U94 of human herpesvirus 6 inhibits in vitro angiogenesis and lymphangiogenesis

Caruso, Arnaldo; Caselli, Elisabetta; Fiorentini, Simona; Rotola, Antonella; Prandini, Alberto; Garrafa, Emirena; Saba, Elisa; Alessandri, Giulio; Cassai, Enzo; Luca, Dario Di

doi:10.1073/pnas.0905535106

Cited by 53 publications

(85 citation statements)

References 37 publications

(53 reference statements)

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“…Human umbilical vein endothelial cells (HUVECs) have been previously developed and characterized62. Cells were cultured in Endothelial Cell Growth Medium (EGM™, Lonza, Milan, Italy) supplemented with 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

Cellular aspartyl proteases promote the unconventional secretion of biologically active HIV-1 matrix protein p17

Caccuri

Iaria

Campilongo

et al. 2016

Sci Rep

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The human immune deficiency virus type 1 (HIV-1) matrix protein p17 (p17), although devoid of a signal sequence, is released by infected cells and detected in blood and in different organs and tissues even in HIV-1-infected patients undergoing successful combined antiretroviral therapy (cART). Extracellularly, p17 deregulates the function of different cells involved in AIDS pathogenesis. The mechanism of p17 secretion, particularly during HIV-1 latency, still remains to be elucidated. A recent study showed that HIV-1-infected cells can produce Gag without spreading infection in a model of viral latency. Here we show that in Gag-expressing cells, secretion of biologically active p17 takes place at the plasma membrane and occurs following its interaction with phosphatidylinositol-(4,5)-bisphosphate and its subsequent cleavage from the precursor Gag (Pr55Gag) operated by cellular aspartyl proteases. These enzymes operate a more complex Gag polypeptide proteolysis than the HIV-1 protease, thus hypothetically generating slightly truncated or elongated p17s in their C-terminus. A 17 C-terminal residues excised p17 was found to be structurally and functionally identical to the full-length p17 demonstrating that the final C-terminal region of p17 is irrelevant for the protein’s biological activity. These findings offer new opportunities to identify treatment strategies for inhibiting p17 release in the extracellular microenvironment.

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Section: Methodsmentioning

confidence: 99%

Cellular aspartyl proteases promote the unconventional secretion of biologically active HIV-1 matrix protein p17

Caccuri

Iaria

Campilongo

et al. 2016

Sci Rep

Self Cite

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“…Cytomegaloviruses of rats [38] and bats [39] encode U94 homologs, indicating that the gene may have been acquired prior to the divergence of roseoloviruses and cytomegaloviruses. HHV-6 U94 binds ssDNA [40] and its ectopic expression inhibits betaherpesvirus replication [41] and impairs lymphatic endothelial cell angiogenesis [42]. Given its homology with the parvovirus integrase, U94 is hypothesized to promote integration and excision of HHV-6A and HHV-6B, either by host-mediated base excision repair or by exonuclease strand invasion [14].…”

Section: Latency and Reactivationmentioning

confidence: 99%

Roseolovirus molecular biology: recent advances

Krug

Pellett

2014

Current Opinion in Virology

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Human herpesviruses 6A, −6B, and −7 (HHV-6A, −6B, and −7) are classified within the roseolovirus genus of the betaherpesvrus subfamily. Most humans likely harbor at least two of these large DNA viruses, and 1% of humans harbor germline chromosomally integrated HHV-6A or HHV-6B genomes. Differences at the genetic level manifest as distinct biologic properties during infection and disease. We provide a brief synopsis of roseolovirus replication and highlight the unique properties of their lifecycle and what is known about the viral gene products that mediate these functions. In the nearly 30 years since their discovery, we have only begun to unlock the molecular strategies these highly evolved pathogens employ to establish and maintain chronic infections in humans.

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“…HHV-6 is capable of infecting vascular endothelium both in vivo and in vitro, which might support a role in the genesis of diseases affecting coronary and peripheral arteries (47,192). These effects might be strengthened by the inhibition of angiogenesis induced by U94 gene expression (75).…”

Section: Chronic Infectionsmentioning

confidence: 99%

“…The products of the DR7 gene appear to demonstrate a cell-transforming activity, presumably through an interaction with p53 (73). Regarding the U94 gene, which is analogous to the AAV rep gene, it can bind to the human TATA-binding protein, and its expression in endothelial cells decreases cell migration and angiogenesis (74,75). The U95 gene product interacts with the mitochondrial GRIM-19 protein, a component of the oxidative phosphorylation system involved in apoptotic processes (76).…”

Section: Impacts Of Viral Gene Expression On Cell Functionsmentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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SUMMARY Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus.

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U94 of human herpesvirus 6 inhibits in vitro angiogenesis and lymphangiogenesis

Cited by 53 publications

References 37 publications

Cellular aspartyl proteases promote the unconventional secretion of biologically active HIV-1 matrix protein p17

Cellular aspartyl proteases promote the unconventional secretion of biologically active HIV-1 matrix protein p17

Roseolovirus molecular biology: recent advances

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

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