Antibody dependent enhancement
Encyclopedia
Antibody dependent enhancement (ADE) occurs when non-neutralising antiviral antibodies
enhance viral
entry into host
cells, leading to increased infectivity
in the host cells. Some cells do not have the usual receptors on their surfaces that viruses use to gain entry. The antibodies bind to antibody Fc receptor
s that some of these cells have in their plasma membrane. The viruses bind to the antigen binding site at the other end of the antibody. ADE is common in cells cultured in the laboratory, but rarely occurs in vivo except for dengue virus
. This virus can use this mechanism to infect human macrophage
s, causing a normally mild viral infection to become life-threatening.
(DENV). DENV is a single-stranded positive-polarity
RNA virus
of the Flaviviridae
family. It causes a disease
of varying severity in humans, from dengue fever
(DF), which is usually self-limited, to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), either of which may be life-threatening. It is estimated that as many as 100 million individuals are infected with DENV annually.
The phenomenon of ADE may be observed when a person who has previously been infected with one serotype of DENV becomes infected many months or years later with a different serotype. In such cases, the clinical course of the disease is more severe, and these people have higher viremia
compared with those in whom ADE has not occurred. This explains the observation that while primary (first) infections cause mostly minor disease (DF) in children, secondary infection (re-infection at a later date) is more likely to be associated with severe disease (DHF and/or DSS) in both children and adults.
There are four antigen
ically different serotype
s of DENV (DENV-1 - DENV-4). Infection with DENV induces the production of neutralizing
homotypic immunoglobulin G
(IgG) antibodies which provide lifelong immunity
against the infecting serotype. Infection with DENV also produces some degree of cross-protective
immunity against the other three serotypes. Neutralizing heterotypic (cross-reactive) IgG antibodies are responsible for this cross-protective immunity, which typically persists for a period of several months to a few years. These heterotypic antibody titer
s decrease over long time periods (4 to 20 years). While heterotypic IgG antibody titers decrease, homotypic IgG antibody titers increase over long time periods. This could be due to the preferential survival of long-lived memory B cell
s producing homotypic antibodies.
In addition to inducing neutralizing heterotypic antibodies, infection with DENV can also induce heterotypic antibodies which neutralize the virus only partially or not at all. The production of such cross-reactive but non-neutralizing antibodies could be the reason for more severe secondary infections. It is thought that by binding to but not neutralizing the virus, these antibodies cause it to behave as a "trojan horse
", where it is delivered into the wrong compartment of dendritic cell
s that have ingested the virus for destruction. Once inside the white blood cell, the virus replicates undetected, eventually generating very high virus titers which cause severe disease.
To illustrate the phenomenon of ADE, consider the following example: an epidemic of dengue fever occurred in Cuba
, lasting from 1977–1979. The infecting serotype was DENV-1. This epidemic was followed by two more outbreaks of dengue fever—one in 1981 and one in 1997; DENV-2 was the infecting serotype in both of these later epidemics. 205 cases of DHF/DSS occurred during the 1997 outbreak, all in people older than 15 years. All but three of these cases were demonstrated to have been previously infected by the DENV-1 serotype during the epidemic of 1977–1979. Furthermore, people who had been infected with DENV-1 during the 1977-79 outbreak and secondarily infected with DENV-2 in 1997 had a 3-4 fold increased probability
of developing severe disease than those secondarily infected with DENV-2 in 1981. This scenario can be explained by the presence of neutralizing heterotypic IgG antibodies in sufficient titers in 1981, the titers of which had decreased by 1997 to the point where they no longer provided significant cross-protective immunity.
viruses have not only shown enhanced entry but also also favorable signalling cascades for HIV replication in iDCs. HIV-1 has also showed enhancement of infection in HT-29 cells when the viruses were pre-opsonized with complements C3 and C9 in seminal fluid. This enhanced rate of infection was almost 2 times greater than infection of HT-29 cells with virus alone. Subramanian et al., reported that almost 72% of serum samples out of 39 HIV positive individuals contained complements that were known to enhance the infection. They also suggested that presence of neutralizing antibody (NA) or antibody-dependent cellular cytotoxicity-mediating antibodies (ADCC) in the serum contains infection enhancing antibodies(IEAs). The balance between the NAs and IEAs changes as the disease progresses. During advanced stages of disease the proportion of IEAs are generally higher than NAs. Increase in viral protein synthesis and RNA production have been reported to occur during the complement mediated enhancement of infection. Cells that are challenged with non neutralizing levels of complements have been found have accelerated release of reverse transcriptase and the viral progeny. The interaction of anti-HIV antibodies with non-neutralizing complement exposed viruses also aid in binding of the virus and the erythrocytes which can lead to a more efficient delivery of viruses to the immune compromised organs.
ADE in HIV has raised questions about the risk of infections to volunteers who have taken subneutalizing levels of vaccine just like any other viruses that exhibit ADE. Gilbert et al., in 2005 reported that there was no ADE of infection when they used rgp120 vaccine in phase 1 and 2 trials. It has been emphasized that much research needs to be done in the field of immunity response to HIV-1, information from these studies can be used to produce a more effective vaccine.
Antibody
An antibody, also known as an immunoglobulin, is a large Y-shaped protein used by the immune system to identify and neutralize foreign objects such as bacteria and viruses. The antibody recognizes a unique part of the foreign target, termed an antigen...
enhance viral
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...
entry into 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...
cells, leading to increased infectivity
Infectivity
In epidemiology, infectivity refers to the ability of a pathogen to establish an infection. More specifically, infectivity is a pathogen's capacity for horizontal transmission that is, how frequently it spreads among hosts that are not in a parent-child relationship...
in the host cells. Some cells do not have the usual receptors on their surfaces that viruses use to gain entry. The antibodies bind to antibody Fc receptor
Fc receptor
An Fc receptor is a protein found on the surface of certain cells - including natural killer cells, macrophages, neutrophils, and mast cells - that contribute to the protective functions of the immune system....
s that some of these cells have in their plasma membrane. The viruses bind to the antigen binding site at the other end of the antibody. ADE is common in cells cultured in the laboratory, but rarely occurs in vivo except for 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...
. This virus can use this mechanism to infect human macrophage
Macrophage
Macrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s, causing a normally mild viral infection to become life-threatening.
In dengue virus infection
The most widely known example of ADE occurs in the setting of infection with the dengue virusDengue 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...
(DENV). DENV is a single-stranded positive-polarity
Sense (molecular biology)
In molecular biology and genetics, sense is a concept used to compare the polarity of nucleic acid molecules, such as DNA or RNA, to other nucleic acid molecules...
RNA virus
RNA virus
An RNA virus is a virus that has RNA as its genetic material. This nucleic acid is usually single-stranded RNA but may be double-stranded RNA...
of the Flaviviridae
Flaviviridae
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...
family. It causes a disease
Disease
A disease is an abnormal condition affecting the body of an organism. It is often construed to be a medical condition associated with specific symptoms and signs. It may be caused by external factors, such as infectious disease, or it may be caused by internal dysfunctions, such as autoimmune...
of varying severity in humans, from dengue fever
Dengue fever
Dengue fever , also known as breakbone fever, is an infectious tropical disease caused by the dengue virus. Symptoms include fever, headache, muscle and joint pains, and a characteristic skin rash that is similar to measles...
(DF), which is usually self-limited, to dengue hemorrhagic fever (DHF) and dengue shock syndrome (DSS), either of which may be life-threatening. It is estimated that as many as 100 million individuals are infected with DENV annually.
The phenomenon of ADE may be observed when a person who has previously been infected with one serotype of DENV becomes infected many months or years later with a different serotype. In such cases, the clinical course of the disease is more severe, and these people have higher viremia
Viremia
Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to bacteremia, a condition where bacteria enter the bloodstream.- Primary versus Secondary :...
compared with those in whom ADE has not occurred. This explains the observation that while primary (first) infections cause mostly minor disease (DF) in children, secondary infection (re-infection at a later date) is more likely to be associated with severe disease (DHF and/or DSS) in both children and adults.
There are four 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...
ically different serotype
Serotype
Serotype or serovar refers to distinct variations within a subspecies of bacteria or viruses. These microorganisms, viruses, or cells are classified together based on their cell surface antigens...
s of DENV (DENV-1 - DENV-4). Infection with DENV induces the production of neutralizing
Neutralizing antibody
A Neutralizing antibody, or NAb is an antibody which defends a cell from an antigen or infectious body by inhibiting or neutralizing any effect it has biologically...
homotypic immunoglobulin G
Immunoglobulin G
Immunoglobulin G are antibody molecules. Each IgG is composed of four peptide chains — two heavy chains γ and two light chains. Each IgG has two antigen binding sites. Other immunoglobulins may be described in terms of polymers with the IgG structure considered the monomer.IgG constitutes 75%...
(IgG) antibodies which provide lifelong immunity
Immunity (medical)
Immunity is a biological term that describes a state of having sufficient biological defenses to avoid infection, disease, or other unwanted biological invasion. Immunity involves both specific and non-specific components. The non-specific components act either as barriers or as eliminators of wide...
against the infecting serotype. Infection with DENV also produces some degree of cross-protective
Cross-reactivity
Cross-reactivity is the reaction between an antibody and an antigen that differs from the immunogen. It is sometimes also referred to as crossimmunity or cross-protective immunity...
immunity against the other three serotypes. Neutralizing heterotypic (cross-reactive) IgG antibodies are responsible for this cross-protective immunity, which typically persists for a period of several months to a few years. These heterotypic antibody titer
Titer
A titer is a way of expressing concentration. Titer testing employs serial dilution to obtain approximate quantitative information from an analytical procedure that inherently only evaluates as positive or negative. The titer corresponds to the highest dilution factor that still yields a positive...
s decrease over long time periods (4 to 20 years). While heterotypic IgG antibody titers decrease, homotypic IgG antibody titers increase over long time periods. This could be due to the preferential survival of long-lived memory B cell
Memory B cell
Memory B cells are a B cell sub-type that are formed following primary infection.-Primary response, paratopes, and epitopes:In wake of first infection involving a particular antigen, the responding naïve cells proliferate to produce a colony of cells, most of which differentiate into the plasma...
s producing homotypic antibodies.
In addition to inducing neutralizing heterotypic antibodies, infection with DENV can also induce heterotypic antibodies which neutralize the virus only partially or not at all. The production of such cross-reactive but non-neutralizing antibodies could be the reason for more severe secondary infections. It is thought that by binding to but not neutralizing the virus, these antibodies cause it to behave as a "trojan horse
Trojan Horse
The Trojan Horse is a tale from the Trojan War about the stratagem that allowed the Greeks finally to enter the city of Troy and end the conflict. In the canonical version, after a fruitless 10-year siege, the Greeks constructed a huge wooden horse, and hid a select force of men inside...
", where it is delivered into the wrong compartment of dendritic cell
Dendritic cell
Dendritic cells are immune cells forming part of the mammalian immune system. Their main function is to process antigen material and present it on the surface to other cells of the immune system. That is, dendritic cells function as antigen-presenting cells...
s that have ingested the virus for destruction. Once inside the white blood cell, the virus replicates undetected, eventually generating very high virus titers which cause severe disease.
To illustrate the phenomenon of ADE, consider the following example: an epidemic of dengue fever occurred in Cuba
Cuba
The Republic of Cuba is an island nation in the Caribbean. The nation of Cuba consists of the main island of Cuba, the Isla de la Juventud, and several archipelagos. Havana is the largest city in Cuba and the country's capital. Santiago de Cuba is the second largest city...
, lasting from 1977–1979. The infecting serotype was DENV-1. This epidemic was followed by two more outbreaks of dengue fever—one in 1981 and one in 1997; DENV-2 was the infecting serotype in both of these later epidemics. 205 cases of DHF/DSS occurred during the 1997 outbreak, all in people older than 15 years. All but three of these cases were demonstrated to have been previously infected by the DENV-1 serotype during the epidemic of 1977–1979. Furthermore, people who had been infected with DENV-1 during the 1977-79 outbreak and secondarily infected with DENV-2 in 1997 had a 3-4 fold increased probability
Odds ratio
The odds ratio is a measure of effect size, describing the strength of association or non-independence between two binary data values. It is used as a descriptive statistic, and plays an important role in logistic regression...
of developing severe disease than those secondarily infected with DENV-2 in 1981. This scenario can be explained by the presence of neutralizing heterotypic IgG antibodies in sufficient titers in 1981, the titers of which had decreased by 1997 to the point where they no longer provided significant cross-protective immunity.
In HIV-1 virus infection
ADE of infection has also been reported in HIV. Like DENV, non-neutralizing level of antibodies have been found to enhance the viral infection through interactions of complement system and receptors. The increase in infection has been reported to be over 350 fold which is comparable to ADE in other viruses like DENV. ADE in HIV can be complement mediated or Fc receptor mediated. Complements in presence of HIV-1 positive sera have been found to enhance the infection of MT-2 T-cell line. The Fc-receptor mediated enhancement was reported when HIV infection was enhanced by sera from HIV-1 positive guinea pig enhanced the infection of peripheral blood mononuclear cells without the presence of any complements. Complement Component receptors CR2, CR3 and CR4 have been found to mediate this Complement –Mediated enhancement of infection. The infection of HIV-1 leads to activation of complements fragments of these complements can assist viruses with infection by facilitating viral interactions with host cells that express complement receptors. The deposition of complement on the virus brings the gp120 protein close to CD4 molecules on the surface of the cells, thus leading to facilitated viral entry. Viruses pre-exposed to non-neutralizing complement system have also been found to enhance infections in interdigitating dendritic cells (iDCs). OpsonizedOpsonin
An opsonin is any molecule that targets an antigen for an immune response. However, the term is usually used in reference to molecules that act as a binding enhancer for the process of phagocytosis, especially antibodies, which coat the negatively-charged molecules on the membrane. Molecules that...
viruses have not only shown enhanced entry but also also favorable signalling cascades for HIV replication in iDCs. HIV-1 has also showed enhancement of infection in HT-29 cells when the viruses were pre-opsonized with complements C3 and C9 in seminal fluid. This enhanced rate of infection was almost 2 times greater than infection of HT-29 cells with virus alone. Subramanian et al., reported that almost 72% of serum samples out of 39 HIV positive individuals contained complements that were known to enhance the infection. They also suggested that presence of neutralizing antibody (NA) or antibody-dependent cellular cytotoxicity-mediating antibodies (ADCC) in the serum contains infection enhancing antibodies(IEAs). The balance between the NAs and IEAs changes as the disease progresses. During advanced stages of disease the proportion of IEAs are generally higher than NAs. Increase in viral protein synthesis and RNA production have been reported to occur during the complement mediated enhancement of infection. Cells that are challenged with non neutralizing levels of complements have been found have accelerated release of reverse transcriptase and the viral progeny. The interaction of anti-HIV antibodies with non-neutralizing complement exposed viruses also aid in binding of the virus and the erythrocytes which can lead to a more efficient delivery of viruses to the immune compromised organs.
ADE in HIV has raised questions about the risk of infections to volunteers who have taken subneutalizing levels of vaccine just like any other viruses that exhibit ADE. Gilbert et al., in 2005 reported that there was no ADE of infection when they used rgp120 vaccine in phase 1 and 2 trials. It has been emphasized that much research needs to be done in the field of immunity response to HIV-1, information from these studies can be used to produce a more effective vaccine.
Mechanism
There are several possibilities to explain the phenomenon:- A viral surface protein laced with antibodies against a virus of one serotype binds to a similar virus with a different serotype. The binding is meant to neutralize the virus surface protein from attaching to the cell, but the antibody bound to virus also binds to the receptor of the cell, the Fc-region antibody receptor FcγR. This brings the virus into close proximity to the virus-specific receptor, and the cell internalizesEndocytosisEndocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
the virus through the normal infection route. - A virus surface protein may be attached to antibodies of a different serotype, activating the classical pathway of the complement systemComplement systemThe 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...
. The complement cascade system instead binds C1Q complexC1Q complexThe C1q complex is potentially multivalent for attachment to the complement fixation sites of immunoglobulin.The sites are on the CH2 domain of IgG and, it is thought, on the CH4 domain of IgM....
attached to the virus surface protein via the antibodies, which in turn bind C1q receptor found on cells, bringing the virus and the cell close enough for a specific virus receptor to bind the virus, beginning infection.. This mechanism has not been shown specifically for DENV infection, but is supposed to occur with Ebola virus infection in vitro. - When an antibody to a virus is present for a different serotype, it is unable to neutralize the virus, which is then ingested into the cell as a sub-neutralized virus particle. These viruses are phagocytosed as antigen-antibody complexes, and degraded by macrophageMacrophageMacrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s. Upon ingestion the antibodies no longer even sub-neutralize the body due to the denaturing condition at the step for acidification of phagosome before fusion with lysosomeLysosomethumb|350px|Schematic of typical animal cell, showing subcellular components. [[Organelle]]s: [[nucleoli]] [[cell nucleus|nucleus]] [[ribosomes]] [[vesicle |vesicle]] rough [[endoplasmic reticulum]]...
. The virus becomes active and begins its proliferation within the cell.