Chapter 14Viruses, Cancer, and Immunology

Mary K. CampbellShawn O. Farrellhttp://academic.cengage.com/chemistry/campbell

Paul D. Adams • University of Arkansas

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• Entire particle is known as a virion• 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

Architecture of a Virus

Families of Viruses

The Virus Life Cycle

How Does a Virus Infect a Cell

• A Virus must attach to the host cell before it can penetrate

• A common 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

• An example is HIV attachment

Retroviruses

• A retrovirus implies that replication is backward compared to the central dogma of molecular biology

• 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

Life cycle of a Retrovirus

Retroviruses (Cont’d)

• Retroviruses have certain genes in common• Coat proteins- genes for proteins of the

nucleoplasmid• All retroviruses have genes for reverse

transcriptase (RT), and for envelope proteins (EP)

HIV retrovirus

- TMV, a virus of tobacco plants, is a filamentous RNA virus. Top right: some of the capsid proteins (cyan) have been stripped away to reveal the RNA helix (yellow).

- The capsid normally consists of 2130 coat protein molecules (with 16.3 units per turn of the helix) and is about 300 nm long by 18 nm in diameter

- The genome is ss(+)RNA, that is a single-strand of positive-sense RNA, sense meaning that it can be directly transcribed by ribosomes

HIV Genome

http://www.hiv.lanl.gov/content/sequence/HIV/MAP/landmark.html

The HIV-1 genome contains a single promoter and uses multiple reading frames and alternative splicing to encode 15 proteins from a single pre-mRNA species.

Summary of 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• Some retroviruses also have identifiably unique

genes, e.g., the Sarcoma oncogene and the Rous sarcoma virus

- Viruses are also used in Gene Therapy (see Biochemical Connections, pg. 412)

US HIV baby 'cured' by early drug treatmentNews headline - Mar 4 2013• A baby girl in the US born with HIV appears to have been cured after very early treatment

with standard drug therapy, doctors say. • The Mississippi child is now two-and-a-half years old and has been off medication for about a

year with no signs of infection. • More testing needs to be done to see if the treatment - given within hours of birth - would

work for others. • If the girl stays healthy, it would be the world's second reported 'cure'.• Dr Deborah Persaud, a virologist at Johns Hopkins University in Baltimore, presented the

findings at the Conference on Retroviruses and Opportunistic Infections in Atlanta.• "This is a proof of concept that HIV can be potentially curable in infants," she said. • Cocktail of drugs In 2007, Timothy Ray Brown became the first person in the world believed

to have recovered from HIV.• His infection was eradicated through an elaborate treatment for leukaemia that involved the

destruction of his immune system and a stem cell transplant from a donor with a rare genetic mutation that resists HIV infection.

• In contrast, the case of the Mississippi baby involved a cocktail of widely available drugs, known as antiretroviral therapy, already used to treat HIV infection in infants.

• It suggests the swift treatment wiped out HIV before it could form hideouts in the body.• These so-called reservoirs of dormant cells usually rapidly reinfect anyone who stops

medication, said Dr Persaud.

Death toll from new SARS-like virus climbs to NINE – March 12 2013

• http://edition.cnn.com/2013/03/13/health/new-coronavirus-case/index.html?eref=mrss_igoogle_cnn

• March 13 2013, (CNN) -- There has been another confirmed case of a mysterious new SARS-like virus.

• The Saudi health ministry informed the World Health Organization that a 39-year-old man was hospitalized with the novel coronavirus on February 28 and died two days later.

• So far, WHO has recorded 15 confirmed cases of the novel coronavirus, including nine deaths, since the fall.

• The spread of coronavirus in UK • The Saudi patient did not appear to have had any contact with anyone who was already

infected. As a result, WHO is investigating other potential exposure sources.

Viruses – Biochemical connections

• Read Gene Therapy Page 412-413• Adenosine deaminase• Severe combined immune deficiency (SCID)

Immunology

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

• Can be cellular, molecular, acquired or innate (always present)

Innate Immunity

• There are several parts to innate immunity: physical barriers(skin, mucus), cells of the immune system (dendritic cells, macrophage, and natural killer (NK) cells)• Dendritic cells are members of a class of cells called

antigen-presenting cells (APCs) (1st line of defense)

• T cells release chemicals called cytokines that stimulate other members of the immune system, e.g. killer T cells and B cells (a level of control)

• Another important cell type in the innate immunity system is the natural killer (NK) cells, which is a type of leukocyte.

Dendritic cells

NK Cells

Innate Immunity (T-cells)

• T cells or T lymphocytes belong to a group of white blood cells known as lymphocytes,

• play a central role in cell-mediated immunity. • They can be distinguished from other lymphocytes,

such as B cells and natural killer cells (NK cells), by the presence of a T-cell receptor (TCR) on the cell surface.

• TCR binds ANTIGEN• They are called T cells because they mature in the

thymus.

T Cells cont

• There are several subsets of T cells, each with a distinct function.

• T cells differentiate, and become specialized for one of several possible functions

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

Types of T Cells

Helper

•(TH cells) assist other white blood cells in immunologic processes, including maturation of B cells into plasma cells and memory B cells, and activation of cytotoxic T cells and macrophages. •become activated when they are presented with peptide antigens by MHC class II molecules, which are expressed on the surface of antigen presenting cells (APCs).•Once activated, they divide rapidly and secrete small proteins called cytokines that regulate or assist in the active immune response.

Cytotoxic – Killer (CD8 cell)

•(TC cells,) destroy virally infected cells and tumor cells, and are also implicated in transplant rejection. •These cells recognize their targets by binding to antigen associated with MHC class I, which is present on the surface of all nucleated cells.

T-cell

Growth and Differentiation of T cells

Interaction Between Cytotoxic T cells and Antigen-Presenting Cells

Killer T also called a CD8 cells as it is such a distinguishing feature

antigen

TCR

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

• Double recognition needed = control, activating the immune system is a serious game so you have to be sure!

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 (Cont’d)

• 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

Antibody Heavy and Light Chains

Monoclonal Abs

Antibodies (Cont’d)

• If a cell’s receptors encountered self-antigens that are recognized with high affinity, it undergoes a process called negative selection and is programmed for apoptosis, or cell death

• There are several safeguards that leads to the delicate balance that must be maintained by the immune system

Differentiation of T Cells

This section is a huge topic (as all of these sections in this chapter.)

However this Selection process is covered very poorly so we wont emphasize it.

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

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

Summary (cont’d)

• 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. T cells and B cells are conditioned not to recognize proteins from that individual

• 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 (Cont’d)

• 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 not

2) Cancer cells continue to grow even when the neighboring cells send out “stop-growth” signals

3) Cancer cell manage to keep going and avoid a “self-destruct” signal that usually occurs when DNA damage has occurred

4) 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 immortal (cell culture in the lab)

6) Cancer cells have the ability to break loose, travel to other parts of the body and create new which tumors 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-oncongenes

MAP Kinase Signal Transduction

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

Action of p53

• Mutations in the p53 gene are found in more than 50% of all human cancers

How do We Fight Cancer?

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

1) Surgeries to remove tumors

2) Radiation and chemotherapy

3) 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

Transductional Targeting in Virotherapy

Transcriptional Targeting in Virotherapy (Cont’d)

Summary

• All potentially fatal cancers have several things in common, such as having cells that are immortal, that divide despite “stop growth” signals from nearby cells, that stimulate blood-vessel formation near to themselves, and that spread to other parts of the body

• The development of cancer requires multiple breakdowns in normal metabolism

Summary (Cont’d)

• 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