Virus Immunology

Viruses are strongly immunogenic and induces 2 types of immune responses; humoral and cellular. The repertoire of specificities of T and B cells are formed by rearrangements and somatic mutations. T and B cells do not generally recognize the same epitopes present on the same virus. B cells see the free unaltered proteins in their native 3-D conformation whereas T cells usually see the Ag in a denatured form in conjunction with MHC molecules. The characteristics of the immune reaction to the same virus may differ in different individuals depending on their genetic constitutions.

Humoral Response

Humoral response is responsible for blocking the infectivity of the virus (neutralization). Those of the IgM and IgG class are especially relevant for defense against viral infections accompanied by viraemia, whereas those of the IgA class are important in infections acquired through a mucosa. (the nose, the intestine). In contrast, the cellular response kills the virus-infected cells expressing viral proteins on their surfaces, such as the glycoproteins of enveloped viruses and sometimes core proteins of these viruses. Antibodies (Abs) are elicited by the surface components of intact virions as well by the internal components of disrupted virions. Also they are elicited by viral products built into the surface of infected cells or released by the cells. Antibodies provide the key to protection against many viral infections. Sometimes, they are also pathogenic e.g. immune complexes are thought to be responsible for causing the rash in rubella. Interactions of virions with Abs to different components of their coats have different consequences.

Neutralization

Virus neutralization consists of a decrease in the infectious titre of a viral preparation following its exposure to Abs. The loss of infectivity is bought about by interference by the bound Ab with any one o the steps leading to the release of the viral genome into the host cells. the consequences of the virion-Ab interaction therefore depends on many factors;-

The structure of the virions: The target of the Ab e.g. Abs against the HA but not the NA of influenza virus are neutralizing.Mutations affecting surface molecules that may alter the susceptibility to certain Abs. The type of Ab, especially its affinity for the components of the virions. The number of Ab molecules attached to the virions.

Reversible neutralization - The neutralization process can be reversed by diluting the Ab-Ag mixture within a short time of the formation of the Ag-Ab complexes (30 mins). It is thought that reversible neutralization is due to the interference with attachment of virions to the cellular receptors. The process requires the saturation of the surface of the virus with Abs.

Stable neutralization - with time, Ag-Ab complexes usually become more stable (several hours) and the process cannot be reversed by dilution. Neither the virions nor the Abs are permanently changed in stable neutralization, for the unchanged components can be recovered. The neutralized virus can be reactivated by proteolytic cleavage. Intact Abs can be recovered by dissociating the Ab- Ag complexes at acid or alkaline pH. Stable neutralization has a different mechanism to that of reversible neutralization. It had been shown that neutralized virus can attach and that already attached virions can be neutralized. The number of Ab molecules required for stable neutralization is considerably smaller than that of reversible neutralization, Kinetic evidence shows that even a single Ab molecule can neutralize a virion. Such neutralization is generally produced by Ab molecules that establish contact with 2 antigenic sites on different monomers of a virion, greatly increasing the stability of the complexes.

Virion sites for neutralization - only epitopes on molecules involved in the release of the viral genome into the cells are targets of neutralization. In influenza viruses, only the HA and not the NA are targets for neutralization. In polioviruses, all antigenic sites recognizable on the capsid are targets for neutralization, because the capsid is a unit for releasing the nucleic acid. For adenoviruses, the main targets are the hexons rather than the pentons, as the hexons are strongly interconnected and work together for the release of the viral DNA. Occasionally, Abs bound to non-neutralizing epitopes can be detected by neutralization in the presence of complement, whereby the viral enveloped is attacked by the complement cascade.

Protective role of neutralizing antibodies - the neutralizing power of a serum usually reflects the degree of protection in an infected animal. The correlation, however, is not always perfect. Discrepancies may be generated by differences in the neutralizability of a virus in the cells used for assay in vitro compared to those that the virus infects in vivo. e.g. the sera of mice protected from yellow fever did not neutralize the virus in vero cells but did so in a mouse neuroblastoma cell line. Another possible reason for discrepancy is that an Ab that does not neutralize in cultures may act in vivo by activating host responses against the virus or virus-infected cells. e.g. complement or macrophages. In addition, neutralizing Abs may fail to protect because rapid viral multiplication overcomes the neutralizing power. In the early period of immunization, low affinity Abs act predominantly by activating complement and have low neutralizing power in cultures. The degree of neutralization in cultures is probably best estimated by carrying out neutralization in the presence of complement.

Evolution of viral antigens

Viral evolution must tend to select for mutations that change the antigenic determinants involved in neutralization. In contrast, other antigenic sites would tend to remain unchanged because mutations affecting them would not be selected for and could even be detrimental. A virus would thus evolve from an original type to a variety of types, different in neutralization (and sometimes in HI) tests, but retaining some of the original mosaic of antigenic determinants recognizable by CFTs. These evolutionary arguments are consistent with the observation that the clearest differentiation of types within a family is present in viruses of rather complex architecture, in which the Ags involved in the interaction with the cell vary more than other proteins. Thus enveloped viruses have a strain-specific envelope but a cross-reactive internal capsid; adenoviruses have type-specific fibers and family-specific (and also type-specific) capsomers. Moreover, the C Ag of polioviruses, which appears only after heating, reveals antigenic sites that are normally hidden and hence are not affected by selective pressure. The extent of antigenic variation differs widely among viruses and is most extensive with lentiviruses and influenza viruses.

Click for second part (Viral Immunology 2)