Viruses, Cancer and Immunology

Chapter 14

What are viruses?

• Viruses are pathogens of bacteria, plants, and animals

• Can be deadly (e.g., Ebola, HIV)• Can be merely annoying (e.g., Rhinovirus)• Viruses are small particles composed of

nucleic acid and protein - Virion

What is the structure of a virus?• Capsid- surround the center

of the virion

• Nucleocapsid- combination of the nucleic acid and the capsid

• Membrane envelope- surrounds the nucleocapsid

• Protein spikes- help viruses attach themselves to the host cell

Families of Viruses

Virus Life Cycles

• Virus binds to cell membrane and releases its DNA into host cell

• Replicated, transcribed and translated• Makes proteins necessary to make protomeres• New virions are produced – lysis - lytic pathway• Lysogeny - No lysis – incorporate viral DNA into

host chromosome. Example: Simian Virus 40 (SV 40)

How Does a Virus Infect a Cell?

• Method of attachment -involves the binding of one of the spike proteins on envelope of the virus to a specific receptor on the host cell

• Example - HIV attachment

Retroviruses

• The genome of a retrovirus is single-stranded RNA

• Once it infects the cell, the RNA strand is used as template to make double-stranded DNA

• Retroviruses have been linked to cancer and AIDS

Common genes

• Coat proteins- genes for proteins of the nucleoplasmid

• All retroviruses have genes for reverse transcriptase (RT), and for envelope proteins (EP)

Summary for Retroviruses

• Retroviruses have a genome based on DNA. When they infect cells, their RNA is turned into DNA by RT. The DNA is then incorporated into the host’s DNA genome as a part of the replication cycle for the virus

• Retroviruses all have certain genes in common

The Immune System• The immune system allows for the distinction between self

from nonself

• This allows cells and molecules responsible for immunity to recognize and destroy pathogens

• The immune system can also go awry in distinguishing self from nonself. This results in an autoimmune disease, in which the immune system attacks the body’s own tissues

• Allergies are also another type of improper functioning of the immune system

What is Innate Immunity?

• Pathogen has attacked your front line of defense.

• Physical barriers – skin, mucus and tears

• Breaching of physical barriers – cellular warriors – dendritic cells, macrophages and natural killer cells

Cellular warriors

• Dendritic cells are members of a class of cells called antigen-presenting cells (APCs)

• T cells release chemicals called cytokines that stimulate other members - killer T cells and B cells

• Natural killer (NK) cells - is a type of leukocyte- NK kills off cells infected by viruses or cancerous

cells. - Secretes cytokines (Macrophages) that destroy

microbes

Acquired Immunity• T cells differentiate, and

become specialized for one of several possible functions

• Killer T cells involve T-cell receptors (TCRs) on their surfaces that recognize and bind to antigens

• Proliferation of killer T cells is triggered when macrophages bound to T cells produce small proteins called interleukins

Interaction Between Cytotoxic T cells and Antigen-Presenting Cells

Clonal selection

• The process by which only the cells that respond to a given antigen grow in preference to other T cells is called clonal selection

Interaction Between Helper T cells and Antigen-Presenting Cells

How Helper T Cells Aid in the Development of B Cells?

Antibodies

• Antibodies are Y-shaped molecules consisting of two identical heavy chains and two identical light chains held together by disulfide bonds

• Antibodies are glycoproteins

Antibodies bind to Antigens

• The variable region is found at the prongs of the Y and is the part of the antibody that binds to the antigen

• The binding sites for the antibody on the antigen are called epitopes

Summary

• Vertebrates have an immune system• Innate immunity consists of physical barriers

and cellular warriors

• Acquired immunity is based on two types of T cells and on B cells. These cells are generated randomly with receptors that can be specific for an unimaginable number of antigens

Summary

• When cells encounter their specific antigens, they are stimulated to multiply

• Acquired immune cells also leave behind memory cells so that if the same pathogen is seen again, the body is faster to eliminate it

• Immune cells must be able to recognize self from nonself.

• In some cases, the immune system breaks down, and a person may be attacked by his or her own immune system leading to an autoimmune disease

CANCER

• Cancer is the leading cause of death in human beings

• It is characterized by cells that grow and divide out of control, often spreading to other tissues and causing them to become cancerous

Cancer • All life-threatening cancers have at least six characteristics in

common1) Cancer cells continue to grow and divide in situations in which

normal cells do not2) Cancer cells continue to grow even when the neighboring cells

send out “stop-growth” signals3) Cancer cell manage to Keep going and avoid a “self-destruct”

signal that usually occurs when DNA damage has occurred4) The can co-opt the body’s vascular system, causing the growth

of new blood vessels to supply the cancerous cells with nutrients

5) They are essentially immortal6) Cancer cells have the ability to break loose, travel to other parts

of the body and create new tumors which make them lethal, this is called metastasis

What Causes Cancer?

• Changes in DNA cause changes to specific proteins that are responsible for controlling the cell cycle

• Most mutations of DNA affect two types of genes:1) Tumor suppressor, a gene that makes a protein that restricts the cell’s ability to divide

2) An oncogene is one whose protein product stimulates growth and cell division. Mutations of an oncogene cause it to be permanently active

Proto-oncogenes

Tumor Suppression• Tumor suppressors inhibit transcription of

genes that would cause increased replication• When a mutation occurs in any suppressor,

replication and division become uncontrolled and tumors result

How do We Fight Cancer?

• Cancer has been treated in a variety of ways• Traditional approaches include:

1) Surgeries to remove tumors2) Radiation and chemotherapy3) Treatment with monoclonal antibodies to target specific tumors

• More current foci include attempts to reactivate p53 in cancerous tissues when they have lost their function

Drug Targets in the p53 Pathway

Virotherapy

• 1990s – used adenovirus to target human grafted onto mice

• Use virus to attack and kill the cancer cell directly

• Use virus ferry in a gene to cancer cell that makes the cell susceptible to a chemotherapy agent

Transductional Targeting in Virotherapy

• Antibodies are attached to virus – target cancer cells

• Inside – viruses reproduce and lyse the cancer cells

Transcriptional Targeting in Virotherapy

• Replication genes for adenovirus are placed after a promoter specific for a cancer cell

• Promoters are triggered more often – adenovirus replicates quicker in skin-cancer cells

Summary

• Most cancers have been linked to specific genes called oncogenes or to tumor-suppressor genes. When these genes mutated, the cell loses the ability to control its replication

• There are many classical ways to fight cancer, such as radiation therapy and chemotherapy

• Novel techniques using viruses are now being tried to target cancer cells more directly, and some of these are showing tremendous promise

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