Antigenic Variation in Microbial Evasion of Immune Responses


Antigenic variation is the means by which a number of highly pathogenic microorganisms, ranging from the electronmicroscopic human viruses to bacteria to fungi and unicellular protozoan parasites, passively evade immune surveillance. Through the understanding of the growing variety of mechanisms of the antigenic variation of surface proteins, it has become possible for us to determine what is preventing the host organism from mounting an effective immune response. Antigenic variation has serious public health consequences, for example, the current human immunodeficiency virus pandemic and the looming influenza pandemic, as well as a significant challenge to developing vaccines capable of eliciting long‐lasting or life‐long protective immunity against several pathogens.

Key Concepts:

  • Antigenic variation is a major mechanism of passively evading the host immune surveillance.

  • Antigenic variation is exhibited by a number of highly pathogenic microorganisms including human viruses, bacteria, fungi and unicellular protozoans.

  • Antigenic variation poses challenges to vaccine development against microorganisms causing major public health problems globally.

  • HIV‐1 surface glycoproteins display antigenic variation due to a high mutation rate during replication and significant tolerance of the variation.

  • Heterochromatin in the chromososome ends (telomers) in the malarial parasites mediate epigenetic regulation in the malaria parasite Plasmodium falciparum.

  • African trypanosomes control antigenic variation by periodically switching its variant surface glycoprotein involving transposition followed by recombination occurring at the telomeric expression site.

  • Targeting conserved regions of surface glycoproteins by using broadly neutralising antibodies against highly conserved exposed sites in surface proteins.

  • Targeting the oligosaccharides on surface glycoproteins, such as by the use of enveloped virus neutralising compounds (EVNCs).

Keywords: mutation; antigenic drift and shift; pandemic; gene switching; gene duplication; challenges to vaccine design

Figure 1.

Surface variation in trypanosomes. (a) Mechanism of transposition of trypanosomes in developing a large repertoire of VSGs. (b) Levels of antibody response following trypanosome infection. The level of antibody peaks after surface expression of the corresponding VSG has ceased.

Figure 2.

Proposed model for the broad‐spectrum neutralising, prophylactic and preventive oral vaccine against retroviruses (HIV and influenza). HIV and influenza (and their subtypes) surface glycoproteins play an important role in the pathogenesis mediated by these viruses. Owing to constant mutations in the cell surface glycoproteins, neutralising antibodies targeting one glycoprotein may not necessarily work against other isolates of the virus. Both pomegranate juice and fulvic acid contain acidic compounds. These compounds may bind to the lipid or the sugar chains on glycoproteins, and thereby neutralise the surface of the viruses and their isolates making them avirulant. These less virulant viruses may serve as antigens for the candidate vaccines. Unlike, neutralising antibodies, which target only one glycoprotein, the compounds may bind to most of the glycoproteins, an action, which makes them broad‐spectrum inhibitors of HIV, influenza and their subtypes.



Balzarini J (2007) Carbohydrate‐binding agents: a potential future cornerstone for the chemotherapy of enveloped viruses? Antiviral Chemistry and Chemotherapy 18: 1–11.

Blundell PA and Borst P (1998) Analysis of a variant surface glycoprotein gene expression site promoter of Trypanosoma brucei by remodeling the promoter region. Molecular and Biochemical Parasitology 94(1): 67–85.

Burton DR, Poignard P, Stanfield RL and Wilson IA (2012) Broadly neutralizing antibodies present new prospects to counter highly antigenically diverse viruses. Science 337(6091): 183–186.

Cahoon LA and Seifert S (2011) Focussing homologous recombination: pilin antigenic variation in the pathogenic Neisseria. Molecular Microbiology 81(5): 1136–1143.

Citti C and Rosengarten R (1997) Mycoplasma genetic variation and its implication for pathogenesis. Wiener Klinische Wochenschrift 109(14–15): 562–568.

Cui L and Miao J (2010) Chromatin‐mediated epigenetic regulation in the malaria parasite Plasmodium falciparum. Eucaryotic Cell 9: 1138–1149.

El Abd YS, Tabll AA, El Din NG et al. (2011) Neutralizing activities of caprine antibodies towards conserved regions of the HCV envelope glycoprotein E2. Virology Journal 8: 391.

Fields BN, Knipe DM and Howley PM (1996) Fundamental Virology, 3rd edn. Philadelphia, PA: Lippincott‐Raven.

Habte HH, Kotwal GJ, Lotz ZE et al. (2007) Antiviral activity of purified human breast milk mucin. Neonatology 92(2): 96–104.

Habte HH, Mall AS, de Beer C, Lotz ZE and Kahn D (2006) The role of crude human saliva and purified salivary MUC5B and MUC7 mucins in the inhibition of human immunodeficiency virus type I in an inhibition assay. Virology Journal 3: 99.

Hernandez‐Rivas R, Pérez‐Toledo K, Herrera Solorio AM, Delgadillo DM and Vargas M (2010) Telomeric heterochromatin in Plasmodium falciparum. Journal of Biomedicine and Biotechnology. doi: 10.1155/2010/290501.

Hill DJ, Griffiths NJ, Borodina E and Virji M (2010) Cellular and molecular biology of Neisseria meningitides colonization and invasive disease. Clinical Science 118: 547–564.

Horn D and McCulloch R (2010) Molecular mechanisms underlying the control of antigenic variation in African trypanosomes. Current Opinion in Microbiology 13(6): 700–705.

Huang S‐W, Kiang D, Smith DJ and Wang J‐R (2011) Evolution of re‐emergent virus and its impact on enterovirus 71 epidemics. Experimental Medicine and Biology 236: 899–908.

Humphreys I, Fleming V, Fabris P et al. (2009) Full‐length characterization of hepatitis C virus subtype 3a reveals novel hypervariable regions under positive selection during acute infection. Journal of Virology 83(22): 11456–11466.

Kaur A, Kamboj SS, Singh J et al. (2007) Purification of 3 monomeric monocot mannose‐binding lectins and their evaluation for antipoxviral activity: potential applications in multiple viral diseases caused by enveloped viruses. Biochemistry and Cell Biology 85(1): 88–95.

Keele BF, Van Heuverswyn F, Li Y et al. (2006) Chimpanzee reservoirs of pandemic and non pandemic HIV‐1. Science 313(5786): 523–526.

Kirkwood CD (2010) Genetic and antigenic diversity of human rotaviruses: potential impact on vaccination programs. Journal of Infectious Diseases 202(Suppl 1): S43–S48.

Kotwal GJ (1997) Microorganisms and their interaction with the immune system. Journal of Leukocyte Biology 62(4): 415–429.

Kotwal GJ (2008) Genetic diversity‐independent neutralization of pandemic viruses (e.g. HIV), potentially pandemic (e.g. H5N1 strain of influenza) and carcinogenic (e.g. HBV and HCV) viruses and possible agents of bioterrorism (variola) by enveloped virus neutralizing compounds (EVNCs). Vaccine 26(24): 3055–3058.

Kotwal GJ, Kacmarek JN, Leivers S et al. (2005) Anti‐HIV, anti‐poxvirus and anti‐SARS activity of a non‐toxic, acidic extract from the trifolium species Secomet/antiVac suggests that it contains a novel broad‐spectrum antiviral. Annals of New York Academy of Sciences 1056: 293–302.

Lan C‐Y (2002) Metabolic specialization associated with phenotypic switching in Candida albicans. PNAS 99: 14907–14912.

La Greca F and Magez S (2011) Vaccination against trypanosomiasis can it be done or is the trypanosome truly the ultimate immune destroyer and escape artist. Human Vaccines 7(11): 1225–1233.

Lauinger IL, Bible JM, Halligan EP et al. (2012) Lineages, sub‐lineages, and variants of enterovirus 68 in recent outbreaks. PLoS One 7(4): e36005.

Lohse MB, Zordan RE, Cain CW et al. (2010) Distinct class of DNA‐binding domain is exemplified by a master regulator of phenotypic switching in Candida albicans. Proceedings of the National Academy of Sciences 107(32): 14105–14110.

Meier UC, Klenerman P, Griffin P et al. (1995) Cytotoxic T lymphocyte lysis inhibited by viable HIV mutants. Science 270(5240): 1360–1362.

Meyer TF (1991) Evasion mechanisms of pathogenic Neisseriae. Behring Institute Mitteilungen 88: 194–199.

Ndung'u T and Weiss RA (2012) On HIV diversity. AIDS 26(10): 1255–1260.

Palacpac NM, Arisue N, Tougan T et al. (2011) Plasmodium falciparum serine repeat antigen 5 (SE36) as a malaria vaccine candidate. Vaccine 29(35): 5837–5845.

Palmer GH, Bankhead T and Lukehart SA (2009) Nothing is permanent but change – antigenic variation in persistent bacterial pathogens. Cellular Microbiology 11(12): 1697–1705.

Patton JT (2012) Rotavirus diversity and Evolution in the post‐Vaccine World. Discovery Medicine 13(68): 85–97.

Reeder JC and Brown GV (1996) Antigenic variation and immune evasion in Plasmodium falciparum malaria. Immunology and Cell Biology 74(6): 546–554.

Ropolo AS and Touz MC (2010) A lesson in survival, by Giardia lamblia. Scientific World Journal 10: 2019–2031.

Sampson SL (2011) Mycobacterial PE/PPE proteins at the Host–pathogen interface. Clinical and Developmental Immunology doi: 10.1155/2011/497203.

Saylor C, Dadachova E and Casadevall A (2009) Monoclonal antibody‐based therapies for microbial diseases. Vaccine 27(suppl. 6): G38–G46.

Shoham D (2006) Review: molecular evolution and the feasibility of an avian influenza virus becoming a pandemic strain – a conceptual shift. Virus Genes 33(2): 127–132.

Stijlemans B, Caljon G, Natesan SK et al. (2011) High affinity nanobodies against the Trypanosoma brucei VSG are potent trypanolytic agents that block endocytosis. PLoS Pathogens 7(6): e1002072.

Takehisa J, Kraus MH, Decker JM et al. (2007) Generation of infectious molecular clones of simian immunodeficiency virus from fecal consensus sequences of wild chimpanzees. Journal of Virology 81: 7463–7475.

Van Rensburg C, Dekker J, Weis R et al. (2002) Investigation of the anti‐HIV properties of oxihumate. Experimental Chemotherapy 48: 138–143.

Further Reading

Abbas AK, Lichtman AH and Pallai S (2007) Cellular and Molecular Immunology, 6th edn. Philadelphia, PA: WB Saunders.

Brisson D, Drecktrah D, Eggers CH and Samuels DS (2012) Genetics of Borrelia burgdorferi. Annual Reviews of Genetics 46(1): 11112–112140.

Delves PJ, Martin SJ, Burton DR and Roitt IM (2006) Essential Immunology, 11th edn. Oxford: Blackwell Publishing.

Murphy K, Travers P and Walport M (2007) Janeway's Immunobiology, 7th edn. London/New York: Current Biology/Garland.

Nash TE (2002) Surface antigenic variation in Giardia lamblia (2002). Molecular Microbiology 45(3): 585–590.

Pruca CG, Rivero FD and Lujan HD (2011) Regulation of antigenic variation in Giardia lamblia. Annual Reviews of Microbiology 65: 611–630.

Rainey PB, Beaumont HJ, Ferguson GC et al. (2011) The evolutionary emergence of stochastic phenotype switching in bacteria. Microbial Cell Factories 10(suppl. 1): S14.

Rudenko G, Cross M and Borst P (1998) Changing the end: antigenic variation orchestrated at the telomeres of African trypanosomes. Trends in Microbiology 6(3): 113–116.

Yewdell JW (2011) Viva la revolución: rethinking influenza a virus antigenic drift. Current Opinion in Virology 1(3): 177–183.

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Kotwal, Girish J, and Kulkarni, Amod P(May 2013) Antigenic Variation in Microbial Evasion of Immune Responses. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0001207.pub3]