Skip to main content
Top
Published in: Virology Journal 1/2017

Open Access 01-12-2017 | Review

Hepatitis delta: virological and clinical aspects

Authors: Luan Felipo Botelho-Souza, Mariana Pinheiro Alves Vasconcelos, Alcione de Oliveira dos Santos, Juan Miguel Villalobos Salcedo, Deusilene Souza Vieira

Published in: Virology Journal | Issue 1/2017

Login to get access

Abstract

There are an estimated 400 million chronic carriers of HBV worldwide; between 15 and 20 million have serological evidence of exposure to HDV. Traditionally, regions with high rates of endemicity are central and northern Africa, the Amazon Basin, eastern Europe and the Mediterranean, the Middle East and parts of Asia. There are two types of HDV/HBV infection which are differentiated by the previous status infection by HBV for the individual. Individuals with acute HBV infection contaminated by HDV is an HDV/HBV co-infection, while individuals with chronic HBV infection contaminated by HDV represent an HDV/HBV super-infection. The appropriate treatment for chronic hepatitis delta is still widely discussed since it does not have an effective drug. Alpha interferon is currently the only licensed therapy for the treatment of chronic hepatitis D. The most widely used drug is pegylated interferon but only approximately 25% of patients maintain a sustained viral response after 1 year of treatment. The best marker of therapeutic success would be the clearance of HBsAg, but this data is rare in clinical practice. Therefore, the best way to predict a sustained virologic response is the maintenance of undetectable HDV RNA levels.
Literature
1.
go back to reference Rizzetto M, Canese MG, Aricò S, Crivelli O, Trepo C, Bonino F, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut. [Internet]. 1977;18:997–1003. Available from: http://www.ncbi.nlm.nih.gov/pubmed/75123. Cited 29 Mar 2016.CrossRef Rizzetto M, Canese MG, Aricò S, Crivelli O, Trepo C, Bonino F, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut. [Internet]. 1977;18:997–1003. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​75123. Cited 29 Mar 2016.CrossRef
5.
go back to reference Rizzetto M, Shih JW, Gerin JL. The hepatitis B virus-associated delta antigen: isolation from liver, development of solid-phase radioimmunoassays for delta antigen and anti-delta and partial characterization of delta antigen. J Immunol. [Internet]. 1980;125:318–24. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6769999. Cited 29 Mar 2016. Rizzetto M, Shih JW, Gerin JL. The hepatitis B virus-associated delta antigen: isolation from liver, development of solid-phase radioimmunoassays for delta antigen and anti-delta and partial characterization of delta antigen. J Immunol. [Internet]. 1980;125:318–24. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​6769999. Cited 29 Mar 2016.
8.
12.
26.
34.
35.
go back to reference Mu J-J, Tsay Y-G, Juan L-J, Fu T-F, Huang W-H, Chen D-S, et al. The small delta antigen of hepatitis delta virus is an acetylated protein and acetylation of lysine 72 may influence its cellular localization and viral RNA synthesis. Virology. 2004;319:60–70.PubMedCrossRef Mu J-J, Tsay Y-G, Juan L-J, Fu T-F, Huang W-H, Chen D-S, et al. The small delta antigen of hepatitis delta virus is an acetylated protein and acetylation of lysine 72 may influence its cellular localization and viral RNA synthesis. Virology. 2004;319:60–70.PubMedCrossRef
39.
go back to reference Huang C-R, Wang RYL, Hsu S-C, Lo SJ. Lysine-71 in the large delta antigen of hepatitis delta virus clade 3 modulates its localization and secretion. Virus Res. 2012;170:75–84.PubMedCrossRef Huang C-R, Wang RYL, Hsu S-C, Lo SJ. Lysine-71 in the large delta antigen of hepatitis delta virus clade 3 modulates its localization and secretion. Virus Res. 2012;170:75–84.PubMedCrossRef
47.
go back to reference Webb C-HT, Nguyen D, Myszka M, Lupták A, Jimenez RM, Polanco JA, et al. Topological constraints of structural elements in regulation of catalytic activity in HDV-like self-cleaving ribozymes. Sci Rep. [Internet] Nature Publishing Group. 2016;6:28179. Available from: http://www.nature.com/articles/srep28179. Cited 5 July 2016. Webb C-HT, Nguyen D, Myszka M, Lupták A, Jimenez RM, Polanco JA, et al. Topological constraints of structural elements in regulation of catalytic activity in HDV-like self-cleaving ribozymes. Sci Rep. [Internet] Nature Publishing Group. 2016;6:28179. Available from: http://​www.​nature.​com/​articles/​srep28179. Cited 5 July 2016.
48.
go back to reference Elena SF, Dopazo J, Florest R, Diener TO, Moya A. Phylogeny of viroids, viroidlike satellite RNAs, and the viroidlike domain of hepatitis 6 virus RNA. Evolution (N Y). 1991;88:5631–4. Elena SF, Dopazo J, Florest R, Diener TO, Moya A. Phylogeny of viroids, viroidlike satellite RNAs, and the viroidlike domain of hepatitis 6 virus RNA. Evolution (N Y). 1991;88:5631–4.
51.
go back to reference Chao M, Wang T-C, Lin C-C, Wang RY-L, Lin W-B, Lee S-E, et al. Analyses of a whole-genome inter-clade recombination map of hepatitis delta virus suggest a host polymerase-driven and viral RNA structure-promoted template-switching mechanism for viral RNA recombination. Oncotarget. [Internet]. 2017; Available from: http://www.oncotarget.com/fulltext/18339. Cited 7 Aug 2017. Chao M, Wang T-C, Lin C-C, Wang RY-L, Lin W-B, Lee S-E, et al. Analyses of a whole-genome inter-clade recombination map of hepatitis delta virus suggest a host polymerase-driven and viral RNA structure-promoted template-switching mechanism for viral RNA recombination. Oncotarget. [Internet]. 2017; Available from: http://​www.​oncotarget.​com/​fulltext/​18339. Cited 7 Aug 2017.
54.
59.
go back to reference Alves C, Freitas N, Cunha C. Characterization of the nuclear localization signal of the hepatitis delta virus antigen. Virology. 2008;370:12–21.PubMedCrossRef Alves C, Freitas N, Cunha C. Characterization of the nuclear localization signal of the hepatitis delta virus antigen. Virology. 2008;370:12–21.PubMedCrossRef
60.
go back to reference Yan H, Li W. Sodium taurocholate cotransporting polypeptide acts as a receptor for hepatitis B and D virus. Dig Dis. 2015;33:388–96.PubMedCrossRef Yan H, Li W. Sodium taurocholate cotransporting polypeptide acts as a receptor for hepatitis B and D virus. Dig Dis. 2015;33:388–96.PubMedCrossRef
66.
go back to reference Sy BT, Nguyen HM, Toan NL, Song LH, Tong HV, Wolboldt C, et al. Identification of a natural intergenotypic recombinant hepatitis delta virus genotype 1 and 2 in Vietnamese HBsAg-positive patients. J Viral Hepat. [Internet]. 2015;22:55–63. Available from: http://doi.wiley.com/10.1111/jvh.12228. Cited 7 Aug 2017.CrossRef Sy BT, Nguyen HM, Toan NL, Song LH, Tong HV, Wolboldt C, et al. Identification of a natural intergenotypic recombinant hepatitis delta virus genotype 1 and 2 in Vietnamese HBsAg-positive patients. J Viral Hepat. [Internet]. 2015;22:55–63. Available from: http://​doi.​wiley.​com/​10.​1111/​jvh.​12228. Cited 7 Aug 2017.CrossRef
78.
go back to reference Botelho-Souza LF, Souza Vieira D, de Oliveira Dos Santos A, Cunha Pereira AV, Villalobos-Salcedo JM. Characterization of the genotypic profile of Hepatitis Delta virus: isolation of HDV Genotype-1 in the western Amazon region of Brazil. Intervirology. [Internet]. 2015;58:166–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/26112316. Cited 6 July 2016.CrossRef Botelho-Souza LF, Souza Vieira D, de Oliveira Dos Santos A, Cunha Pereira AV, Villalobos-Salcedo JM. Characterization of the genotypic profile of Hepatitis Delta virus: isolation of HDV Genotype-1 in the western Amazon region of Brazil. Intervirology. [Internet]. 2015;58:166–71. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​26112316. Cited 6 July 2016.CrossRef
82.
go back to reference Alvarado-Mora MV, Fernandez MFG, Gomes-Gouvêa MS, de Azevedo Neto RS, Carrilho FJ, Pinho JRR. Hepatitis B (HBV), hepatitis C (HCV) and hepatitis delta (HDV) viruses in the Colombian population--how is the epidemiological situation? PLoS One. [Internet]. 2011;6:e18888. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21559488. Cited 6 July 2016.CrossRef Alvarado-Mora MV, Fernandez MFG, Gomes-Gouvêa MS, de Azevedo Neto RS, Carrilho FJ, Pinho JRR. Hepatitis B (HBV), hepatitis C (HCV) and hepatitis delta (HDV) viruses in the Colombian population--how is the epidemiological situation? PLoS One. [Internet]. 2011;6:e18888. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​21559488. Cited 6 July 2016.CrossRef
83.
go back to reference Gomes-Gouvêa MS, do Pereira Soares MC, Guedes de Carvalho Mello IMV, Brito EMF, de Pereira Moia LJM, Bensabath G, et al. Hepatitis D and B virus genotypes in chronically infected patients from the eastern Amazon Basin. Acta Trop. [Internet]. 2008;106:149–55. Available from: http://www.ncbi.nlm.nih.gov/pubmed/18420172. Cited 6 July 2016.CrossRef Gomes-Gouvêa MS, do Pereira Soares MC, Guedes de Carvalho Mello IMV, Brito EMF, de Pereira Moia LJM, Bensabath G, et al. Hepatitis D and B virus genotypes in chronically infected patients from the eastern Amazon Basin. Acta Trop. [Internet]. 2008;106:149–55. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​18420172. Cited 6 July 2016.CrossRef
84.
go back to reference Gomes-Gouvêa MS, Soares MCP, Bensabath G, de Carvalho-Mello IMVG, Brito EMF, Souza OSC, et al. Hepatitis B virus and hepatitis delta virus genotypes in outbreaks of fulminant hepatitis (Labrea black fever) in the western Brazilian Amazon region. J Gen Virol. [Internet]. 2009;90:2638–43. Available from: http://www.ncbi.nlm.nih.gov/pubmed/19605587. Cited 6 July 2016.CrossRef Gomes-Gouvêa MS, Soares MCP, Bensabath G, de Carvalho-Mello IMVG, Brito EMF, Souza OSC, et al. Hepatitis B virus and hepatitis delta virus genotypes in outbreaks of fulminant hepatitis (Labrea black fever) in the western Brazilian Amazon region. J Gen Virol. [Internet]. 2009;90:2638–43. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​19605587. Cited 6 July 2016.CrossRef
90.
go back to reference Fonseca JC, Simonetti SR, Schatzmayr HG, Castejón MJ, Cesário AL, Simonetti JP. Prevalence of infection with hepatitis delta virus (HDV) among carriers of hepatitis B surface antigen in Amazonas state, Brazil. Trans R Soc Trop Med Hyg. [Internet]. 1988;82:469–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3232188. Cited 6 July 2016.CrossRef Fonseca JC, Simonetti SR, Schatzmayr HG, Castejón MJ, Cesário AL, Simonetti JP. Prevalence of infection with hepatitis delta virus (HDV) among carriers of hepatitis B surface antigen in Amazonas state, Brazil. Trans R Soc Trop Med Hyg. [Internet]. 1988;82:469–71. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​3232188. Cited 6 July 2016.CrossRef
91.
go back to reference Vasconcelos M, Pereira DB, Paraná R, Villalobos-Salcedo JM. Clinic and laboratory analysis of patients with hepatitis delta in Amazon region, Brazil. J Med Med Sci. [Internet]. 2012;3:263–9. Available from: http://www.interesjournals.org/JMMS. Cited 6 July 2016. Vasconcelos M, Pereira DB, Paraná R, Villalobos-Salcedo JM. Clinic and laboratory analysis of patients with hepatitis delta in Amazon region, Brazil. J Med Med Sci. [Internet]. 2012;3:263–9. Available from: http://​www.​interesjournals.​org/​JMMS. Cited 6 July 2016.
94.
go back to reference Mendes-Correa MC, Gomes-Gouvêa MS, Alvarado-Mora MV, Da Silva MH, Lázari C, Cavalcanti NCS, et al. Hepatitis delta in HIV/HBV co-infected patients in Brazil: is it important? Int J Infect Dis. 2011;15:e828–32.PubMedCrossRef Mendes-Correa MC, Gomes-Gouvêa MS, Alvarado-Mora MV, Da Silva MH, Lázari C, Cavalcanti NCS, et al. Hepatitis delta in HIV/HBV co-infected patients in Brazil: is it important? Int J Infect Dis. 2011;15:e828–32.PubMedCrossRef
98.
go back to reference Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, de Franchis R, et al. A 28-year study of the course of hepatitis Δ infection: a risk factor for cirrhosis and Hepatocellular carcinoma. Gastroenterology. 2009;136:1629–38.PubMedCrossRef Romeo R, Del Ninno E, Rumi M, Russo A, Sangiovanni A, de Franchis R, et al. A 28-year study of the course of hepatitis Δ infection: a risk factor for cirrhosis and Hepatocellular carcinoma. Gastroenterology. 2009;136:1629–38.PubMedCrossRef
102.
103.
go back to reference Casey JL, Niro GA, Engle RE, Vega A, Gomez H, McCarthy M, et al. Hepatitis B virus (HBV)/hepatitis D virus (HDV) coinfection in outbreaks of acute hepatitis in the Peruvian Amazon basin: the roles of HDV genotype III and HBV genotype F. J Infect Dis. [Internet]. 1996;174:920–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8896491. Cited 7 July 2016.CrossRef Casey JL, Niro GA, Engle RE, Vega A, Gomez H, McCarthy M, et al. Hepatitis B virus (HBV)/hepatitis D virus (HDV) coinfection in outbreaks of acute hepatitis in the Peruvian Amazon basin: the roles of HDV genotype III and HBV genotype F. J Infect Dis. [Internet]. 1996;174:920–6. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​8896491. Cited 7 July 2016.CrossRef
104.
go back to reference Schaper M, Rodriguez-Frias F, Jardi R, Tabernero D, Homs M, Ruiz G, et al. Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D. J Hepatol. 2010;52:658–64.PubMedCrossRef Schaper M, Rodriguez-Frias F, Jardi R, Tabernero D, Homs M, Ruiz G, et al. Quantitative longitudinal evaluations of hepatitis delta virus RNA and hepatitis B virus DNA shows a dynamic, complex replicative profile in chronic hepatitis B and D. J Hepatol. 2010;52:658–64.PubMedCrossRef
105.
go back to reference Lozano JL, Crespo J, de la Cruz F, Casafont F, Lopez-Arias MJ, Martín-Ramos L, et al. Correlation between hepatitis B viremia and the clinical and histological activity of chronic delta hepatitis. Med Microbiol Immunol. [Internet]. 1994;183:159–67. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7997189. Cited 7 July 2016.CrossRef Lozano JL, Crespo J, de la Cruz F, Casafont F, Lopez-Arias MJ, Martín-Ramos L, et al. Correlation between hepatitis B viremia and the clinical and histological activity of chronic delta hepatitis. Med Microbiol Immunol. [Internet]. 1994;183:159–67. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​7997189. Cited 7 July 2016.CrossRef
106.
go back to reference Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, Realdi G, et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European concerted action on viral hepatitis (Eurohep). Gut. [Internet]. 2000;46:420–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/10673308. Cited 7 July 2016.CrossRef Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, Realdi G, et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European concerted action on viral hepatitis (Eurohep). Gut. [Internet]. 2000;46:420–6. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​10673308. Cited 7 July 2016.CrossRef
108.
go back to reference Buti M, Esteban R, Roggendorf M, Fernandez J, Jardi R, Rashofer R, et al. Hepatitis D virus RNA in acute delta infection: serological profile and correlation with other markers of hepatitis D virus infection. Hepatology. [Internet]. 1988;8:1125–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/3417234. Cited 7 July 2016.CrossRef Buti M, Esteban R, Roggendorf M, Fernandez J, Jardi R, Rashofer R, et al. Hepatitis D virus RNA in acute delta infection: serological profile and correlation with other markers of hepatitis D virus infection. Hepatology. [Internet]. 1988;8:1125–9. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​3417234. Cited 7 July 2016.CrossRef
110.
go back to reference Buti M, Lopez-Talavera JC, Allende H, Jardi R, Esteban R, Guardia J. Serological diagnosis of chronic delta infection: correlation between serological markers and hepatitis delta virus RNA in hepatic tissue. Prog Clin Biol Res. [Internet]. 1993;382:319–23. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8502697. Cited 7 July 2016. Buti M, Lopez-Talavera JC, Allende H, Jardi R, Esteban R, Guardia J. Serological diagnosis of chronic delta infection: correlation between serological markers and hepatitis delta virus RNA in hepatic tissue. Prog Clin Biol Res. [Internet]. 1993;382:319–23. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​8502697. Cited 7 July 2016.
112.
go back to reference Jardi R, Buti M, Cotrina M, Rodriguez F, Allende H, Esteban R, et al. Determination of hepatitis delta virus RNA by polymerase chain reaction in acute and chronic delta infection. Hepatology. [Internet] WB Saunders. 1995;21:25–9. Available from: http://doi.wiley.com/10.1002/hep.1840210106. Cited 7 July 2016. Jardi R, Buti M, Cotrina M, Rodriguez F, Allende H, Esteban R, et al. Determination of hepatitis delta virus RNA by polymerase chain reaction in acute and chronic delta infection. Hepatology. [Internet] WB Saunders. 1995;21:25–9. Available from: http://​doi.​wiley.​com/​10.​1002/​hep.​1840210106. Cited 7 July 2016.
113.
118.
128.
go back to reference Gheorghe L, Iacob S, Simionov I, Vadan R, Constantinescu I, Caruntu F, et al. Weight-based dosing regimen of peg-interferon α-2b for chronic hepatitis delta: a multicenter Romanian trial. J Gastrointestin Liver Dis. [Internet]. 2011;20:377–82. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22187703. Cited 8 July 2016. Gheorghe L, Iacob S, Simionov I, Vadan R, Constantinescu I, Caruntu F, et al. Weight-based dosing regimen of peg-interferon α-2b for chronic hepatitis delta: a multicenter Romanian trial. J Gastrointestin Liver Dis. [Internet]. 2011;20:377–82. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​22187703. Cited 8 July 2016.
131.
137.
go back to reference Manesis EK, Vourli G, Dalekos G, Vasiliadis T, Manolaki N, Hounta A, et al. Prevalence and clinical course of hepatitis delta infection in Greece: a 13-year prospective study. J Hepatol. 2013;59:949–56.PubMedCrossRef Manesis EK, Vourli G, Dalekos G, Vasiliadis T, Manolaki N, Hounta A, et al. Prevalence and clinical course of hepatitis delta infection in Greece: a 13-year prospective study. J Hepatol. 2013;59:949–56.PubMedCrossRef
145.
go back to reference Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of interferon α therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology. 2004;126:1740–9.PubMedCrossRef Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, et al. Long-term benefit of interferon α therapy of chronic hepatitis D: regression of advanced hepatic fibrosis. Gastroenterology. 2004;126:1740–9.PubMedCrossRef
146.
go back to reference Madejón A, Cotonat T, Bartolomé J, Castillo I, Carreño V. Treatment of chronic hepatitis D virus infection with low and high doses of interferon-alpha 2a: utility of polymerase chain reaction in monitoring antiviral response. Hepatology. [Internet]. 1994;19:1331–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8188163. Cited 8 July 2016.CrossRef Madejón A, Cotonat T, Bartolomé J, Castillo I, Carreño V. Treatment of chronic hepatitis D virus infection with low and high doses of interferon-alpha 2a: utility of polymerase chain reaction in monitoring antiviral response. Hepatology. [Internet]. 1994;19:1331–6. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​8188163. Cited 8 July 2016.CrossRef
148.
go back to reference Yurdaydin C, Bozkaya H, Gürel S, Tillmann HL, Aslan N, Okçu-Heper A, et al. Famciclovir treatment of chronic delta hepatitis. J Hepatol. 2002;37:266–71.PubMedCrossRef Yurdaydin C, Bozkaya H, Gürel S, Tillmann HL, Aslan N, Okçu-Heper A, et al. Famciclovir treatment of chronic delta hepatitis. J Hepatol. 2002;37:266–71.PubMedCrossRef
151.
go back to reference Canbakan B, Senturk H, Tabak F, Akdogan M, Tahan V, Mert A, et al. Efficacy of interferon alpha-2b and lamivudine combination treatment in comparison to interferon alpha-2b alone in chronic delta hepatitis: a randomized trial. J Gastroenterol Hepatol. [Internet]. 2006;21:657–63. Available from: http://www.ncbi.nlm.nih.gov/pubmed/16677149. Cited 8 July 2016.CrossRef Canbakan B, Senturk H, Tabak F, Akdogan M, Tahan V, Mert A, et al. Efficacy of interferon alpha-2b and lamivudine combination treatment in comparison to interferon alpha-2b alone in chronic delta hepatitis: a randomized trial. J Gastroenterol Hepatol. [Internet]. 2006;21:657–63. Available from: http://​www.​ncbi.​nlm.​nih.​gov/​pubmed/​16677149. Cited 8 July 2016.CrossRef
Metadata
Title
Hepatitis delta: virological and clinical aspects
Authors
Luan Felipo Botelho-Souza
Mariana Pinheiro Alves Vasconcelos
Alcione de Oliveira dos Santos
Juan Miguel Villalobos Salcedo
Deusilene Souza Vieira
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Virology Journal / Issue 1/2017
Electronic ISSN: 1743-422X
DOI
https://doi.org/10.1186/s12985-017-0845-y

Other articles of this Issue 1/2017

Virology Journal 1/2017 Go to the issue