Chapter 14 Viruses, Cancer, and Immunology Mary K. Campbell Shawn O. Farrell 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)

Typical Retrovirus Genes

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)

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

Innate Immunity (Cont’d) There are several parts to innate immunity: physical barriers, 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) T cells release chemicals called cytokines that stimulate other members of the immune system, e.g. killer T cells and B cells Another important cell type in the innate immunity system is the natural killer (NK) cells, which is a type of leukocyte

Innate Immunity (Cont’d) 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

Growth and Differentiation of T cells

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 (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

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

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 common 1)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 deep 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 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