Adaptive immunity against viruses and viral evasion strategies Flashcards
What are the Effector mechanisms of Antibodies
List the steps of the virus life cycle
How do antibodies limit viral spread?
Antibodies can neutralize the infectivity of viruses
Virus are only outside of a host cell whilst
spreading to new cells. These would be targeted by neutralising antibodies.
Antibodies provide a major barrier to virus spread between cells and tissues and are particularly important in restricting virus spread in the bloodstream. IgA production becomes focused at mucosal surfaces where it serves to prevent reinfection.
An important mechanism of IgA-mediated neutralization occurs intracellularly as IgA passes from the luminal to the apical surface of the cell. During this transcytosis vesicles containing IgA interact with those containing virus, leading to neutralization.
Q. Which proteins are likely to be the most important targets of antibody-mediated defenses?
A. Only antibodies directed against glycoproteins that are expressed on the virion envelope or on the infected cell membrane are of importance in controlling infection.
Infected cells can have viral proteins on
their surface
Summarise the mechanisms by which antibody acts to neutralize virus or kill virally infected cells
How is the Complement involved in the neutralization of some free viruses?
Complement can also damage the virion envelope, a process known as virolysis, and some viruses can directly activate the classical and alternative complement pathways. However, complement is not considered to be a major factor in the defense against viruses because individuals with complement
deficiencies are not predisposed to severe viral
infection.
This should be contrasted with those herpesviruses and poxviruses that carry viral homologues of complement regulatory proteins (CD46, CD55) that regulate complement activation. Presumably these viruses are susceptible to control by complement-dependent mechanisms
How do antibodies mediate the destruction of virus-infected cells
This can occur by antibody-mediated
activation of the complement system, leading to the assembly of the membrane attack complex and lysis of the infected cell
Q. How can NK cells use antibody to recognize and destroy virus-infected cells?
A. The IgG-coated target cells are bound using the NK cell’s FcgRIII (CD16), and are rapidly destroyed by a perforin-dependent killing mechanism
T cells mediate viral immunity in several ways
Describe this
T cells exhibit a variety of functions in antiviral immunity:
* CD8+ T-cells are important effector cells
* most of the antibody response is T-dependent, requiring the presence of helper CD4+ T-cells for class switching and affinity maturation;
* CD4+ T-cells also help in the induction of CD8+
T-cell responses and in the recruitment and activation of macrophages at sites of virus infection;
* memory CD8+ T cells are effective in combating reinfection with viruses such as influenza virus and respiratory syncytial virus – however, even memory T cells need time to develop a response when infection is re-encountered, so antibodies typically assume a more dominant role in protection against reinfection by neutralizing incoming virus, containing the infection and preventing spread to other tissues.
Q. How do CD4+ T cells help to induce and recruit CD8+ T-cells?
A. CD4+ T cells interact with dendritic cells and help to activate them to stimulate an effective CD8+ T cell response. Cytokines, including IL-2, released by CD4+ T-cells are also required for division of CD8+ T cells. CD4+ T cells can recruit CD8+ T cells to sites of infection by the release of chemokines and induction of chemokine synthesis by endothelium.
How do CD8+ T cells target virus-infected cells?
CD8+ T cells identify virus-infected cells by recognizing MHC class I molecules presenting virus-derived peptides on the cell surface, and are triggered to mediate effector functions that clear the infection.
CD8+ T cells:
* kill infected cells through the release of perforin, granzymes, and other cytolytic proteins;
* trigger the death of infected cells through binding of soluble factors (e.g. TNFa) or ligands they express (e.g. FasL) to cell-surface receptors (such as Fas) that signal the cell to undergo apoptosis
* produce soluble factors such as IFNg and/or TNFa that can ‘cure’ infection with some viruses (e.g. hepatitis B virus) without death of the cell. This can result in eradication of virus from not only the target cell with which the CD8+ T cell is interacting, but also from neighboring cells.
Q. Why might it be advantageous to the host to present viral peptides that are produced early in the replication cycle, and which may not be part of the assembled virus?
A. Viral proteins expressed early in the replication cycle can be
presented on infected cells relatively soon after they have been
infected, enabling T cell recognition to occur long before new viral progeny are produced.
For example, CD8+ T cell mediated immunity against murine cytomegalovirus (MCMV) is mediated predominantly by T cells recognizing an epitope in the immediate early protein pp89 (80–90% of the T cell response is directed against pp89). Immunization of mice
with a recombinant vaccinia virus containing pp89 is sufficient
to confer complete protection from MCMV-induced disease.
Describe the development of CD4+ T-cells during a viral infection
Other cell types can up-regulate MHC class II during
infection and can by lysed by cytolytic CD4+ cells
Describe how CD4+ T cells are a major effector cell population in the response to some virus infections (use HSV-1) as an example
A good example is in HSV-1 infection of epithelial
surfaces. Here, CD4+ T cells participate in a delayed-type hypersensitivity responsethat results in accelerated clearance of virus. They produce cytokines such as IFNg and TNFa, which mediate direct antiviral effects and also help to activate macrophages at the site of infection.
Describe how CD4+ T cells are a major effector cell population in the response to some virus infections (use EBV + Measles) as an example
In measles virus and Epstein–Barr virus (EBV) infections, CD4+ CTLs are generated that recognize and kill MHC class II-positive cells infected with the virus using the cytolytic mechanisms also employed by CD8+ CTLs. This suggests that measles virus and EBV peptides are generated by normal pathways of antigen presentation (i.e. following phagocytosis and degradation). However, other pathways have been implicated in which some measles proteins/peptides enter class II vesicles from the cytosol.
