HIV-1) on cell cycle G2/M regulation. Based on our current knowledge about this viral effect, we hypothesize that Vpr induces cell cycle G2 arrest through a mechanism that is to some extent different from the classic G2/M checkpoints. One the unique features distinguishing Vpr-induced G2 arrest from the classic checkpoints is the role of phosphatase 2A (PP2A) in Vpr-induced G2 arrest. Interestingly, PP2A is targeted by a number of other viral proteins including SV40 small T antigen, polyomavirus T antigen, HTLV Tax and adenovirus E4orf4. Thus an in-depth understanding of the molecular mechanisms underlying Vpr-induced G2 arrest will provide additional insights into the basic biology of cell cycle G2/M regulation and into the biological significance of this effect during host-pathogen interactions.

show abstract

Section: Cell Cycle G2/m Arrest Induced By Hiv-1 Vprmentioning

confidence: 99%

Viral infections and cell cycle G2/M regulation

Zhao

Elder

2005

Cell Res

View full text Add to dashboard Cite

show abstract

“…As HIV Vpr circulates freely in plasma, 3 paracrine effects from this retroviral accessory protein could impact cell function (including cardiomyocyte function) in AIDS. Based on data herein, it may be reasonable to suggest that circulating Vpr of sufficient concentration could cause deleterious effects on the cardiomyocyte in analogous ways to observed Vpr effects on immunocytes (defined by others 8,9 ).…”

Section: Discussionmentioning

confidence: 99%

“…The gene/dose-related TG phenotype in vivo underscores in vitro and in vivo findings that point to Vpr effects on nuclear morphological abnormalities that are considered hallmarks of Vpr damage to terminally differentiated cells. 8,9 The a-MyHC promoter is extensively used, 10 and is robust and cardiac-specific. It exhibits excellent tissue specificity and minimal positional effects of insertion.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

HIV viral protein R causes atrial cardiomyocyte mitosis, mesenchymal tumor, dysrhythmia, and heart failure

Lewis

Miller

Haase

et al. 2005

Laboratory Investigation

View full text Add to dashboard Cite

HIV viral protein R (Vpr) affects the immunocyte cell cycle and circulates as free polypeptide in plasma of AIDS patients. Effects of Vpr on cardiomyocytes were explored using transgenic mice (TG) with Vpr targeted to cardiomyocytes by the a-myosin heavy-chain promoter. TG and WT littermate hearts were evaluated histopathologically, ultrastructurally, molecularly via RNA microarray analysis and quantitative RT-PCR, and functionally by cardiac magnetic resonance imaging (MRI) and electrocardiograms (ECG). Six hemizygous lines were created (Vpr a,b,c,d,e,h ). Vpr RNA was expressed exclusively in myocardium and Vpr mRNA expression correlated with phenotypic changes. Vpr b exhibited the highest expression and mortality. TGs developed congestive heart failure (E8 weeks), abnormal cardiomyocyte nuclei and mitoses (E12 weeks), and became moribund (E20 weeks) with atrial mesenchymal tumors. MRI revealed four-chamber dilation, defective contraction, and atrial masses. Pathologically, cardiomegaly and atrial mesenchymal tumors occurred (E16-20 weeks). ECGs showed prolonged R-R, Q-T, and P-R intervals (E12 weeks). RNA encoding collagen and bone morphogenic protein 4, 6, and 7 were increased. Vpr targeted to cardiomyocytes caused defective contractility and atrial tumors. Since some Vpr cardiomyocytic effects resemble those found in terminally differentiated immunocytes, some pathogenetic mechanisms may be shared at the subcellular level.

show abstract

“…Similarly, an NLS in ASV IN might mediate import through the NPC during ASV infection [Kukolj et al, 1998]. (2) A second entry mechanism in non-cycling cells may involve NPC-independent penetration of the nuclear membrane, mediated by the membrane disruptive activity of the HIV-1 Vpr protein [de Noronha et al, 2001]. (3) In cycling cells the PIC could be captured passively during mitotic re-assembly of the nucleus.…”

Section: Nuclear Entrymentioning

confidence: 99%

Effects of cell cycle status on early events in retroviral replication

Katz

Greger

Skalka

2005

J of Cellular Biochemistry

View full text Add to dashboard Cite

The study of retroviruses over the last century has revealed a wide variety of disease-producing mechanisms, as well as apparently harmless interactions with animal hosts. Despite their potential pathogenic properties, the intrinsic features of retroviruses have been harnessed to create gene transfer vectors that may be useful for the treatment of disease. Retroviruses, as all viruses, have evolved to infect specific cells within the host, and such specificities are relevant to both pathogenesis and retrovirus-based vector design. The majority of cells of an animal host are not progressing rapidly through the cell cycle, and such a cellular environment appears to be suboptimal for replication of all retroviruses. Retrovirus-based vectors can therefore be restricted in many important target cells, such as post-mitotic differentiated cells or stem cells that may divide only infrequently. Despite intense interest, our understanding of how cell cycle status influences retroviral infection is still quite limited. In this review, we focus on the importance of the cell cycle as it relates to the early steps in retroviral replication. Retroviruses have been categorized based on their abilities to complete these early steps in non-cycling cells. However, all retroviruses are subject to a variety of cell cycle restrictions. Here, we discuss such restrictions, and how they may block retroviral replication, be tolerated, or overcome. J. Cell. Biochem. 94: 880-889, 2005. ß 2005 Wiley-Liss, Inc.

show abstract

Dynamic Disruptions in Nuclear Envelope Architecture and Integrity Induced by HIV-1 Vpr

Cited by 258 publications

References 43 publications

Viral infections and cell cycle G2/M regulation

Viral infections and cell cycle G2/M regulation

HIV viral protein R causes atrial cardiomyocyte mitosis, mesenchymal tumor, dysrhythmia, and heart failure

Effects of cell cycle status on early events in retroviral replication

Contact Info

Product

Resources

About