DEPARTMENT OF VIRUS-CELL INTERACTION


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Vadim Izrailevich Agol

Head of Department, Corresponding Member of Russian Academy of Sciences and Russian Academy of Medical Sciences, Sc.D., Professor

The Department was organized in 1965, and is headed until present, by Prof. V. I.Agol.

The Department includes Laboratory of molecular epidemiology ( Head:  PhD G.Yu. Lipskaya).  Among staff members and graduate students working in the Department during different period of times – G.A.Belov,  E.A.Cherkasova, I.M.Chumakov, K.M.Chumakov, V.A.Ginevskaya, A.P.Gmyl, A,E,Gorbalenya, T.M.Dmitrieva, E.V.Koonin, T.V.Pestova, E.V.Pilipenko, Yu.V.Svitkin, T.G.Senkevich, T.Yu.Ugaroiva.

Main lines of investigation:   Replication and recombination of viral RNA; translation of viral RNA, its control and role in viral pathogenicity; cell response to viral infection; molecular epidemiology and evolution of poliovirus.

Participation in research projects (programs) and grant support.
In Russia, the research is carried out in collaboration with some other Departments of the Belozersky Institute as well as with the M.P.Chumakov Institute of Poliomyelitis and Viral Encephalitides of the Russian Academy of Mededical Sciencies. The Department also collaborated with the Institute of Protein Research of the Russ. Acad. Sci. Among foreign collaborators have been Food and Drug Administration (USA); National Institutes of Health (USA), Univ. of Wisconsin (USA), Univ of Basel (Switzerland), Radboud Univ. of Nijmegen (the Netherlands) and oth. The research has been supported by the Russian Foundatioon for Basic Research, the Program for Support of Leading Scientific Schools, International Science Foundation, Human Frontier Science Program, INTAS, World Health Organization, Fogarty, Copernicus. Ludwig Cancer Research Institute and oth.
 

Major research advances:   Working out of the first cell-free system for efficient synthesis and processing of picornavirus proteins [Svitkin et al., 1978]. Identification of a protease (now called 3C) involved in this processing  [Gorbalenya et al., 1979; Svitkin et al., 1979]. Characterization of structure-function relationships in the translational cis-elements of picornaviral RNAs [Pilipenko et al., 1989; 1989a; 1992; 1994; Gmyl et al., 1993]. Discovery of dependence of neurovirulence of picornaviruses on the structure and functional efficiency of translational cis-elements of their RNAs [Svitkin et al., 1985; Pilipenko et al., 1995; 1999]. Characterization of protein trans-factors controlling translation of viral RNAs [Svitkin et al., 1988; 1994; Pilipenko et al., 2000; 2001; Pestova et al., 2001]. First cell-free translation of the tick-borne encephalitis (flavivirus) RNA and demonstration that the proteins of this virus are generated by membrane-dependent limited proteolysis of a high-molecular-mass precursor and mapping of the genes for structural protein of this virus [Svitkin et al., 1978; 1981; 1984; Lyapustin et al., 1986]. Discovery of differences in the molecular mechanisms of translational shut-off induced by different picornaviruses [Svitkin et al., 1978]. First biochemical evidence for the existence of intermolecular recombination between RNA genomes [Romanova et al., 1980]. Elaboration of models for replicative (template-switch) RNA recombination [Romanova et al., 1986; Tolskaya et al., 1987; Pilipenko et al., 1995]. Discovery of nonreplicative recombination between viral RNA genomes [Gmyl et al., 1999; 2003]. Introduction of recombinational analysis for genetic mapping picornavirus functions, in particular, attenuation determinants of poliovirus vaccine strains [Agol et al., 1984]. Discovery of circular  [Romanova, Agol, 1979] and palindromic [Senkevich et al., 1980] forms of virus-specific RNAs. Discovery of participation of host proteins in replication of picornavirus RNA [Dmitrieva et al., 1979]. Structural and functional characterization of a cis-element involved in the initiation of negative strands of enterovirus RNA [Pilipenko et al., 1992; 1996]. Discovery of a kinetic coupling between substrate (rNTP) synthesis and polymerization of picornavirus RNA [Koonin, Agol, 1982; 1984]. Discovery of apoptosis-inducing and apoptosis-preventing functions of poliovirus [Tolskaya et al., 1995]. Poliovirus-induced cell death may result from one of the competing programs, apoptosis or canonical cytopathic effect [Agol et al., 1998; 2000]. The poliovirus-triggered apoptotic program involves mitochondrial damage accompanied by the exit of pro-apoptotic factors, whereas one of the anti-apoptotic mechanisms involves aberrant processing of caspase-9 [Belov et al., 2003] but the implementation of this program may vary in a host-dependent way [Romanova et al., 2005] . Poliovirus non-structural protein 3A reduces presentation of TNF- receptor (and of some other receptors) on cellular membrane, suppressing thereby the ability of TNF- to induce apoptosis of the infected cells [Neznanov et al., 2001]. Poliovirus infection destroys, through the protease activity of its protein 2A, nuclear pores and consequently the barrier function of nuclear envelope, facilitating thereby bidirectional nucleo-cytoplasmic protein trafficking [Belov et al., 1999, 2004]. Another picornavirus, encephalomyocarditis virus, induces similar alterations in nucleo-cytoplasmic traffic but in this case the effect is due to the viral leader protein devoid of any known enzymatic activity [Lidsky et al., 2006].It is demonstrated that the majority of polioviruses isolated from patients with vaccine-associated poliomyelitis are represented by intertypic recombinants  [Lipskaya et al., 1991]. Derivatives of the Sabin poliovaccine exhibit a significant capacity to circulate in poorly immunized [Korotkova et al., 2003; Cherkasova et al., 2005] and apparently adequately immunized [Cherkasova et al., 2002; 2003] human populations. Oligonucleotide microarray-based methods for characterization of genomes of poliovaccine derivatives have been worked out [Cherkasova et al., 2003]. The genomes of wild polioviruses circulating on the territory of the former USSR have been characterized and the possible routes of their circulation were suggested [Lipskaya et al., 1995]. Some general regularities of evolution of wild and vaccine polioviruses have been revealed [Gavrilin et al., 2000; Agol, 2002, 2006].

Some important publications:
1.    Svitkin YV, Agol VI. Complete translation of encephalomyocarditis virus RNA and faithful cleavage of virus-specific proteins in a cell-free system from krebs-2 cells. FEBS Lett. 1978; 87: 7-11.
2.    Svitkin YV, Gorbalenya AE, Kazachkov YA. Agol VI. Encephalomyocarditis virus-specific polypeptide p22 possessing a proteolytic activity. FEBS Lett. 1979; 108: 6-9.
3.    Romanova LI, Tolskaya EA, Kolesnikova MS, Agol VI. Biochemical evidence for intertypic genetic recombination of polioviruses. FEBS Lett. 1980; 118: 109-12.
4.    Agol VI, Grachev VP, Drozdov SG, Frolova MP, Kolesnikova MS, Kozlov VG, Ralph NM, Romanova LI, Tolskaya EA, Tyufanov AV, Viktorova EG. Construction and pro-perties of intertypic poliovirus recombinants: First approximation mapping of the major determinants of neurovirulence. Virology. 1984; 136: 41-55.
5.    Svitkin YV, Maslova SV, Agol VI. The genomes of attenuated and virulent poliovirus strains differ in their in vitro translation efficiencies. Virology. 1985; 147: 243-52.
6.    Romanova LI, Blinov VM, Tolskaya EA, Viktorova EG, Kolesnikova MS, Guseva E A, Agol VI. The pimary structure of crossover regions of intertypic poliovirus recombinants: a model of recombination between RNA genomes. Virology. 1986; 155: 202-13.
7.    Svitkin YV, Pestova TV, Maslova SV, Agol VI. Point mutations modify the response of poliovirus RNA to a translation initiation factor: a comparison of neurovirulent and attenuated strains. Virology. 1988; 166: 394-404.
8.    Pilipenko EV, Blinov VM, Romanova LI, Sinyakov AN, Maslova SV, Agol VI. Conserved structural domains in the 5'-untranslated region of picornaviral genomes: an analysis of the segment controlling translation and neurovirulence. Virology. 1989; 168: 201-9.
9.    Pilipenko EV, Blinov VM, Chernov TM, Agol VI. Conservation of the secondary structure elements of the 5'-untranslated region of cardio- and aphthovirus RNAs. Nucl Acids Res. 1989; 17: 5701-11.
10.    Lipskaya GYu, Muzychenko AR, Kutitova OK, Maslova SV, Equestre M, Drozdov SG, Perez-Bercoff R, Agol VI. Frequent isolation of intertypic poliovirus recombinants with serotype 2 specificity from vaccine-associated polio cases. J Med Virol. 1991; 35: 290-6.
11.    Pilipenko EV, Gmyl AP, Maslova SV, Svitkin YV, Sinyakov AN, Agol VI. Prokaryotic-like cis element in the cap-independent internal initiation of translation on picornavirus RNA. Cell. 1992; 68: 119-31.
12.    Teterina NL, Kean KM, Gorbalenya AE, Agol VI, Girard M. Analysis of functional significance of amino acid residues in the putative NTP-binding pattern of the poliovirus 2C protein. J Gen Virol. 1992; 73: 1977-86.
13.    Cho MW, Richards OC, Dmitrieva TM, Agol VI, Ehrenfeld E. RNA duplex unwinding activity of poliovirus RNA-dependent RNA polymerase 3Dpol. J Virol. 1994; 67: 3010-8.
14.    Tolskaya EA, Romanova LI, Kolesnikova MS, Gmyl AP, Gorbalenya AE, Agol VI. Genetic studies on the NTP-binding pattern containing 2C protein of poliovirus: Possible mechanism of guanidine effect on 2C function and evidence for importance of 2C oligomerization. J Mol Biol. 1994; 236: 1310-23.
15.    Pilipenko EV, Gmyl AP, Maslova SV, Belov GA, Sinyakov AN, Huang M, Brown TDK, Agol VI. Starting window, distinct element in the cap-independent internal initiation of translation on picornaviral RNA. J Mol Biol. 1994; 241: 398-414.
16.    Tolskaya EA, Romanova LI, Kolesnikova MS, Ivannikova TA, Smirnova EA, Raikhlin NT, Agol VI. Apoptosis-inducing and apoptosis-preventing functions of poliovirus. J Virol. 1995; 69: 1181-9.
17.    Pilipenko EV, Poperechny KV, Maslova SV, Melchers WJG, Bruins Slot HJ, Agol VI. Cis-element, oriR, involved in the initiation of (-) strand poliovirus RNA: a quasi-globular multi-domain RNA structure maintained by tertiary ("kissing") interactions. EMBO J. 1996; 119: 5428-36.
18.    Gmyl AP, Belousov EV, Maslova SV, Khitrina EV, Chetverin AB, Agol VI. Nonreplicative RNA recombination in poliovirus. J Virol. 1999; 73: 8958-65.
19.    Belov GA, Evstafieva AG, Mikitas OV, Vartapetian AB, Agol VI. Early alteration of nucleo-cytoplasmic traffic induced by some RNA viruses. Virology. 2000; 275: 244-8.
20.    Pilipenko EV, Pestova TV, Kolupaeva VG, Khitrina EV, Poperechnaya AN, Agol VI, Hellen CUT. A cell-cycle dependent protein serves as a template-specific translation initiation factor. Genes Dev. 2000; 14: 2028-45.

Some publications of 2001-2003:

1.    Pestova TV, Kolupaeva VG, Lomakin IB, Pilipenko EV, Shatsky IN, Agol VI, Hellen CU. Molecular mechanisms of translation initiation in eukaryotes. Proc Natl Acad Sci USA. 2001; 98: 7029-36.
2.    Neznanov N, Kondratova A, Chumakov KM, Angres B, Zhumabayeva B, Agol VI, Gudkov AV. Poliovirus protein 3A inhibits TNF-induced apoptosis by eliminating TNF receptor from the cell surface. J Virol. 2001; 75: 10409-20.
3.    Pilipenko EV, Viktorova EG, Guest ST, Agol VI, Roos RP. Cell-specific proteins regulate viral RNA translation and virus-induced disease. EMBO J. 2001; 20: 6899-908.
4.    Cherkasova EA, Korotkova EA, Yakovenko ML,. Ivanova OE, Eremeeva TP, Chumakov KM, Agol VI. Long-term circulation of vaccine-derived poliovirus that causes paralytic disease. J Virol. 2002; 76: 6791-9.
5.    Agol VI. Picornavirus genome: An overview. In: B. Semler, E. Wimmer, Eds. Molecular Biology of Picornàviruses. ASM Press, Washington, DC, 2002; 127-48.
6.    Agol VI. Picornavirus genetics: An overview. In: In: B. Semler, E. Wimmer Eds Molecular Biology of Picornàviruses. ASM Press, Washington, DC, 2002; 269-84.
7.    Belov GA, Romanova LI, Tolskaya EA, Kolesnikova MS, Lazebnik YA, Agol VI. The major apoptotic pathway activated and suppressed by poliovirus. J Virol. 2003; 77: 45-56.
8.    Cherkasova EA, Laassri M, Chizhikov V, Korotkova EA, Dragunsky E, Agol VI, Chumakov KM. Microarray analysis of evolution of RNA viruses: Evidence of circulation of virulent highly divergent vaccine- derived polioviruses. Proc Natl Acad Sci USA 2003; 100: 9398-403.
9.    Gmyl AP, Korshenko SA, Belousov EV, Khitrina EV, Agol VI. Nonreplicative homologous RNA recombination: Promiscuous joining of RNA pieces? RNA. 2003; 9: 1221-31.
10.    Korotkova EA, Park R, Cherkasova, EA, Lipskaya GYu, Chumakov KM, Feldman EV, Kew OM, Agol VI. Retrospective analysis of a local cessation of vaccination against poliomyelitis: a possible scenario for the future. J Virol. 2003; 77: 12460-5.

Some publications since 2004:
1.    Belov GA, Lidsky PV, Mikitas OV, Egger D, Lukyanov KA, Bienz K, Agol VI. 2004. Bidirectional increase in permeability of nuclear envelope upon poliovirus infection and accompanying alterations of nuclear pores . J. Virol. 78: 10166-10177.
2.    Kew OM, Wright PF, Agol VI, Delpeyroux F, Shimizu H, Nathanson N, and Pallansch MA. 2004. Circulating vaccine-derived polioviruses: current state of knowledge. Bulletin of the WHO 82(1):16-23. 
3.    Cherkasova EA, Yakovenko ML, Rezapkin GV, Korotkova EA, Ivanova OE, Eremeeva TP, Krasnoproshina LI, Romanenkova NI, Rozaeva NR, Sirota L, Agol VI, Chumakov KM. 2005. Spread of vaccine-derived poliovirus from a paralytic case in immunodeficient child: an insight into natural evolution of oral polio vaccine. J. Virol. 79:1062-1070.
4.    Romanova LI, Belov GA, Lidsky PV, Tolskaya EA, Kolesnikova MS, Evstafieva AG, Vartapetian AB, Egger, D, Bienz, K, Agol VI. 2005. Variability in apoptotic response to poliovirus infection. Virology 331:292-306.
5.    Agol VI, Chumakov KM, Ehrefeld E, Wimmer E. 2005. Don, t drop current vaccine until we have new ones. Nature 435, p. 881.
6.    Ãìûëü ÀÏ,  Àãîë ÂÈ. 2005. Ìíîãîîáðàçèå ìåõàíèçìîâ ÐÍÊ ðåêîìáèíàöèè. Ìîë. Áèîë. ¹4, ñ. 618-632.
7.    Lidsky PV, Hato S, Bardina MV, Aminev AG, Palmenberg AC, van Kuppeveld FJM and Agol VI. 2006. Nucleo-cytoplasmic traffic disorder induced by cardioviruses. J. Virol. 80:2705-2717.
8.    Ëèäñêèé ÏÂ, Àãîë ÂÈ. 2006. Êàê ïîëèîâèðóñ èçìåíÿåò êëåòêó? Âîïð. âèðóñîë. ¹1 ñ.4-11.
9.    Â. È. Àãîë. 2006. Âèðóñû. Áîëüøàÿ Ðîññèéñêàÿ Ýíöèêëîïåäèÿ (â ïå÷àòè)
10.    Agol VI. 2006. Vaccine-derived polioviruses. Biologicals. (in press)
11.    Agol VI.. Molecular mechanisms of poliovirus variation and evolution. Curr. Top. Microbiol. Immunol. 299:211.
12.    Yakovenko ML, Cherkasova EA, Rezapkin GV, Ivanov AP, Ivanova OE, Eremeeva TP, and Agol VI. 2006. Antigenic evolution of vaccine-derived polioviruses: Changes in individual epitopes and relative stability of the overall immunological properties. J. Virol. 80:2641-2653.