Antigenic variation
Encyclopedia
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 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
, site-specific DNA inversions, hypermutation, as well as recombination of sequence cassettes. In all cases, antigenic variation and phase variation
, a type of antigenic variation, result in a heterogenic phenotype of a clonal population. 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.
. 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 polymer
s 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.
are some of the most well studied examples of protozoan parasites that exhibit antigenic variation.
), 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. 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). 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"). 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.
. Moreover, the parasite is able to evade host defense mechanisms by changing the var allele used to code the PfEMP1 protein. 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. Var switching has been shown to take place soon after invasion of an erythrocyte by a P. falciparum parasite. 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.
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.
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. 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 reasssortment 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.
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.
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.
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.
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.
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.
Pathogen
A pathogen gignomai "I give birth to") or infectious agent — colloquially, a germ — is a microbe or microorganism such as a virus, bacterium, prion, or fungus that causes disease in its animal or plant host...
such as a protozoan, bacterium or virus alters its surface proteins
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
in order to evade a host
Host (biology)
In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...
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
Antigen
An antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
(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
Gene conversion
Gene conversion is an event in DNA genetic recombination, which occurs at high frequencies during meiotic division but which also occurs in somatic cells. It is a process by which DNA sequence information is transferred from one DNA helix to another DNA helix, whose sequence is altered.It is one...
, site-specific DNA inversions, hypermutation, as well as recombination of sequence cassettes. In all cases, antigenic variation and phase variation
Phase variation
Phase variation is a method for dealing with rapidly varying environments without requiring random mutation employed by various types of bacteria, including Salmonella species. It involves the variation of protein expression, frequently in an on-off fashion, within different parts of a bacterial...
, a type of antigenic variation, result in a heterogenic phenotype of a clonal population. 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.
Antigenic Variation in Bacteria
To generate intra-population diversity, some bacteria can produce variation by various methods such as antigenic or phase variationPhase variation
Phase variation is a method for dealing with rapidly varying environments without requiring random mutation employed by various types of bacteria, including Salmonella species. It involves the variation of protein expression, frequently in an on-off fashion, within different parts of a bacterial...
. 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
Neisseria
The Neisseria is a large genus of commensal bacteria that colonize the mucosal surfaces of many animals. Of the 11 species that colonize humans, only two are pathogens. N. meningitidis and N. gonorrhoeae often cause asymptomatic infections, a commensal-like behavior...
(most notably, Neisseria meningitidis
Neisseria meningitidis
Neisseria meningitidis, often referred to as meningococcus, is a bacterium that can cause meningitis and other forms of meningococcal disease such as meningococcemia, a life threatening sepsis. N. meningitidis is a major cause of morbidity and mortality during childhood in industrialized countries...
and Neisseria gonorrhoeae
Neisseria gonorrhoeae
Neisseria gonorrhoeae, also known as gonococci , or gonococcus , is a species of Gram-negative coffee bean-shaped diplococci bacteria responsible for the sexually transmitted infection gonorrhea.N...
, the gonococcus); species of the genus Streptococcus
Streptococcus
Streptococcus is a genus of spherical Gram-positive bacteria belonging to the phylum Firmicutes and the lactic acid bacteria group. Cellular division occurs along a single axis in these bacteria, and thus they grow in chains or pairs, hence the name — from Greek στρεπτος streptos, meaning...
and the Mycoplasma
Mycoplasma
Mycoplasma refers to a genus of bacteria that lack a cell wall. Without a cell wall, they are unaffected by many common antibiotics such as penicillin or other beta-lactam antibiotics that target cell wall synthesis. They can be parasitic or saprotrophic. Several species are pathogenic in humans,...
. The Neisseria species mentioned variate their pili (protein polymer
Polymer
A polymer is a large molecule composed of repeating structural units. These subunits are typically connected by covalent chemical bonds...
s made up of subunits called pilin
Pilin
Pilin refers to a class of fibrous proteins that are found in pilus structures in bacteria. Bacterial pili are used in the exchange of genetic material during bacterial conjugation, and a short pilus called a fimbrium is used as a cell adhesion mechanism. Although not all bacteria have pili or...
which play a critical role in bacterial adhesion
Cell adhesion
Cellular adhesion is the binding of a cell to a surface, extracellular matrix or another cell using cell adhesion molecules such as selectins, integrins, and cadherins. Correct cellular adhesion is essential in maintaining multicellular structure...
, they are antigens which stimulate a vigorous host immune response) and the Streptococci variate their M-protein.
Additionally, Lyme disease
Lyme disease
Lyme disease, or Lyme borreliosis, is an emerging infectious disease caused by at least three species of bacteria belonging to the genus Borrelia. Borrelia burgdorferi sensu stricto is the main cause of Lyme disease in the United States, whereas Borrelia afzelii and Borrelia garinii cause most...
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.
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 falciparumPlasmodium
Plasmodium is a genus of parasitic protists. Infection by these organisms is known as malaria. The genus Plasmodium was described in 1885 by Ettore Marchiafava and Angelo Celli. Currently over 200 species of this genus are recognized and new species continue to be described.Of the over 200 known...
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. complementComplement system
The complement system helps or “complements” the ability of antibodies and phagocytic cells to clear pathogens from an organism. It is part of the immune system called the innate immune system that is not adaptable and does not change over the course of an individual's lifetime...
), as well as cellular components of the innate
Innate immune system
The innate immune system, also known as non-specific immune system and secondary line of defence, comprises the cells and mechanisms that defend the host from infection by other organisms in a non-specific manner...
and adaptive immune
Adaptive immune system
The adaptive immune system is composed of highly specialized, systemic cells and processes that eliminate or prevent pathogenic growth. Thought to have arisen in the first jawed vertebrates, the adaptive or "specific" immune system is activated by the “non-specific” and evolutionarily older innate...
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. 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
Genetic recombination
Genetic recombination is a process by which a molecule of nucleic acid is broken and then joined to a different one. Recombination can occur between similar molecules of DNA, as in homologous recombination, or dissimilar molecules, as in non-homologous end joining. Recombination is a common method...
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). 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"). 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.
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 endotheliumEndothelium
The endothelium is the thin layer of cells that lines the interior surface of blood vessels, forming an interface between circulating blood in the lumen and the rest of the vessel wall. These cells are called endothelial cells. Endothelial cells line the entire circulatory system, from the heart...
. Moreover, the parasite is able to evade host defense mechanisms by changing the var allele used to code the PfEMP1 protein. 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. Var switching has been shown to take place soon after invasion of an erythrocyte by a P. falciparum parasite. Fluorescent in situ hybridization
Fluorescent in situ hybridization
FISH is a cytogenetic technique developed by biomedical researchers in the early 1980s that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes. FISH uses fluorescent probes that bind to only those parts of the chromosome with which they show a high...
analysis has shown that activation of var alleles is linked to altered positioning of the genetic material to distinct “transcriptionally permissive” areas.
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 poliovirusPoliovirus
Poliovirus, the causative agent of poliomyelitis, is a human enterovirus and member of the family of Picornaviridae.Poliovirus is composed of an RNA genome and a protein capsid. The genome is a single-stranded positive-sense RNA genome that is about 7500 nucleotides long. The viral particle is...
to nearly 100 serotypes in rhinovirus
Rhinovirus
Human rhinoviruses are the most common viral infective agents in humans and are the predominant cause of the common cold. Rhinovirus infection proliferates in temperatures between 33–35 °C , and this may be why it occurs primarily in the nose...
. 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 hemagglutininHemagglutinin
Influenza hemagglutinin or haemagglutinin is a type of hemagglutinin found on the surface of the influenza viruses. It is an antigenic glycoprotein. It is responsible for binding the virus to the cell that is being infected...
and neuraminidase
Neuraminidase
Neuraminidase enzymes are glycoside hydrolase enzymes that cleave the glycosidic linkages of neuraminic acids. Neuraminidase enzymes are a large family, found in a range of organisms. The most commonly known neuraminidase is the viral neuraminidase, a drug target for the prevention of the spread...
. 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. Antigenic variation may be classified into two types, antigenic drift
Antigenic drift
The immune system recognizes viruses when antigens on the surfaces of virus particles bind to immune receptors that are specific for these antigens. This is similar to a lock recognizing a key. After an infection, the body produces many more of these virus-specific receptors, which prevent...
that results from a change in few amino acids and antigenic shift
Antigenic shift
Antigenic shift is the process by which two or more different strains of a virus, or strains of two or more different viruses, combine to form a new subtype having a mixture of the surface antigens of the two or more original strains...
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 reasssortment 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 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
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.
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 individual’s CTL response is limited to a few epitopes of a specific HLA allele although six HLAHLA
-Biochemistry:*Human leukocyte antigen, a key part of the human immune system, or the paternity test based upon it*Hyaluronic Acid, an important molecule that plays a role throughout the body's skin and connective tissues.-Computing:...
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.
The region gp120
Gp120
Envelope glycoprotein GP120 is a glycoprotein exposed on the surface of the HIV envelope. The 120 in its name comes from its molecular weight of 120 kilodaltons...
of HIV-1 Env which contacts CD4
CD4
CD4 is a glycoprotein expressed on the surface of T helper cells, monocytes, macrophages, and dendritic cells. It was discovered in the late 1970s and was originally known as leu-3 and T4 before being named CD4 in 1984...
, 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.
Flaviviruses
FlaviviridaeFlaviviridae
The Flaviviridae are a family of viruses that are primarily spread through arthropod vectors . The family gets its name from Yellow Fever virus, a type virus of Flaviviridae; flavus means yellow in Latin...
is a family of viruses that encompasses well known viruses such as West Nile virus
West Nile virus
West Nile virus is a virus of the family Flaviviridae. Part of the Japanese encephalitis antigenic complex of viruses, it is found in both tropical and temperate regions. It mainly infects birds, but is known to infect humans, horses, dogs, cats, bats, chipmunks, skunks, squirrels, domestic...
and Dengue virus
Dengue virus
Dengue virus in one of four serotypes is the cause of dengue fever. It is a mosquito-borne single positive-stranded RNA virus of the family Flaviviridae; genus Flavivirus...
. 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.