Title: Virus Killers and Killer T cells

A major challenge for those of us who are interested in minimizing the toll of infectious disease is that RNA viruses with poor genomic fidelity throw off large numbers of variants that emerge as viable escape mutants following immune selection. This is a particular problem for designing vaccines to combat the killer viruses that cause AIDS, hepatitis C and influenza, all of which are major causes of human morbidity and mortality. Of these, our greatest success has been with influenza, though it is necessary to maintain constant global surveillance and to design new vaccines annually. Considerable effort is being made via the multi-centre HIV/AIDS neutralizing antibody consortium to develop strategies for skewing B cell immunity towards more conserved, shared determinants, such as the binding site on the external HIV Env molecule that engages with the CD4 cell-surface receptor. If successful, there will be a big push to apply such approaches to other pathogens. In the meantime, it is the case that the killer cytotoxic T lymphocytes (CTLs) that are specific for virus peptides presented by self major histocompatibility complex class I (MHCI) glycoproteins tend to be directed at relatively conserved virus components. The nature of the effector and memory phases of CTL-mediated immunity will be discussed, together with the limitations and potential benefits of vaccines that emphasize this aspect of host responsiveness.

http://www.mrs.org.sg/icmat2009/programme/plenary-lectures/peter-c-doherty/default.htm IMATC-2009

Role in disease pathogenesis

During hepatitis B virus (HBV) infection cytotoxic T cells play an important pathogenetic role. They contribute to nearly all of the liver injury associated with HBV infection and, by killing infected cells and by producing antiviral cytokines capable of purging HBV from viable hepatocytes, cytotoxic T cells also eliminate the virus.[1] Recently platelets have been shown to facilitate the accumulation of virus-specific cytotoxic T cells into the infected liver.[2] Recently CTLs have been implicated in the progression of arthritis: depletion of knee joint cartilage macromolecules such as glycosaminoglycans by CTLs and macrophages has been observed in a rat model of the disease.

Virus Killers and Killer T Cells Mammals like us are large, complex, slow-reproducing life forms that are subject to parasitism by simpler, rapidly dividing (and mutating) organisms. Through evolutionary time, this need to counter infection has led to the evolution of innate immune mechanisms that are common to many species, and to the extraordinarily specific, adaptive immune system that is characteristic of higher vertebrates. Replicating only in living cells, the viruses are obligate intracellular parasites that throw up two types of challenges for immune control. In free form, the viruses must in some way transit via the air, through protective mucus layers (or in the blood) to access, then enter, the body cells that will support their growth. At that stage, they are vulnerable to attack by secreted antibodies that bind, in the main, to conformed (tertiary) structures on surface glycoproteins. Antibody immunity is the basis of all successful vaccines to date. Then, if a virus has succeeded in bypassing antibody control, there's the need to eliminate the infected cells that serve as "factories" to produce new virus particles and propagate the disease process. That's the role of the CD8+ or "killer" T cells (T Cells), that are targeted to modified (by virus peptide) transplantation or major histocompatibility complex (MHC) molecules on the surface of infected cells. With potentially lethal pathogens, it is this interplay between the kinetics of virus spread on the one hand, and immunity on the other, that determines the fate of the infected individual.
http://www.med.hku.hk/centenary_lecture2011/abstract.html HKU

obel Prize winner to speak on virus killers

By Erika L. Martinez June 5, 2008

Nobel Prize winner Peter Doherty will talk about potentially pandemic virus infections and tools society has to combat them during a Directors Colloquium this morning at the Laboratory. The talk, Virus Killers and T Cells, will include quantitative and qualitative analysis of the influenza virus-specific CD8+ killer T cell response in mouse model systems. The complexity of these experimental systems also will be discussed. The talk begins at 10:30 a.m. in the Physics Building Auditorium and is open to all Laboratory employees. The talk also will be shown on LABNET Channel 9 and on desktop computers using Real Media Stream or IPTV technology. A cytotoxic T cell (also known as CTL) belongs to a sub-group of T lymphocytes - a type of white blood cell. They kill cells that are infected with viruses or other pathogens, or are otherwise damaged or dysfunctional. Doherty won the Nobel Prize in Physiology (medicine) in 1996 with Swiss colleague Rolf Zinkernagel for their discovery of how the immune system recognizes virus-infected cells. He was Australian of the Year in 1997 and has since been commuting between St Jude Childrens Research Hospital in Memphis, Tennessee, and the Department of Microbiology and Immunology at the University of Melbourne. Doherty's research is mainly in the area of defense against viruses. He also has written several books.
http://www.lanl.gov/news/index.php/fuseaction/nb.story/story_id/%2013519 Los Alamos NEWS

Cytotoxic T cell
Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells.

A cytotoxic T cell (also known as TC, CTL, T-Killer cell, cytolytic T cell, CD8+ Tcells or killer T cell) belongs to a sub-group of T lymphocytes (a type of white blood cell) that are capable of inducing the death of infected somatic or tumor cells; they kill cells that are infected with viruses (or other pathogens), or are otherwise damaged or dysfunctional. Most cytotoxic T cells express T-cell receptors (TCRs) that can recognize a specific antigenic peptide bound to Class I MHC molecules, present on all nucleated cells, and a glycoprotein called CD8, which is attracted to non-variable portions of the Class I MHC molecule. The affinity between CD8 and the MHC molecule keeps the TC cell and the target cell bound closely together during antigen-specific activation. CD8+ T cells are recognized as TC cells once they become activated and are generally classified as having a pre-defined cytotoxic role within the immune system.

Effector functions
When exposed to infected/dysfunctional somatic cells, TC cells release the cytotoxins perforin, granzymes, and granulysin. Perforin forms pores (aqueous channels) in the target cell's plasma membrane allowing granzymes, types of serine proteases that cleave at aspartate residues in the substrate, to enter the target cell, which then activate a series of cysteine proteases, the caspasecascade, that eventually lead to apoptosis (programed cell death). A second way to induce apoptosis is via cell-surface interactions between the TC and the infected cell. When a TC is activated it starts to express the surface protein FAS ligand (FasL)(Apo1L)(CD95L), which can bind to Fas (Apo1)(CD95) molecules expressed on the target cell. However, this Fas-Fas ligand interaction is thought to be more important to the disposal of unwanted T lymphocytes during their development or to the lytic activity of certain TH cells than it is to the cytolytic activity of TC effector cells. Engagement of Fas with FasL allows for recruitment of the death-induced silencing complex (DISC). The Fasassociated death domain (FADD) translocates with the DISC, allowing recruitment of procaspases 8 and 10. These caspases then activate the effector caspases 3, 6, and 7, leading to cleavage of death substrates such as lamin A, lamin B1, lamin B2, PARP (poly-ADP ribose polymerase), and DNAPK (DNAactivated protein kinase). The final result is apoptosis of the cell that expressed Fas.

A virus is a small infectious agent that can replicate only inside the living cells of organisms. Most viruses are too small to be seen directly with a light microscope. Viruses infect all types of organisms, from animals and plants to bacteria and archaea. Since the initial discovery of the tobacco mosaic virusby Martinus Beijerinck in 1898, about 5,000 viruses have been described in detail,although there are millions of different types.Viruses are found in almost every ecosystem on Earth and are the most abundant type of biological entity.The study of viruses is known as virology, a sub-speciality of microbiology. Virus particles (known as virions) consist of two or three parts: the genetic material made from either DNA or RNA, long molecules that carry genetic information; a protein coat that protects these genes; and in some cases an envelope of lipids that surrounds the protein coat when they are outside a cell. The shapes of viruses range from simple helical and icosahedral forms to more complex structures. The average virus is about one one-hundredth the size of the average bacterium. The origins of viruses in the evolutionary history of life are unclear: some may have evolved from plasmids pieces of DNA that can move between cells while others may have evolved from bacteria. In evolution, viruses are an important means of horizontal gene transfer, which increases genetic diversity.[7] Viruses spread in many ways; viruses in plants are often transmitted from plant to plant by insects that feed on the sap of plants, such as aphids; viruses inanimals can be carried by blood-sucking insects. These disease-bearing organisms are known as vectors. Influenza viruses are spread by coughing and sneezing. Norovirus and rotavirus, common causes of viral gastroenteritis, are transmitted by the faecal-oral route and are passed from person to person by contact, entering the body in food or water. HIV is one of several viruses transmitted through sexual contact and by exposure to infected blood. The range of host cells that a virus can infect is called its "host range". This can be narrow or, as when a virus is capable of infecting many species, broad.[8] Viral infections in animals provoke an immune response that usually eliminates the infecting virus. Immune responses can also be produced by vaccines, which confer an artificially acquired immunity to the specific viral infection. However, some viruses including those causing AIDS and viral hepatitis evade these

immune responses and result in chronic infections. Antibiotics have no effect on viruses, but several antiviral drugs have been developed.

Structure- Microbiology
Diagram of how a virus capsid can be constructed using multiple copies of just two protein molecules Viruses display a wide diversity of shapes and sizes, called morphologies. Generally viruses are much smaller than bacteria. Most viruses that have been studied have a diameter between 20 and 300 nanometres. Some filoviruses have a total length of up to 1400 nm; their diameters are only about 80 nm. Most viruses cannot be seen with a light microscope so scanning and transmission electron microscopes are used to visualise virions. To increase the contrast between viruses and the background, electron-dense "stains" are used. These are solutions of salts of heavy metals, such as tungsten, that scatter the electrons from regions covered with the stain. When virions are coated with stain (positive staining), fine detail is obscured. Negative staining overcomes this problem by staining the background only. A complete virus particle, known as a virion, consists of nucleic acid surrounded by a protective coat of protein called a capsid. These are formed from identical protein subunits called capsomers. Viruses can have a lipid "envelope" derived from the host cell membrane. The capsid is made from proteins encoded by the viral genome and its shape serves as the basis for morphological distinction. Virally coded protein subunits will self-assemble to form a capsid, generally requiring the presence of the virus genome. Complex viruses code for proteins that assist in the construction of their capsid. Proteins associated with nucleic acid are known as nucleoproteins, and the association of viral capsid proteins with viral nucleic acid is called a nucleocapsid. The capsid and entire virus structure can be mechanically (physically) probed through atomic force microscopy. In general, there are four main morphological virus types: Helical, Icosahedral, Envelope, Complex
http://en.wikipedia.org/wiki/Virus