Created by Catherine Wong
Humans & Viruses (Human Biology 115A)
Winter 2004: Dr. Robert Siegel, instructor

Reoviridae

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Update 2003-2004

Rotavirus cell entry is not through clathrin-mediated nor caveolae-mediated endocytosis
Whereas the mechanism of enveloped virus cell entry has been well characterized as a process of membrane fusion, the mechanism of naked virus cell entry still remains uncertain. It has long been thought that large, hydrophilic naked virus particles pass through hydrophobic cell membrane via endocytosis. Studies by Sanchez-san et al. on the uptake of Rhesus rotavirus by MA104 cells, however, show that neither traditional clathrin-mediated nor caveolae-mediated endocytosis is the pathway. Despite the presence of clathrin-mediated and caveolar-mediated endocytosis inhibitors and despite the use of cells missing proteins essential for clathrin-mediated and caveolar endocytosis, rotavirus still penatrated the cell. Instead, otherwise healthy cells treated with methyl--cyclodextrin, a drug that sequesters cholesterol from cell membranes, and cells deficient in dynamin, a GTPase that regulates membrane action, were not infected by rotaviruses. These results indicate that cholesterol and dynamin play a role in the entry of rotaviruses and perhaps of other naked viruses too. The Sanchez-san et al. study suggests that rotavirus enters the cell either through non-clathrin-mediated, non-caveolae-mediated endocytosis or a direct mechanism at the cell surface. Continued developments in naked virus uptake can lead to the development of novel drugs that can inhibit cells from being infected with naked viruses.

Sanchez-San Martin C, Lopez T, Arias CF, Lopez S. Characterization of rotavirus cell entry. J Virol. 2004 Mar;78(5):2310-8.

Gene reassortment continues to add to rotavirus diversity
Recent rotavirus strain surveillance (Esona et. al) in Cameroon revealed the emergence of an unusual strain with G5 specificity. Found in a 12-month-old girl in South West Cameroon who had a community-acquired infection, this strain (MRC3105) more closely resembles a porcine G5 strain (CC117) than a human G5 strain (IAL-28). This finding is the first detection of a G5 strain outside of Latin America and suggests natural reassortment between animal and human rotavirus strains. Current vaccine efforts for rotavirus target the usual rotavirus strains with G1 to G4 specificity. The growing number of uncommon strains including G8, G9 in Africa, G9 in Asia, and G5 in Latin America, reveal the need for continued surveillance programs in humans and animals. (A study done by Banyai et al shows that the unusual strains P[9],G6 and P[8],G9 are not only present but common in Hungary.) Surveillance will be integral in developing effective vaccines that target the correct strains.

Esona MD, Armah GE, Geyer A, Steele AD. Detection of an unusual human rotavirus strain with G5P[8] specificity in a Cameroonian child with diarrhea. J Clin Microbiol. 2004 Jan;42(1):441-4.

Banyai K, Gentsch JR, Glass RI, Uj M, Mihaly I, Szucs G. Eight-year survey of human rotavirus strains demonstrates circulation of unusual G and P types in Hungary. J Clin Microbiol. 2004 Jan;42(1):393-7.

Reovirus effective in purging cancer cells within autografts
Autologous hematopoietic progenitor stem cell (ASC) transplantation, in which healthy blood and marrow cells (autograft) from one part of the body are transplated to areas that underwent high-dose chemotherapy, has become a more and more routine procedure. Unfortunately about 30% of these supposedly healthy cells are contaminated with cancer-infected cells. This contamination eventually leads to cancer relapse in some patients. Studies by Thirukkumaran et al. suggest that reovirus is effective in purging cancer-infected cells from autografts without detrimentally affecting too many healthy cells. Healthy CD34 and CD35 stem cells exposed to reovirus were found to replicate at the same rate as uninfected cells. Autografts contaminated with monocytic and myeloma cancer cells, however, witnessed significant cancer reduction upon introduction of reovirus as measured by flow cytometry and cancer cell outgrowth. Further studies are being conducted on different types of cancers as well as under more in vivo like conditions. Promising developments may eventually lead to patient testing.

Thirukkumaran CM, Luider JM, Stewart DA, Cheng T, Lupichuk SM, Nodwell MJ, Russell JA, Auer IA, Morris DG. Reovirus oncolysis as a novel purging strategy for autologous stem cell transplantation. Blood. 2003 Jul 1;102(1):377-87. Epub 2003 Mar 13.

Myocarditis may be linked to reovirus
An adult male patient complaining of fever, myalgia, and cardiac rhythm disorders was found to have reovirus in his stool. Other laboratory tests came back normal, and the patient tested negative to dengue, coxsackievirus, adenovirus, toxoplasmosis, cytomegalovirus, mycoplasma, anad plasmodium. Earlier an autopsied 10-month-old child was found to have reovirus caused myocarditis. Acute viral myocarditis, however, seems to be nonfatal.

Terheggen F, Benedikz E, Frissen PH, Brinkman K. Myocarditis associated with reovirus infection. Eur J Clin Microbiol Infect Dis. 2003 Mar;22(3):197-8. Epub 2003 Mar 01.<\p>

Reovirus treatment combined with immune suprression therapy increases survival
Hirasawa et. al recently conducted the first study of systematic combined therapy, involving reovirus treatment and immuno suppression, against oncolytic agents. Their studies conducted on mice (C3-L5 cells) showed that combined therapy resulted in enhanced tumor regressions as compared to reovirus therapy alone. Furthermore, mice survival rates were prolonged by combined therapy. It is believed that combined therapy helps overcome developed immunity to reovirus. Although preexisting immunity to reovirus has been shown not to decrease oncolytic effects when reovirus is directly injected into tumors, when reovirus is systematically introduced immunity does come into play. Studies have proven combined therapy safe enough that this method is currently undergoing Phase I clinical trials in Canada.

Hirasawa K, Nishikawa SG, Norman KL, Coffey MC, Thompson BG, Yoon CS, Waisman DM, Lee PW. Systemic reovirus therapy of metastatic cancer in immune-competent mice. Cancer Res. 2003 Jan 15;63(2):348-53.

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Images

1. Camazine, Scott. 2001. http://www.scottcamazine.com/photos/virus/pages/reovirus_jpg.htm

2. Veterinary Sciences Division. 2004. http://www.qub.ac.uk/afs/ vs/vsd6e.html

3. Sgro, Jean-yves. 2004. http://rhino.bocklabs.wisc.edu/virusworld/images/rep_virion.GIF

4. Steffens, W.L. 1998. http://www.vet.uga.edu/ivcvm/1998/steffens/fig16.jpg

5. Creekmore, Terry. 2002. http://wdhfs.state.wy.us/vector_borne/_borders/Image155.gif

6. Boulder County. 2004. http://www.co.boulder.co.us/health/hpe/images/rota.h2.gif

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Created: March 10, 2004
Last modified: March 10, 2004
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