Immune System Function

1
Viruses
2
Some Random Statistics 1918-1919 Spanish Flu
(A/H1N1) 20-40 million deaths world-wide 1957
Asian (A/H2N2) 1968 Hong-Kong (A/H3N2) 1.5
million deaths 35 50 million infected with
influenza (USA) each year 20,000
deaths/year 64,000 deaths/year due to
influenza pneumonia Hantavirus (flu-like
symptoms which may progress to severe difficulty
in breathing death) 50 mortality (USA- Four
corners, Canadian prairies) HIV 30 million
infected worldwide 100 mortality Ebola
(fever, headache, joint-muscle aches, weakness
progressing to diarrhea, vomiting,
internal/external bleeding) 90 mortality West
Nile (USA) (flu-like symptoms) 2002 3389
infected 201 deaths... 5.9 2003 9862
infected 264 deaths... 2.6 2004 2539
infected 100 deaths... 3.9 2005 3000
infected 119 deaths... 3.9 2006 4269
infected 177 deaths... 4.4 2007 3623
infected 124 deaths... 3.4
3
Measles 30 million cases world-wide with 1
million deaths Hepatitis A 1.4 million
infections world-wide Hepatitis B (chronic liver
inflammation, cirrhosis, cancer) 2 BILLION
people infected (total) world-wide 10 develop
liver cancer Hepatitis C (chronic liver
inflammation, cirrhosis, cancer) 3 4 million
infected world-wide 10 develop liver
cancer Rotavirus (vomiting severe diarrhea)
600,000 children die Cervical Cancer 50 due
to HPV 470,000 million new cases
world-wide 230,000 deaths Obviously viruses
are an important contributor to human disease and
mortality
4
There are more varieties of viruses than any
other biological entity on the planet simply
millions of different ones. Most, however, are
irrelevant to human disease because most are
incapable of infecting humans. Those that do,
however, are capable of causing a devastating
array of diseases from the common cold and
influenza to Ebola, hepatitis, and AIDS. Like
any other pathogen, they illicit an immune
response that then eliminates the virus
providing, of course, that the virus is
recognized as foreign, and that the genes exist
that allow us to develop immunity. As inferred,
an inability to develop immunity to the small pox
virus probably wiped out as many as 80 of the
native population in North America, allowing the
Europeans to dominate and subjugate the remaining
population. AIDS, on the other hand, develops
because it is only the exceedingly rare human
that is capable of recognizing the fast-mutating
HIV and amazingly evasive HIV virus. As recent
research indicates, it is possible to develop
immunity against the virus from a carefully
crafted vaccine indicating that humans possibly
can develop immunity against HIV but it is the
fast mutation rate and evasive abilities of the
virus that prevents immune recognition. As the
list on the previous slides attests, a lot of
people die as a result of viral infections. And
from the West Nile data... It appears that lots
of publicity and education about avoiding
mosquitoes and early diagnosis can reduce
infections and deaths...
5
Types of Viruses DNA Viruses ds-DNA ss-DNA
Smallpox Parovirus B19 Herpes
Adenovirus Human Papillomavirus RNA
Viruses antisense RNA sense RNA
Measles Polio Mumps
Rhinovirus Ebola Corona Virus
Influenza West Nile Virus Rabies
Ruebella diploid ssRNA Retrovirus
HIV HTLV
6
There are different variations of viruses based
on the form of their genetic material. DNA
viruses such as the smallpox, herpes, and human
papillomavirus have their genetic material in the
form of double-stranded DNA just like ours.
When the DNA is injected into the cell it is
picked up by the normal enzymes for transcription
and transcribed into mRNA and then translated
into viral proteins by the normal protein
synthesis machinery that is already active in the
cell. RNA viruses such as measles, mumps, ebola,
influenza and rabies have their genetic material
in the form of antisense RNA while the
rhinovirus, corona virus, ruebella virus, and
West Nile virus have their genetic material in
the form of sense RNA. RNA retroviruses have
genetic material in the form of diploid,
single-stranded RNA that must first be
reverse-transcribed into double-stranded DNA (DNA
sequence converted into RNA sequence is
transcription so RNA sequence to DNA sequence
must be reverse transcription) which is then
handled like any other DNA-based genes. The
resulting DNA from most retroviruses is
integrated into the DNA of the host. The enzyme
to do this is supplied by the virus hence the
name retrovirus meaning reverse transcriptase
virus (or something like that). The human
immunodeficiency virus is an example of a retro
virus. This virus infects the helper T-cells and
ultimately can greatly impair their function and
reduce their numbers to ineffective amounts.
This would explain why HIV infections can lead to
autoimmune deficiency disease an individual
cant develop immunity toward any new infection
and very often dies due to complications from
infectious diseases that normally would not be
fatal. Most viruses are pretty selective in
terms of their ability to infect specific types
of cell. For example, there are viruses that can
only infect bacteria cells (bacteriophages) and
some viruses that can only infect upper
respiratory epithelial cells (influenza virus,
rhino virus), or sensory nerve cells (varicella),
and so on. The virus capsid has receptor-type
proteins on the outer surface that can recognize
only one type of cell on the basis of the
membrane-bound proteins or phospholipids which
exist on the cell surface. For example, the HA
protein of the influenza virus recognizes the
sialic acid component of a sialyl-lactose
glycolipid (a membrane phospholipid). If the
virus mutates and starts producing a capsid
protein that recognizes a different cell type,
then the virus will be able to invade a new cell
type. This has happened with a strain of avian
(bird) influenza virus in Hong Kong in 1997 the
HA protein of a avian influenza virus mutated to
recognize the sialyl-lactose configuration of
human cells and caused an epidemic of influenza.
Sometimes simply being exposed to mass quantities
of a particular non-human virus can still lead to
infection. An example of this would be the
A/H5N1 strain of avian influenza virus
7
Viruses do not have the capacity to reproduce
because they do not possess the genes necessary
to code for all of the appropriate
proteins. They have a minimal genome sufficient
only for replicating capsid proteins, viral
genome, and viral-specific enzymes. They must
infect other cells and use the cellular array of
protein-synthesis enzymes to reproduce the viral
proteins and genome and assemble new viruses.
8
Viruses are strange creatures which are barely
alive. They do not fit the normal definition of
living because they cannot reproduce on their
own. They need another living species to do that
for them. A virus consists of a protein capsule
called a capsid, inside of which are contained
the viral genes in the form of DNA, or RNA as
well as possibly an enzyme or two (or more)
depending of which virus we are talking about.
The only function of a virus is to bind to a
living cell of some sort (specific viruses can
bind only to specific cell types with the proper
receptor or receptors) and inject its contents
into the cell. Once the viral contents are
inside the cell then the viral genes are
translated into the viral proteins by the normal
protein synthesis machinery that already exists
inside the cell. When all of the viral proteins
are synthesized they are assembled into new
viruses. Many new copies of the virus will be
made by the cell and the newly made viruses then
are released from the cell or they break out of
the cell and then diffuse around to infect other
nearby cells with the same surface
receptors. Obviously because some the viruses
break out of the cell, the cell membrane will be
ruptured. Either the cell dies and initiates an
acute inflammatory response (or enough cells die
that the organ fails and the infected person
dies) or the damage is not severe enough to kill
the cell but an inflammatory response in
initiated anyway. Very often it is the
inflammatory response to the virus-induced damage
that produces the symptoms of the infection. Any
resulting cell death from the infection can
possibly lead to more serious consequences if the
damage is extensive enough (organ dysfunction or
failure). In some instances the viruses exit
through a budding mechanism which does not kill
or even damage the cell. Some of these viruses
even get encapsulated with the cell membrane and
therefore acquire the ability to evade immune
surveillance (human cell membrane coat no
immune response).
9
Viruses attach to specific cells via their
docking proteins. For example Influenza -
HA recognizes sialic acid on glycoproteins
/glycolipids Rhinovirus ICAM-1 receptor/LDL
receptor HIV CD4 receptor of
hT-cells/macrophages Measles CD46 receptor
(inhibits complement activation) SLAM
(Signaling Lymphocyte Activation Molecule) of T-
cells
In many cases, once inside, the viral contents
are released into the cell and the genome is
incorporated into the nucleus and the cells
protein synthesis machinery is hijacked to
replicate the viral proteins. Viruses supply
their own specialized enzymes to ensure that the
replication process proceeds if the cell cannot
handle the specific form of viral genome.
10
After the viruses have been replicated by the
cell, the viral particles either rupture the cell
membrane to break out of the cell or fuse with
the membrane and break off as a
cell-membrane-enveloped particle. These
processes will either kill the cell or injure the
cell. In many cases, a local inflammatory
response (please see PPt HumanDisease-2-ImmuneFun
ction) is initiated as a result of the viral
release. In some cases viral release doesnt
injure the cells but, rather, induces release of
inflammatory-related cytokines
11
A little more on avian influenza the avian
influenza viruses of type A are classified by the
particular type of haemagglutinin protein (15
different subtypes) and neuraminidase protein (9
different subtypes) on their surface. The
influenza A/H5N1 strain of avian influenza is a
particularly virulent strain of virus which is
highly infective in birds and the only one which
causes severe/fatal disease in humans. Because
many humans happen to work with large numbers of
birds (poultry farmers for example) it is
possible that some humans may be exposed to huge
numbers of this strain if they closely handle
infected birds. This, of course has happened
over the last 10 years where by late fall of the
year 2005 about 100 people who have had very
close contact with large numbers of infected
poultry have become infected with the A/H5N1
virus. Unfortunately, this strain of virus is
highly pathogenic and there is about a 25 to 80
fatality rate (depending on where the outbreak
occurred) if infected. Why the avain H5N1
doesnt easily infect humans is because the H5N1
subtype prefers a sialic acid joined to lactose
with an a 2-3 linkage which is observed only in
ciliated respiratory cells of humans (think mucus
here) but in a very high percentage of intestinal
cells of birds. Thus it takes exposure to large
numbers of A/H5N1 virus to produce an effective
infection in humans. On the other hand, if the
HA protein of the A/H5N1 virus mutates to
recognize the much more common sialic acid
version (a 2-6 linkage) of human respiratory
cells than it will become very easy to be
infected by this virus. This is, of course a
major fear today and governments all over the
world are finally trying to do something to
protect their citizens from possible infection by
a highly virulent virus which has not been seen
in humans before (no one has any immunity so it
can be both deadly and spread very fast).
12
Human flu, on the other hand is commonly caused
by a similar Type A influenza virus but there are
only 3 known H proteins and 2 known N proteins.
The seasonal form of influenza is typically the
A/H3N2 or the A/H1N1 (and the Type B virus),
where small changes in the genes of these viruses
resulting from genetic drift produce slight
changes in the H3 (or H1/H2 or N2/N1) proteins,
producing a strain (same strain) of virus that is
no longer recognized (or recognized not very
well, ie. some cross-reactivity) by antibodies
produced from the previous infection by the same
(now, slightly different) strain. Type A/H1N1
strains have been responsible for the massive
influenza pandemic of 1918-1919 where tens of
millions of people died worldwide 2.7 fatality
rate compared to 0.1 for seasonal flu and about
0.5 to 1 for the 2009 A/H1N1 strain. The new
A/H1N1 strain is an interesting virus because it
has a unique genetic heritage. The RNA genes of
this virus include genes from a North American
avian H1N1, a North American version of swine
H1N1, a human A/H1N1 and a couple non-North
American swine A/H1N1 viruses. This combination
comes about from a process called genetic shift.
For this to happen, an animal (or human) needs to
be infected with 2 different influenza viruses at
the same time. When the 2 viruses inject their
RNA into the host cells at the same time, then
there can be a re-combination of the viral genes
to produce H1N1 proteins that are very much
different from the parent proteins. Apparently,
this genetic shift has happened several times to
result in the current A/H1N1 strain, a strain
that most people have partial immunity against
since the last H1N1 pandemic was in the 50s.
13
Specific symptoms of a viral infection depend on
the specific type of cells infected on the
severity of cellular damage or extent of altered
cell function. An example of differing symptoms
from different viruses can be illustrated with
the rhinovirus and influenza virus. Both are
families of viruses that are highly infective in
humans and are not (usually) fatal. Both infect
the upper respiratory epithelia but lead to a
different (but overlapping) array of symptoms due
to the different degrees of damage and
inflammation in response to the virus infections
and to the different (but overlapping) array of
cells infected. The HA (haemagglutinin) surface
protein of influenza viruses bind to sialic acid
residues of membrane lipoprotein polysaccharides
while the rhino virus binds to the ICAM receptor
(or LDL receptor). One major difference in
ability to grow is that the rhinovirus likes
temperatures 33C while the influenza virus
likes temperatures a little warmer (34-35C).
This is probably one reason why rhinoviruses
infect the nose and sinuses (they are cooler)
much more while influenza virus infects the
warmer lungs much more. A cold rarely causes a
fever or headache while the flu always does a
cold rarely causes aches and pains and weakness
and never causes exhaustion while the flu causes
severe exhaustion, weakness, and lots of aches
and pains. A major reason for these different
symptoms is that the influenza virus causes
extensive damage to the infected cells when they
break out of them. The influenza virus also
stimulates the infected cells to release
interferon. The interferon is the inflammatory
cytokine which causes fever and is largely
responsible for the fatigue and aches and pains
which accompany an influenza infection. On the
other hand, the rhinovirus does not cause
cellular damage but only induces the infected
cells to release histamine. The stuffy and runny
nose and sinus congestion are a result of the
local effects of histamine release from the
infected cells.
14
Herpes Virus HHV-1 (Herpes Simplex Virus I)
virus infects oral skin epithelial/mucosal
cells, multiplies within them breaks out,
causing blisters some viral particles travel
through sensory nerves to ganglion where they
become inert. Later activation results in
secondary lesions HHV-2 (Herpes Simplex Virus
II) same as above except more infectious in
genital epithelia/mucosa. HHV-3 (Varicella
zoster Virus) same as above except more
infectious to skin epithelia on upper body
resulting in chickenpox. Secondary activation
results in shingles. HHV-4 (Epstein-Barr Virus)
associated with Burkett Lymphoma, nasopharyngeal
cancer, and mononucleosis. HHV-8 (Human
Herpesvirus 8 - Kaposis sarcoma-associated) Herp
es type viruses comprise one of the more common
families of viruses which infect humans. Herpes
simplex I, II, or III probably infect 80 (and
most likely everyone) of the world. They cause
cold-sore like skin eruptions and the Herpes
Simplex I is mostly responsible for cold-sores on
the face and lips, Simplex II is mostly
responsible for genital herpes, and Simplex III
(Varicella Zoster) is mostly responsible for the
Chicken Pox, and if the virus is re-activated,
for Shingles. There is really no cure for any of
the Herpes infections although there is a vaccine
available for Varicella Zoster (since 1995). The
virus infects skin epithelial cells and on the
first outbreak, the viral particles infect
sensory nerves in the different areas (I mostly
face, II mostly genitals, III mostly skin of
trunk and scalp) and lay dormant in the ganglions
of the infected nerves. Many years later an
outbreak can occur again, resulting in a
re-appearance of the cold-sore like lesions (I
II) or in the severe pain and rash of Shingles
(III). Epstein-Barr virus (EBV) (also one of the
Herpes viruses) is responsible for infectious
mononucleosis. As with the other Herpes viruses
there is no known prevention (except for the
varicella zoster one, of course) other than
avoiding contact with infected persons and no
treatment other than treating the symptoms.
There are no drugs which can directly kill
viruses!
15
Human Papilloma Virus HPV provides a nice
example of how a virus can produce different
symptoms based on the cell type infected and the
specific cellular function which is
altered. There are over 80 different types of
this DNA virus some of which cause warts, and in
some cases, cervical cancer. To see how this
works a little information on cell division and
control of cell division is necessary. The
normal progression from a single cell through the
cell-division process is called the Cell
Cycle. Human papilloma virus (HPV) is actually
a family of viruses (more than 80 different
strains) that cause benign tumors of the
epidermis commonly called warts. Some strains
of the HPV cause cancer for example cervical
cancer is caused by this little beast. How HPV
does this is a rather interesting story. In
order to cause a tumor, the virus must somehow
increase rates of cell division. The epithelial
cells of the epidermal tissue (whether it be
skin, oral mucosa, or genital mucosa) are
infected by the virus which then is replicated by
the infected cells. Normally this would end up
causing some sort of damage to the cells membrane
when the viral particles leave. HPV is a weird
virus which requires cells to divide in order to
replicate the virus. The virus does this in a
very clever way.
16
Cell Division Signals
Cancer cells continuously divide in an
uncontrolled fashion
DNA Damage
Promotion
Initiation
Normal cells enter the cell cycle only when
stimulated by well-controlled growth signals.
Progression
17
Normally cells will not divide. They are in what
is called G0 Arrest (Growth Zero, arrest).
Most cells also are terminally differentiated.
This means that they are no longer immature,
small, all-cells-look-the-same-and-can-turn-into-a
ny-other cell-stem cells, but rather, grown up
and look like mature tissue cells (and different
from other tissue cells). A normal cell-division
cycle would be G0 (the cell is quiescent) -
progresses into G1 (grows to be a bigger cell) -
which progresses into S Phase (all of the DNA is
duplicated so the cell can divide into two cells
each with its own complete set of DNA) - which
progresses into the G2 phase (grows again so
there is enough of the larger cell to make two
complete new cells when it divides) - which
finally progresses into the M phase (mitosis, or
division). If the original cell was a stem cell
then one of the two new cells differentiates into
a tissue cell while the other stays as a stem
cell (in G0 arrest - at least it stays in G0
arrest until it receives signals to enter the
cell cycle again). If one looks at the different
events that control whether a cell enters the
cell cycle from G0 arrest, it is clear that there
are a lot of complicated steps involving a lot of
different proteins to make it happen. Very often
it takes a signal coming from outside the cell
for example estradiol can do this for any cell
with an estrogen receptor. Some growth factors
and cytokines produced during inflammation also
can do this. Once the cycle is started by these
external signals, then internal regulatory
signals take over and the cycle continues until
the cell divides.
18
Events which alter the cell division cycle are
very important in carcinogenesis.



While this is probably more information than
humans should be allowed to understand note that
growth factors, inflammatory cytokines estrogen
can start the cell division thing rolling.
19
While we can ignore most of the control
mechanisms in the diagram you will notice that
the growth factors as well as estrogen work by
interacting with a regulatory protein called Rb.
This protein is the key to understanding how HPV
works. In order to force a cell to divide (and
thereby replicate the virus) HPV genes code for a
few proteins that interfere with the cell cycle
control mechanisms. One of them is called E7 and
this protein interferes with Rb function. Rb
normally prevents entry into cell cycle and when
E7 complexes with Rb the cell will enter the G1
phase of the cell cycle. (OK, so a lot more
things happen and it is a lot more complicated
than this but the point is clear, if you
interfere with cell-cycle control mechanisms, you
can get inappropriate cell division.) The end
result is that the HPV infected epithelial cells
which would not normally divide will start
dividing and pile up to produce a benign tumor (a
wart). Only after an adaptive immune response
to these infected cells occurs will cytolytic T
cells attack and get rid of the virus-infected
cells (and the wart then disappears).
20
The series of reactions pictured here happen
inside of those cells which have receptors for
the signaling proteins. Note that these factors
lead to increased protein synthesis and
activation of Rb -
21
If one looks at the different events that control
whether a cell enters the cell cycle from G0
arrest, it is clear that there are a lot of
complicated steps involving a lot of different
proteins to make it happen. Very often it takes
a signal coming from outside the cell for
example estradiol can do this for any cell with
an estrogen receptor. Some growth factors and
cytokines produced during inflammation also can
do this. Once the cycle is started by these
external signals, then internal regulatory
signals take over and the cycle continues until
the cell divides. If the HPV infection happens in
cells with receptors for some of the external
cell-cycle signals (lets say - cervical cells
which respond to estrogen) then the cell division
rate can be faster than in those cells that do
not respond to external signals. This can have a
detrimental effect, ie. decreased time for repair
of DNA damage in these cells. If any DNA damage
exists while the cell is duplicating all of the
genes during the S phase, then there is a very
high likelihood of producing a gene mutation in
the resulting daughter cells. One form of DNA
damage is the binding of any chemical to a DNA
base. If there is an unwanted chemical bound to
the DNA base, then that base will not be
recognized as the correct base during DNA
replication and a wrong DNA base will be put in
its place instead. The end result is a change in
DNA sequence. For example, if a hydroxyl radical
(the most reactive and damaging of the oxygen
radicals) binds to a Guanine then very often the
G will be misread as an Adenine resulting in a
mutation (an A is there instead of the G). On
the other hand, if a malondiadehyde (a larger
carcinogen molecule produced during lipid
peroxidation) binds to the G then a Thymine will
be put there instead. The faster the rate of
cell division, the less time for repair and the
greater the likelihood of collecting mutations.
If mutations occur in those proteins involved in
controlling the cell cycle, then there is a high
likelihood of the mutations leading to cancer
(uncontrolled cell division). This progression
towards cancer (collecting mutations with every
cell division cycle until you mutate enough of
the right genes to produce a cancer) occurs in
cervical cells which are infected with HPV. One
of the HPV genes also codes for another protein
which is very much involved in this progression
to cancer. One of the normal cell-cycle control
proteins is called P53.
22

• Also, please note that P53 is important for
  initiating transcription of proteins responsible
  for
• Shutting down the cell cycle when there is too
  much DNA damage
• DNA repair
• Initiating apoptosis when there is too much DNA
  damage to repair (next slide)

23
P53 is an important transcription activator for
many proteins including the Fas BAX proteins
which are responsible for initiating apoptosis.
P53 also inhibits synthesis of bcl2 which is a
protein that blocks apoptosis. The end result is
cells with elevated P53 will be killed.
24
P53 coordinates the stopping of the cell cycle
and the repair of DNA damage when it exists. P53
does this by acting as an transcription activator
to enhance synthesis of DNA repair enzymes (by
inducing GADD45) and synthesis of P21, a protein
which complexes with various proteins involved in
the G1 phase to prevent further progression of
the cell cycle until the DNA damage is repaired.
Once the damage is repaired, then the cycle
continues. Another important function of the P53
protein is to promote synthesis of proteins which
activate the process of apoptosis when there is
too much DNA damage to repair. Apoptosis is a
process of cell death where the cell synthesizes
an array of DNAase enzymes which then degrade
genomic DNA to small fragments in order to
destroy the cell. This is a form of cell suicide
in order to protect the organism from developing
cancer (or any other aberrant and possibly deadly
form of mutation-induced cellular dysfunction).
25
So what does this have to do with HPV? The HPV
virus has genes which code for several proteins
necessary for viral replication. Two of the
proteins are important for the symptoms of HPV
infection E6 and E7. E6 binds to P53 and
inactivates it E7 binds to Rb and inactivates
it Because of these effects rates of cell
division in infected cells will increase, rates
of DNA repair will decrease, and rates of
apoptosis will decrease.
26
Infection of epithelial cells with HPV will
increase rates of cell division. Because skin
epithelial cells do not respond to estrogen,
there is a slight increase in cell division
leading to the accumulation of cells producing a
benign tumor called a wart.
27
Infection of epithelial cells that are capable of
responding to estrogen will greatly increase risk
for cancer. There is a large increase in rates
of cell division due to the combined effects of
E6, E7, and Estrogen. Infected cells divide too
fast for the DNA damage to be repaired and
mutations accumulate, leading to increased risk
for cancer P53 is partially inactivated which
decreases rates of DNA repair, leading to the
accumulation of more mutations and an increased
risk for cancer Rates of apoptosis are reduced
which increases the number of viable cells which
contain DNA mutations, leading to an increased
risk for cancer
28
Obviously, the E6 and E7 viral proteins are a
major cause of increased risk for cancer as a
result of HPV infection. Endogenous production
of signals which can stimulate entry of stem
cells or committed stem cells into the cell cycle
(estrogen, inflammatory cytokines) are also
intimately involved in the elevated risk for
cancer resulting from HPV infection. Of the many
different strains of HPV, several are resistant
to immune recognition and infection with these
strains results in long-term chronic infections
while infection with those that are easily
recognized results in relatively short-term
infections. High risk for HPV-induced cervical
cancer is only associated with those HPV strains
which are resistant to immune recognition
indicating the possible importance of chronic
inflammation in producing cancer risk. Thus,
the end result of some HPV infections in cervical
epithelia can be cervical cancer although
cervical cancer is relatively rare in HPV
infected women, over 80 of cervical cancer cases
are in HPV-infected women.
29
Infection by HPV can interfere with P53 function
and the HPV protein called E6 is the problem
here. This protein inhibits the function of P53,
greatly increasing the likelihood that DNA damage
will not be repaired, increasing the possibility
that cells with too much DNA damage will NOT be
killed, and therefore increasing the likelihood
that mutations will occur. One reason why warts
do not become cancerous is that skin epithelial
cells do not normally divide and the rate of
division in infected cells is quite slow.
Cervical cells normally can divide so the rate of
division in infected cells would be much faster,
greatly increasing the risk for producing a
cancer. Thus HPV infection high risk for
cervical cancer (and penile cancer too so dont
think the guys are home free) but not wart
cancer. Now, just imagine if the P53 gene is one
of the genes which acquire a mutation as a result
of this process! Not only will its function be
inhibited by the E6 protein but it will be
destroyed by the mutation. Obviously this will
not just increase risk for cancer but rather it
will GUARANTEE cancer. One other source of risk
from HPV infections which contributes greatly to
the cancer process is that derived from the
inflammatory process itself. Prolonged exposure
of cells which are capable of dividing to the
growth signals produced during an inflammatory
response can ultimately lead to stimulation of
cell division. A local infection which is
resolved quickly is rarely relevant to the cancer
process however, a chronic infection which never
resolves will lead to high risk for cancer. From
a clinical standpoint, those strains of HPV which
lead to warts or other skin/genital lesions which
go away are rarely a risk for cancer. Those
strains which are highly resistant to immune
recognition and immune attack are the same
strains which are associated with long-term
chronic infection and high risk for cervical
cancer. The introduction of the drug Gardisil,
is a major development for the prevention of
HVP-caused cervical, penile, and anal cancer. HPV
strains number 16, 18 (cervical cancer), 6, 11
(genital warts) are the major causes of these two
diseases while another 15 strains also are major
risks for these same diseases. What the 19 HPV
strains have in common is the inability of the
human adaptive immune system to develop an
effective response to their antigens, resulting
in chronic infections. The vaccinations contain
antigenic particles from the viruses that happen
to be capable of being recognized by our adaptive
immune cells and therefore will provoke an immune
response against these viruses. The vaccination
(prior to first infection) provides nearly 100
protection from both pre-cancer lesions and
genital warts by insuring that on first infection
the viruses will be killed.