Biochemistry II - BCHM 362 - UAEU - Viruses and intro to immunology

1. Mary K. Campbell
Shawn O. Farrell
http://academic.cengage.com/chemistry/campbell
Chapter 14
Viruses, Cancer, and Immunology
Paul D. Adams • University of Arkansas

2. 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

3. Architecture of a Virus

4. Families of Viruses

5. The Virus Life Cycle

6. 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

7. 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

8. Life cycle of a Retrovirus

9. 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)

10. HIV retrovirus

11. - 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,

12. 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.

13. 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)

14. US HIV baby 'cured' by early drug treatment
News 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.

15. 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.

16. Viruses – Biochemical connections
• Read Gene Therapy Page 412-413
• Adenosine deaminase
• Severe combined immune deficiency (SCID)

17. Immunology

18. 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)

19. 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.

20. Dendritic cells

21. NK Cells

22. 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.

23. 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

24. 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.

25. T-cell

26. Growth and Differentiation of T cells

27. 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

28. 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!

29. Interaction Between Helper T Cells and
Antigen-Presenting Cells

30. How Helper T Cells Aid in the Development
of B Cells

31. 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

32. 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

33. Antibody Heavy and Light Chains

34. Monoclonal Abs

35. 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

36. 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.

37. 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

38. 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

39. 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

40. 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 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

41. 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

42. Proto-oncongenes

43. MAP Kinase Signal Transduction

44. 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

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

46. 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

47. Drug Targets in the p53 Pathway

48. Transductional Targeting in Virotherapy

49. Transcriptional Targeting in Virotherapy
(Cont’d)

50. 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

51. 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