Antigenic variation

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Antigenic variation refers to the mechanism by which an infectious agent such as a protozoan, bacterium or virus alters its surface proteins in order to avoid a host immune response. It is related to phase variation. Immune evasion is particularly important for organisms that target long-lived hosts, repeatedly infect a single host and are easily transmittable. Antigenic variation not only enables immune evasion by the pathogen, but also allows the microbes to cause re-infection, as their antigens are no longer recognized by the host's immune system. When an organism is exposed to a particular antigen (i.e. a protein on the surface of a bacterium) an immune response is stimulated and antibodies are generated to target that specific antigen. The immune system will then "remember" that particular antigen, and defenses aimed at that antigen become part of the immune system’s acquired immune response. If the same pathogen tries to re-infect the same host the antibodies will act rapidly to target the pathogen for destruction. However, if the pathogen can alter its surface antigens, it can evade the host's acquired immune system. This will allow the pathogen to re-infect the host while the immune system generates new antibodies to target the newly identified antigen. Antigenic variation can occur by altering a variety of surface molecules including proteins and carbohydrates. There are many molecular mechanisms behind antigenic variation, including gene conversion,[1] site-specific DNA inversions,[2] hypermutation,[3] as well as recombination of sequence cassettes.[4] In all cases, antigenic variation and phase variation result in a heterogenic phenotype of a clonal population.[5] Individual cells either express the phase-variable protein(s) or express one of multiple antigenic forms of the protein. This form of regulation has been identified mainly, but not exclusively, for a wide variety of surface structures in pathogens and is implicated as a virulence strategy.[6]

In bacteria[edit]

Antigenic variation in bacteria is best demonstrated by species of the genus Neisseria (most notably, Neisseria meningitidis and Neisseria gonorrhoeae, the gonococcus); species of the genus Streptococcus and the Mycoplasma. The Neisseria species mentioned variate their pili (protein polymers made up of subunits called pilin which play a critical role in bacterial adhesion, they are antigens which stimulate a vigorous host immune response) and the Streptococci variate their M-protein.

Additionally, Lyme disease is caused by the bacterium Borrelia burgdorferi. The surface lipoprotein VlsE can undergo recombination which results in antigenic diversity. The bacterium carries a plasmid that contains fifteen silent vls cassettes and one functional copy of vlsE. Segments of the silent cassettes recombine with the vlsE gene. Variety generated of the surface lipoprotein antigen allows the bacterium to evade the host humoral immune system.[7]

In protozoa[edit]

Antigenic variation is employed by a number of different protozoan parasites. Trypanosoma brucei (the model for study of protozoan antigenic variation) and Plasmodium falciparum are some of the most well studied examples of protozoan parasites that exhibit antigenic variation.

Trypanosoma brucei[edit]

Trypanosoma brucei, the organism that causes sleeping sickness,

Mechanisms of VSG switching2.png

replicates extracellularly in the bloodstream of infected mammals. In later stages, the parasite crosses the blood brain barrier, resulting in a devastating and usually fatal outcome. As a result of replicating in the bloodstream, T. brucei parasites are subjected to numerous host defense mechanisms including soluble components of the immune system ( i.e. complement), as well as cellular components of the innate and adaptive immune systems. In order to protect itself from host defenses, the parasite decorates itself with a dense, homogeneous coat (~10^7 molecules) of glycoprotein known as the variant surface glycoprotein (VSG).

In the early stages of invasion, the dense protein coat is sufficient to protect the parasite from immune detection. However, the host eventually identifies the VSG as a foreign antigen and mounts an attack against the microbe. The T. brucei parasite has evolved an elegant mechanism to display a completely new coat of VSG antigen, rendering it once again invisible to the host’s immune system. The parasite’s genome has over 1,000 genes that code for different variants of the VSG protein. VSG genes can be found on the subtelomeric portion of large chromosomes, or on intermediate chromosomes. VSG genes also exist in arrays and many exist as pseudogenes. There is a hierarchy by which the VSG genes are activated. Telomeric VSGs are activated first, followed by array VSGs, and finally pseudogene VSGs.[8] Switching of VSG proteins occurs at a rate substantially higher than the background mutation rate of other genes in the parasite (suggesting that it is a regulated process). The process is partially dependent on homologous recombination of DNA, which is mediated in part by the interaction of the T. brucei BRCA2 gene with RAD51 (however, this is not the only responsible mechanism, as BRCA2 variants still display some VSG switching).[9] In addition to homologous recombination, transcriptional regulation also plays an important role in antigen switching. This is in contrast to other pathogens, where antigenic variation is typically mediated by DNA rearrangements or transcriptional regulation. The process by which VSG switching occurs has not been fully elucidated, but it is known that activation of VSGs requires recombination of the VSG genes into a VSG expression site (ES). The ES consists of a single vsg gene flanked by an upstream array of 70 base pair repeats and expression site associated genes (ESAGs). T. brucei expresses one VSG at any given time, and the active VSG can either be selected by activation of a previously silent ES, or by recombination of a VSG sequence into the active ES (see the figure "Mechanisms of VSG Switching in T. brucei").[8] Although the biological triggers that result in VSG switching are not fully known, mathematical modeling suggests that the ordered appearance of different VSG variants is controlled by at least two key parasite-derived factors: differential activation rates of parasite VSG and density-dependent parasite differentiation.[10]

Plasmodium falciparum[edit]

Plasmodium falciparum, the major etiologic agent of human malaria, has a very complex life cycle that occurs in both humans and mosquitoes. While in the human host, the parasite spends most of its life cycle within hepatic cells and erythrocytes (in contrast to T. brucei which remains extracellular). As a result of its mainly intracellular niche, parasitized host cells which display parasite proteins must be modified to prevent destruction by the host immune defenses. In the case of Plasmodium, this is accomplished via the dual purpose Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). PfEMP1 is encoded by the diverse family of genes known as the var family of genes (approximately 60 genes in all). The diversity of the gene family is further increased via a number of different mechanisms including exchange of genetic information at telomeric loci, as well as meiotic recombination. The PfEMP1 protein serves to sequester infected erythrocytes from splenic destruction via adhesion to the endothelium. Moreover, the parasite is able to evade host defense mechanisms by changing which var allele is used to code the PfEMP1 protein.[11] Like T. brucei, each parasite expresses multiple copies of one identical protein. However, unlike T. brucei, the mechanism by which var switching occurs in P. falciparum is thought to be purely transcriptional.[12] Var switching has been shown to take place soon after invasion of an erythrocyte by a P. falciparum parasite.[13] Fluorescent in situ hybridization analysis has shown that activation of var alleles is linked to altered positioning of the genetic material to distinct “transcriptionally permissive” areas.[14]

In viruses[edit]

Different virus families have different levels of ability to alter their genomes and trick the immune system into not recognizing. Some viruses have relatively unchanging genomes like paramyxoviruses while others like influenza have rapidly changing genomes that inhibit our ability to create long lasting vaccines against the disease. Viruses in general have much faster rate of mutation of their genomes than human or bacterial cells. In general viruses with shorter genomes have faster rates of mutation than longer genomes since they have a faster rate of replication.[15] It was classically thought that viruses with an RNA genome always had a faster rate of antigenic variation than those with a DNA genome because RNA polymerase lacks a mechanism for checking for mistakes in translation but recent work by Duffy et al. shows that some DNA viruses have the same high rates of antigenic variation as their RNA counterparts.[15] Antigenic variation within viruses can be categories into 6 different categories called antigenic drift, shift, rift lift, sift, and gift

Antigenic rift: Recombination of viral gene. This again occurs when there are again two viral cells that infect the same host cell. In this instance through the viruses recombine with pieces of each gene creating a new gene instead of simply switching out genes. Recombination has been extensively studied in avian influenza strains as to how the genetics of H5N1 have changed over time.[16]

Antigenic drift: point mutations that occur through imperfect replication of the viral genome. All viruses exhibit genetic drift over time but the amount that they are able to drift without occurring a negative impact on their fitness varies between families.

Antigenic shift: reassortment of the viral genome that occurs when a single host cells is infected with two viral cells. As the viral cells go through replication they reassort and the genes of the two species get mixed up and make 256 new variations of the virus. This occurs in influenza every couple of decades.

Antigenic sift: direct transmission with a zoonotic strain of a virus. This occurs when a human is infected during a spillover event.

Antigenic lift: Viral transmission of host derived gene. Some viruses steal host genes and then incorporate them into their own viral genome, encoding genes that sometimes give them an increased virulence. An example of this is the pox virus vaccinia which encoded a viral growth factor similar that is very similar to the human growth factor and thought to be stolen from the human genome.[17]

Antigenic gift: Occurs when humans deliberately modify a virus's genome either in a lab setting or in order to make a bioweapon.

Influenza virus[edit]

The antigenic properties of influenza viruses are determined by both hemagglutinin and neuraminidase. Specific host proteases cleave the single peptide HA into two subunits HA1 and HA2. The virus becomes highly virulent if the amino acids at the cleavage sites are lipophilic. Selection pressure in the environment selects for antigenic changes in the antigen determinants of HA, that includes places undergoing adaptive evolution and in antigenic locations undergoing substitutions, which ultimately results in changes in the antigenicity of the virus. Glycosylation of HA does not correlate with either the antigenicity or the selection pressure.[18] Antigenic variation may be classified into two types, antigenic drift that results from a change in few amino acids and antigenic shift which is the outcome of acquiring new structural proteins. A new vaccine is required every year because influenza virus has the ability to undergo antigenic drift. Antigenic shift occurs periodically when the genes for structural proteins are acquired from other animal hosts resulting in a sudden dramatic change in viral genome. Recombination between segments that encode for hemagglutinin and neuraminidase of avian and human influenza virus segments have resulted in worldwide influenza epidemics called pandemics such as the Asian flu of 1957 when 3 genes from Eurasian avian viruses were acquired and underwent reassortment with 5 gene segments of the circulating human strains. Another example comes from the 1968 Hong Kong flu which acquired 2 genes by reassortment from Eurasian avian viruses with the 6 gene segments from circulating human strains.

Vaccination against influenza[edit]

After vaccination, IgG+ antibody-secreting plasma cells (ASCs) increase rapidly and reaches a maximum level at day 7 before returning to a minimum level at day 14. The influenza-specific memory B-cells reach their maxima at day 14–21. The secreted antibodies are specific to the vaccine virus. Further, most of the monoclonal antibodies isolated have binding affinities against HA and the remaining demonstrate affinity against NA, nucleoprotein (NP) and other antigens. These high affinity human monoclonal antibodies can be produced within a month after vaccination and because of their human origin, they will have very little, if any, antibody-related side-effects in humans. They can potentially be used to develop passive antibody therapy against influenza virus transmission.

Mapping antigenic evolution[edit]

The ability of an antiviral antibody to inhibit hemagglutination can be measured and used to generate a two-dimensional map using a process called antigenic cartography so that antigenic evolution can be visualized. These maps can show how changes in amino acids can alter the binding of an antibody to virus particle and help to analyze the pattern of genetic and antigenic evolution. Recent findings show that as a result of antibody-driven antigenic variation in one domain of the H1 hemagglutinin Sa site, a compensatory mutation in NA can result leading to NA antigenic variation. As a consequence, drug resistance develops to NA inhibitors. Such a phenomenon can mask the evolution of NA evolution in nature because the resistance to NA inhibitors could be due to antibody-driven, HA escape.[19]


steric occlusion in Env gp120 contributes to resistance by neutralization by monoclonal b12

The major challenge in controlling HIV-1 infection in the long term is immune escape. The extent and frequency to which an epitope will be targeted by a particular HLA allele differs from person-to-person. Moreover, as a consequence of immunodominance, an individual’s CTL response is limited to a few epitopes of a specific HLA allele although six HLA class 1 alleles are expressed. Although the CTL response in the acute phase is directed against limited number of epitopes, the epitopic repertoire increases with time due to viral escape. Additionally amino acid co-evolution is a challenging issue that needs to be addressed. For example, a substitution in a particular site results in a secondary or compensatory mutation in another site. An invaluable discovery was that when a selective pressure is applied, the pattern of HIV-1 evolution can be predicted. In individuals who express a protective HLA B*27 allele, the first mutation that occurs in the Gag epitope KK10 is at position 6 from an L to an M and after several years there is a change in position 2 from a R to a K. Therefore, the knowledge of the predictability of the escape pathways can be utilized to design immunogens.[20] The region gp120 of HIV-1 Env which contacts CD4, its primary receptor, is functionally conserved and vulnerable to neutralizing antibodies such as monoclonal antibody b12. Recent findings show that resistance to neutralization by b12 was an outcome of substitutions that resided in the region proximal to CD4 contact surface. In this way the virus evades neutralization by b12 without affecting its binding to CD4.[21]


Flaviviridae is a family of viruses that encompasses well known viruses such as West Nile virus and Dengue virus. The genus Flavivirus has a prototypical envelope protein (E-protein) on its surface which serves as the target for virus neutralizing antibodies. E protein plays a role in binding to receptor and could play a role in evading the host immune system. It has three major antigenic domains namely A, B and C that correspond to the three structural domains II, III and I. Structural domain III is a putative receptor binding domain and antibodies against it neutralize the infectivity of flaviviruses. Mutations that lead to antigenic differences can be traced to the biochemical nature of the amino acid substitutions as well as the location of the mutation in the domain III. For example, substitutions at different amino acids results in varying levels of neutralization by antibodies. If mutation in a critical amino acid can dramatically alter neutralization by antibodies then WNV vaccines and diagnostic assays becomes difficult to rely on. Other flaviviruses that cause dengue, louping ill and yellow fever escape antibody neutralization via mutations in the domain III of the E protein.[22][23]


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