Viral Immunology

• Viruses are extremely immunegenic and cause two kinds of immune responses: the humoral and the cellular.
• The range of specificities of B and T cells is derived from changes in the somatic genome and rearrangements.
• T B cells and T typically recognise the exact epitopes within the exact virus. B cells recognize the free proteins unaltered in their original 3-D configuration while T cells typically view Ag in a denatured form. Ag in a denatured state together in conjunction with MHC molecules.
• The features of an immune reaction for the exact virus can be different for different individuals based on their genetic makeup.
• It is responsible for preventing infection by this virus (neutralization).
• The IgG and IgM class are particularly relevant. IgM as well as the IgG class are especially important to protect against viral infections, which are often accompanied by viraemia. The antibodies from IgA class are particularly relevant for defense against viraemia. IgA class are essential for infections contracted through the mucosa. (the nose and the intestinal tract)
• However, the immune system kills the infected cells that express viruses’ proteins onto their surface including glycoproteins that envelope viruses have and occasionally the essential proteins of these viruses.

Humoral Response

• Abs are stimulated by the components that make up the surface of intact virions , as well through the inner components in disintegrated viral particles. Abs are also stimulated by viral proteins that are embedded on the surface of cells that are infected, or released by cells.
• Antibodies are the primary source of defense against many viruses. Sometimes, they can also be pathogenic e.g. immune complexes are believed to cause the rubella rash.
• Interactions between virions and Abs with different parts of their coats may result in different effects.

Neutralization

Neutralization of viruses is a reduction in the infectious dose of a prepared viral after contact with Abs. The loss of infectious capacity can be caused due to interference of binding of Ab with any of the steps that lead to an influx of viral DNA into host cells. The consequences of the interaction between virion and Ab is dependent on several factors.-

• The structure of viral virions.
• The main target for the Ab e.g. Abs against HA and not NA from influenza neutralize.
• Modifications to surface molecules which alter vulnerability to specific Abs
• The kind of Ab particularly its affinity to the components of viral virions
• The amount of Ab molecules attached to viral ions.

Reversible neutralization

The process of neutralization can be reversed by diluting Ab-Ag mixture within a brief period of the formation of Ag-Ab complexes (30 minutes). It is believed that the reversibility of neutralization may be due to inhibition of attachment of virions cell receptors. This process involves the complete saturation of the surface the virus by Abs.

Stable neutralization

Over time, the Ag-Ab complexes tend to become stabilized (several hours) and this process is unable to be reversed through diluting. The virions and the Abs remain unchanged during stable neutralization, as the components that remain unchanged are able to be recovered. The neutralized virus may be revived through proteolytic cutting. The intact Abs are rediscovered through dissociating the Aband Ag complexes with an acid pH or at alkaline pH.

Stable neutralization is a distinct mechanism than reversed neutralization. It has been demonstrated that neutralized viruses can attach, and already attached virions are neutralized. The amount of Ab molecules needed to ensure stable neutralization is significantly lower than that required for an irreversible neutralization. Evidence from kinetics suggests that one Ab molecules can neutralize virion. The neutralization process is typically triggered through Ab molecules that form contact with two antigenic sites that are located on different virion monomers and greatly increase the stability of complexes.

Virion sites for neutralization

Epitopes only on the molecules involved in the release of virus’ genome into cells are targets for neutralization. In influenza viruses there is only those epitopes that are associated with the HA but not the NA are the targets of neutralization. In polioviruses, all the antigenic locations that are visible on the capsid can be targeted for neutralization because the capsid is the unit that releases the nucleic acids.

Adenoviruses’ primary target is the hexons more than pentons since the hexons are highly connected and collaborate to release the viral DNA. Sometimes Abs that are bound to non-neutralizing epitopes may be identified by neutralization when there is complement, in which the envelope of the virus is damaged with complement by the cascade.

Protective role of neutralizing antibodies

The neutralizing ability of a serum typically determines the level of protection it provides to an animal. However, the correlation isn’t always correct. The reason for the discrepancies could be due to different levels of neutralization of a virus cells that are used to test in vitro as compared to those which the virus infects in the vivo. e.g. the serum of mice that was protected from yellow fever didn’t eliminate the disease in Vero cells however it did it in a mouse neuroblastoma line.

Another reason that could be the cause may be due to the fact that an Ab that is not neutralizing in culture could act in vivo through activation of host defenses against viruses or cells infected with virus. e.g. macrophages, or complement. Furthermore macrophages or complement, neutralizing Abs might not be able to protect as rapid viral multiplicity overpowers neutralizing power. In the initial phase of immunization Abs with Abs with low affinity Abs are primarily responsible for activating complement, and they have a low neutralizing capacity in the culture. The amount of neutralization that occurs in the cultures of today is best determined by performing neutralization while in the presence of complement.

Evolution of viral antigens

The evolution of viruses must look for mutations that alter the antigenic factors involved in neutralization. Contrarily other antigenic sites will be able to remain the same since the mutations they affect would not be picked for, and may even be harmful. A virus will therefore change from an initial kind to several varieties, varying in neutralization (and occasionally in high-intensity) tests, yet keeping some of the antigenic mosaic determinates that can be identified by CFTs.

These evolutionary theories are in line with the fact that the most obvious distinction between families of types is evident in viruses with a quite complex architecture that have Ags involved in the interactions with cells are more diverse that other protein. Therefore, enveloped viruses have distinct envelopes for each strain, but also an internal capsid that is cross-reactive; Adenoviruses are characterized by type-specific fibers and family-specific (and also specific to a particular type) capsomers.

Furthermore there is a A Ag of polioviruses occurs only upon heating, shows antigenic sites that are usually concealed and therefore are not affected by pressure that is selective. The amount of antigenic variation is different for each virus and is particularly high with influenza viruses and lentiviruses.

Types of virus-specific antibodies

Different kinds of preparations for viral trigger the formation of various Abs.

• The preparations of the virus that are killed produce Abs mostly directed at their surface virus. These Abs are neutralizing and have activity against HI viruses as also CF and precipitating actions against Ags of the coat of viruses.
• Live virus preparations trigger antibodies to all antigens of the virus, which include internal and external antigens.
• The immunization process involving internal components of the virus causes CF and the subsequent Abs that are active only against specific Ags and the Ags of those components.
• Immunization with peptides that reproduce portions of virion proteins can trigger Abs which are properties which are influenced by the protein as well as the specific sequences that are reproduced.  

Specificity of test methods

The Abs that react in various tests could react in the same way, even though they might not be identical. Neutralization is mostly resulted by Ab molecules specifically targeted to the virion’s sites which are involved in the release nucleic acids from the virus into cells. CF typically involves other Ags that are internal or surface-based. Neutralization may require molecules that have an affinity for virions that is higher as opposed to Hi and CF. After infection with a virus the amounts of Abs to various components increase and decrease with distinctly different timings.

Due to their high specificity, these methods are able to distinguish not just between viruses belonging to different families, but also closely related viruses from the same subfamily or family. This is how family Ags can be distinguished. The majority of antibodies detected through neutralization are less cross-reactive. This makes them important in determining the immune kind. While those that are detected in CF are more reactive, and can be helpful to define the family. With the right procedures like immunization with pure Ags or very specific CF Abs can be made.

Abs’ resolving capability can be increased through Monoclonal Abs. While all methods for measuring antigens from viruses are necessary for identifying a new virus The preferred method to determine the cause is ELISA due to its high sensitivity as well as its low cost.

Cell-Mediated Immunity

Cytotoxic T lymphocytes

CMI plays a crucial role in the localization of viral infections for recovery, and also as a pathogenetic factor in viral illnesses. In animals that are subjected to experiments CMI is the primary CTLs attain their maximum levels about six days after an infection, and then decrease after the virus has gone away. However they remain in memory T cells and are able to be identified through the culturing of spleen cells virus-infected cells. After just a few days secondary CTLs show up in the cultures with significantly higher activity than those in the initial response.

The formation of CTLs is stimulated by cells-associated Ags that are present on the cell’s surface, and not just for enveloped viruses however, but also in other viral species whose nonvirion proteins are able to reach the cell’s surface. In the context of humoral immunity that is characterized by type and group specific responses may be observed. Even inactivated or noninfectious virus can trigger a cellular reaction because their envelopes are fused with the cell’s plasma membrane at the beginning of the viral’s entry.

Additionally, the viruses themselves might also be able to induce a response following their absorption into macrophages. Virion proteins from the internal as well as nonvirion proteins are frequently identified by CTLs. A prime example of this is the nucleocapsid proteins of enveloped viruses. These fragments of which are transported to the cell’s surface via some unknown pathway and are recognized with great speed and can lead in cross-reactive CTLs. In most cases the surface proteins of viruses do not interfere with their interactions with CTLs since the cell and humoral responses are able to recognize various epitopes.

Cytotoxicity mediated by antibody dependent cells

The K cells are cells that act as the effectors in ADCC. In in vitro, they eliminate virus-infected cells that are sensitized to IgG from immune donors , but not targets that aren’t sensitized. ADCC is highly effective in the laboratory in the fight against HSV as well as VZV infected cells, and prevents the normal spread of the virus from infected to non-infected cells. It could therefore contribute to the protection against infection by these viruses. K cells have been proven to enhance immunity to the vaccinia virus, but not Tc cells.

Natural Killer (NK) cells

In the human body, the most important NK cells is called the big lymphocyte (LGL) which make up 2-5 percent of the peripheral blood lymphocytes. But not all lytic cells have the characteristics of LGLs as well. Not all LGLs are NK cells. There is a commonality of LGLs and the NK cell population and K cells. The Fc receptor on the NK cell, however, is non-participant in the process of lysis. There are mechanistic variations and the activity of K cells is not always boosted through interferon and others immune stimulators. NK activities are subject to negative and positive regulation both in vivo and vitro. Interferon gamma as well as IL-2 are powerful inducers. Apart from causing lysis NK cells can also produce alpha-interferon.

The target molecules identified by NK cells are not determined, however it appears that some determinants are universal and others have a restricted distribution. A different hypothesis is that NK cell susceptibility is based on the absence of antigens on the cell surface that are normally present like MHC molecules. The role of NK cells in the course of viral infection is only partially recognized. It was demonstrated that mice that have been depleted of NK cells through treatments with Ab for asialo GM1 exhibit a greater vulnerability to CMV.