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Antigenic variation
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Antigenic variation refers to the mechanism by which an infectious organism such as a
protozoan, bacterium or virus alters its surface proteins in order to evade a host immune
response. 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 systems 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.[1] In all cases, antigenic variation and phase variation, a type of antigenic
variation, result in a heterogenic phenotype of a clonal population.[4] 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.[5]

Contents

1 Antigenic Variation in Bacteria

2 Antigenic Variation in Protozoa
o 2.1 Trypanosoma brucei
o 2.2 Plasmodium falciparum
3 Antigenic variation in viruses
o 3.1 Influenza virus
3.1.1 Vaccination against influenza
3.1.2 Mapping antigenic evolution
o 3.2 HIV-1
o 3.3 Flaviviruses
4 References

Antigenic Variation in Bacteria

To generate intra-population diversity, some bacteria can produce variation by various
methods such as antigenic or phase variation. Antigenic variation is the expression of various
alternative forms of antigen on the cell surface. Whereas phase variation is the phenotypic
switch that is usually reversible and is referred to as an ON-OFF switch. The outcome of
either method of variation has a beneficial effect that can result in increased fitness, evasion
strategies or environmental adaptation.
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.[6]

Antigenic Variation in Protozoa

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
Trypanosoma brucei, the organism that causes sleeping sickness,

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 hosts immune system. The parasites 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.[7] 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).[8] 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").[7] 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.[9]

Plasmodium falciparum
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 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 P. 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 the var allele
used to code the PfEMP1 protein.[10] 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.[11] Var switching has been
shown to take place soon after invasion of an erythrocyte by a P. falciparum parasite.[12]
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.[13]

Antigenic variation in viruses

Acute viral infections can be rapidly cleared by the immune system of the host. Nevertheless,
some viral infections like influenza and HIV recur. The recurrence occurs due to the
production of virions that are resistant to the neutralizing antibodies that were able to
effectively block the infection. These virions can infect survivors of the acute infection
caused by the original virus. These viruses have a structural plasticity that enables them to
tolerate changes in amino acids in their structural proteins while still retaining their
infectivity. There is a lot of diversity in the ability of viruses to exhibit such plasticity. They
can range from as little as 3 serotypes as in poliovirus to nearly 100 serotypes in rhinovirus.
Consequently, vaccines against poliovirus, measles and yellow fever confer lifetime
immunity while a new influenza vaccine is needed every year.

Influenza virus
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.[14] 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
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 influenzaspecific memory B-cells reach their maxima at day 1421. 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
The ability to 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.[15]

HIV-1

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 individuals
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.[16] 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.[17]

Flaviviruses
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.[18][19]

References
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