Title: The Immune System
1Primary and secondary immune deficiencies HIV
Points to ponder in this Module
- What are immune deficiencies?
- What are primary immune deficiencies?
- What are secondary immune deficiencies?
- What are the different types of influenza virus
and the corresponding immune mechanisms? - Who discovered the HIV virus, and how?
- What are the mechanisms responsible for HIV
infection and development of AIDS? - What are the available anti-HIV therapies? HIV
vaccines? - DVD Spanish Flu
2Immunodeficiencies
- Immunodeficiency Failure of the immune system to
protect against disease or malignancy. - Primary Immunodeficiency Caused by genetic or
developmental defects in the immune system. These
defects are present at birth but may show up
later on in life. - Secondary (acquired immunodeficiency) Loss of
immune function as a result of exposure to
pathogens, environmental factors,
immunosuppression, or aging. -
3PRIMARY IMMUNODEFICIENCIES
- Primary immunodeficiencies are inherited defects
of the immune system. - These defects may be in the specific or
non-specific immune mechanisms. - They are classified on the basis of the site of
lesion in the developmental or differentiation
pathway of the immune system. - Individuals with immunodeficiencies are
susceptible to a variety of infections and the
type of infection depends on the nature of
immunodeficiency.
4Characteristic infections of the primary
immunodeficiencies
Component Primary pathogen Primary site Clinical example
T-cells Bacteria, viruses, protozoa, fungi, non-specific SCID, DiGeorge
B-cells Pneumococcus, Streptococcus, Haemophilus Respiratory, skin, CNS, GI, IgG, IgM, IgA deficiency
Phagocytes Staphylococcal, Pseudomonas, Respiratory, skin, lymph nodes chronic granulomatous disease (CGD)
Complement Haemophilus, Pneumococcus, Streptococcus CNS, lung, skin C3, late C components
5Disorders of T cells
- T cell disorders affect both cell- and humoral
immunity making the patient extremely susceptible
to infections. - Severe Combined Immune Deficiency (SCID) is a
primary immunodeficiency in which there is an
absence of functional T-cells. Because T cells
are missing, patients cannot produce also any
antibodies, even though they might have B cells. - The SCID leads to extreme susceptibility to
serious infections. This condition is generally
considered to be the most serious of the primary
immunodeficiencies.
David Vetter was a boy who was born in 1970s with
SCID. In order to survive, he had to live in a
plastic bubble for 12 years, to avoid any
infections. He died at the age of 12 after an
unsuccessful transplantation of bone marrow.
6All T cells are absent in SCID patients
B cell-mediated immunity
X
T cell-mediated immunity
7X-Linked Agammaglobulinemia (XLA)
Disorders of B lymphocytes
- The first immunodeficiency disease to be
described. - It was first characterized by Dr. Bruton in a
1952 case study of an eight year old boy. Bruton
describes the boy as having chronic infections
with a variety of pathogens over a four year
period, each of which was successfully treated
with penicillin. - Since the majority of his infections had been
caused by pneumococcus, Bruton attempted to
vaccinate him against this pathogen. When it was
discovered that no antibody was produced by the
vaccination, the boy was tested to determine
whether he could produce antibodies to any
antigen. It was soon proven that the boy could
produce virtually no immunoglobulin in response
to any pathogen. - Bruton therefore named the condition
agammaglobulinemia (Bruton, 1952). The condition
was soon observed to only occur in males and was
therefore determined to be X-linked. The disease
is now commonly known as Bruton's X-Linked
Agammaglobulinemia.
8IgA deficiency
- IgA deficiency is the most common of all
immunodeficiencies (1/700 of all Caucasians) and
results from a defect in class switching. - IgA-deficient patients are very susceptible to
gastrointestinal, eye and nasopharyngeal
infections. - Patients with IgA deficiency have a high
incidence of autoimmune diseases (particularly
immune complex type) and lymphoid malignancies. - Laboratory diagnosis is based on IgA measurement.
- Selective IgA deficiency is less harmful than
many other immunodeficiency diseases. - Some people with IgA deficiency will recover on
their own and begin to produce IgA in larger
quantities over a period of years.
9Treatment to cure primary immunodeficiencies
- Stem cell transplantation. Stem cell
transplantation offers a permanent cure for
several forms of life-threatening
immunodeficiency. With this treatment, normal
stem cells are transferred to the person with
immunodeficiency, giving them a normally
functioning immune system. Stem cells can be
harvested through bone marrow, or they can be
obtained from the placenta at birth (cord blood
banking). For stem cell transplantation to work,
the donor usually a parent or other close
relative must have body tissues that are a
close biological match to those of the person
with primary immunodeficiency. Stem cells that
aren't a good match may be rejected by the immune
system. Additionally, the treatment often
requires that any functioning immune cells be
destroyed using chemotherapy or radiation prior
to the transplants, leaving the transplant
recipient even more vulnerable to infection
temporarily. - Future treatments Gene therapy. Researchers hope
this treatment will one day be a cure for primary
immune disorders and many other conditions. Gene
therapy actually replaces defective genes with
genes that work correctly. A harmless virus is
used to carry the genes into the body's cells. In
turn, the newly introduced genes trigger the
production of healthy immune system enzymes and
proteins. Although the technique has shown
promise in some initial trials, gene therapy is
still experimental.
10Secondary immune deficiencies
- Immune deficiencies that are acquired, caused by
pathogens - Some pathogens evolved sophisticated ways how to
escape or subvert the immune defenses. - These pathogen-mediated immune deficiencies can
be - A. Genetic variations of pathogen (Strep)
- B. Mutations of pathogen (Flu)
- C. Dormancy of pathogen (Herpes)
- D. Destruction of the immune system (HIV)
11A. Genetic variation within some species of
pathogen prevents effective long-term immunity
- Antibodies directed against macromolecules on the
surfaces of pathogens are the most important
source of long-term immunity to many infectious
diseases - Bacterium Streptococcus pneumoniae (causing
pneumonia) consists of 90 different genetic
strains (mutants serotypes) that differ in the
structure of polysaccharides present on the cell
surface. - After resolution of infection with a particular
serotype, a person will have made antibodies that
prevent re-infection with that strain, but will
not prevent infection with another serotype. - S. pneumonia is a common cause of bacterial
pneumonia because its genetic variation prevents
people from developing an effective immunological
memory.
12Figure 9-1
13B. Mutation and recombination allow influenza
virus to escape from immunity
- Influenza virus is an RNA virus consisting of
eight RNA molecules, and containing hemagglutinin
on the viral envelope. - The flu virus infects epithelium of the
respiratory tract and passes easily from one
person to another. - The virus is cleared from the body by a
combination of cellular and humoral
(antibody-based) immunity. - The antibodies are made against the viral
hemagglutinin, during the primary response to the
virus. - The pattern of flu infection characteristically
causes epidemics, in which the virus spreads
rapidly in the population and then quickly
subsides.
14Variations in flu virus due to mutation and
recombination allow repeated infections
- The flu virus easily mutates, and the new mutant
strains are not recognized by the antibodies made
during the first infection/response, causing
epidemics this type of virus mutation is called
antigenic drift. - In contrast, every 10-15 years a new virus
emerges that is quite different from the previous
strains, and can infect almost everyone. These
new viruses are recombinant viruses that have
part derived from the human flu virus, and part
from an avian (bird) virus. This type of
evolution is called antigenic shift these new
viruses can cause pandemics.
15Epidemic vs. Pandemic
- Epidemic
- Epidemic occurs when an infectious disease
spreads rapidly to many countries and people. - In 2003, the severe acute respiratory syndrome
(SARS) epidemic took the lives of nearly 800
people, mainly in Asia. - Pandemic
- Pandemic is a global disease outbreak. HIV/AIDS
is an example of one of the most destructive
global pandemics in history. - Influenza pandemics have occurred more than once.
- An influenza pandemic occurs when a new subtype
of virus arises. This means humans have little or
no immunity to it. Everyone is at risk. - Pandemic occurred in 1918, when the Spanish
influenza killed 50 million people worldwide.
16Influenza (Flu)
- From the French word influentia, which refers
to the belief that all epidemics were influenced
by the stars - Caused by influenza virus
- classified into three groups (A, B, and C) based
on the hemagglutinin (HA) and neuraminidase (NA
target for TAMIFLU) antigens - Mutations in the viral genome occur
- antigenic drift small changes, result in flu
epidemics - antigenic shift extensive changes in the viral
genome, result in pandemics - clinical manifestations
- chills, fever, headache, malaise, and general
muscular aches and pains - recovery usually within 3 to 10 days
- CDC estimates that each year, about 36,000 people
in the US die from flu infection
17Figure 9-2
Antigenic shift Caused by recombination and
resulting in pandemics
Antigenic drift Caused by mutation and resulting
in epidemics
18How Influenza Viruses Change Drift and Shift
- Influenza viruses can change in two different
ways. - One type is called "antigenic drift," which
occurs through small changes in the virus that
happen continually over time this can cause
epidemics. Antigenic drift produces new virus
strains that may not be recognized by antibodies
to earlier influenza strains. This process works
as follows a person infected with a particular
flu virus strain develops antibody against that
virus. As newer virus strains appear, the
antibodies against the older strains no longer
recognize the "newer" virus, and infection with a
new strain can occur. This is one of the main
reasons why people can get the flu more than one
time. In most years, one or two of the three
virus strains in the influenza vaccine are
updated to keep up with the changes in the
circulating flu viruses. For this reason, people
who want to be immunized against influenza need
to receive a flu vaccination every year. - The other type of change is called "antigenic
shift." Antigenic shift is an abrupt, major
change in the influenza A viruses, resulting in a
new influenza virus that can infect humans and
has a hemagglutinin protein and neuraminidase
protein combination that has not been seen in
humans for many years. Antigenic shift results in
a new influenza A subtype. If a new subtype of
influenza A virus is introduced into the human
population, if most people have little or no
protection against the new virus, and if the
virus can spread easily from person to person, a
pandemic (worldwide spread) may occur.
19Types, Subtypes, and Strains of the Flu Virus
- There are three types of influenza viruses A, B,
and C. - Influenza Type AInfluenza type A viruses can
infect people, birds, pigs, horses, and other
animals, but wild birds are the natural hosts for
these viruses. - Type A flu can cause pandemics.
- Influenza type A viruses are divided into
subtypes based on two proteins on the surface of
the virus. These proteins are called
hemagglutinin (HA) and neuraminidase (NA). There
are 16 different HA subtypes and 9 different NA
subtypes. Many different combinations of HA and
NA proteins are possible. - Subtypes of influenza A virus are named according
to their HA and NA surface proteins. For example,
an H7N2 virus designates an influenza A subtype
that has an HA 7 protein and an NA 2 protein.
Similarly an H5N1 virus has an HA 5 protein and
an NA 1 protein. - Influenza Type BInfluenza B viruses are normally
found only in humans. Unlike influenza A viruses,
these viruses are not classified according to
subtype. Although influenza type B viruses can
cause human epidemics, they have not caused
pandemics. - Influenza Type CInfluenza type C viruses cause
mild illness in humans and do not cause epidemics
or pandemics. These viruses are not classified
according to subtype.
20Influenza pandemics
- Spanish influenza H1N1 killed 50 million people
in 1918. - Asian influenza killed 2 million people in 1957.
- Hong Kong influenza killed 1 million people in
1968. - The World Health Organization (WHO) provides an
influenza pandemic alert system, with a scale
ranging from Phase 1 (a low risk of a flu
pandemic) to Phase 6 (a full-blown pandemic) - Phase 1 A virus in animals has caused no known
infections in humans. - Phase 2 An animal flu virus has caused infection
in humans. - Phase 3 Sporadic cases or small clusters of
disease occur in humans. Human-to-human
transmission, if any, is insufficient to cause
community-level outbreaks. - Phase 4 The risk for a pandemic is greatly
increased but not certain. - Phase 5 Spread of disease between humans is
occurring in more than one country. - Phase 6 A global pandemic is under way.
21The Influenza Pandemic of 1918 (Spanish Flu)
- The influenza pandemic of 1918-1919 killed about
50 million people more than the World War I. - It was caused by the H1N1 type of influenza
virus. - The effect of this pandemic was so severe that
the average life span in the US was depressed by
10 years. The influenza virus had a profound
virulence, with a mortality rate at 2.5 compared
to the previous influenza epidemics, which were
less than 0.1. - The origins of this influenza variant is not
precisely known. It is thought to have originated
in China in a rare genetic shift of the influenza
virus. The recombination of its surface proteins
created a virus novel to almost everyone and a
loss of herd immunity. Recently the virus has
been reconstructed from the tissue of a dead
soldier and is now being characterized. - The name of Spanish Flu came from the early
affliction and large mortalities in Spain, where
it killed 8 million in May 1918. - However, the first wave of influenza appeared
early in the spring of 1918 in Kansas and in
military camps throughout the US. Few noticed the
epidemic in the midst of the war. The war brought
the virus back into the US for the second wave of
the epidemic. It first arrived in Boston in
September of 1918 through the port busy with war
shipments of machinery and supplies. The flu that
winter was beyond imagination as millions were
infected and thousands died. Just as the war had
effected the course of influenza, influenza
affected the war. Entire fleets were ill with the
disease and men on the front were too sick to
fight. The flu was devastating to both sides,
killing more men than their own weapons could.
22Swine flu was type A, H1N1, influenza (the
same type as the Spanish Flue in 1918)This type
of flu virus can cause pandemics.
232009 H1N1 pandemics
Genetic characterization found that the HA gene
is similar to that of swine flu viruses. The
genes from American swine flu are mixtures of
swine flu, bird flu, and human flu viruses. On
June 11, 2009, the WHO declared an H1N1 pandemic,
moving the alert level to phase 6, marking the
first global pandemic since the 1968 Hong Kong
flu.
24TAMIFLU Relenza
- Tamiflu (Oseltamivir ) and Relenza are the main
antiviral drugs available in the United States
for both the treatment and prevention of the most
common strains of influenza, types A and B. - Neuraminidase is an enzyme that enables influenza
virus to spread from infected cells to healthy
cells. - Oseltamivir and Relenza block the action of
neuraminidase (they are neuraminidase
inhibitors), thereby reducing the spread of
influenza. - By preventing the spread of virus from cell to
cell, the symptoms and duration of influenza
infection are reduced.
25Flu vaccines
- Vaccine Production in Eggs
- Traditionally, flu vaccines have been produced in
chicken eggs. - The egg-based production is physically limited by
the availability of specialized eggs and may not
be able to meet the accelerated demands of a
global influenza pandemic. - In order to produce 300 million doses of vaccine,
egg-based production would require 900 million
eggs. - People allergic to eggs cannot receive the
egg-based vaccines. - Vaccine Production in Cell Cultures
- The new approach uses mammalian cells (kidney
cells) to grow the influenza viruses. - In place of eggs, cell-based vaccine production
utilizes laboratory-grown cell lines that are
capable of hosting a growing virus. The virus is
injected into the cells where it multiplies. The
cells' outer walls are removed, harvested,
purified, and inactivated. A vaccine can be
produced in a matter of weeks. Polio vaccine is
currently produced using the cell-based method. - While eggs are perishable, cell lines can be
safely kept frozen indefinitely, increasing the
capability to rapidly produce vaccines if an
influenza pandemic were to occur. - People allergic to eggs cannot receive vaccines
produced from chicken eggs, but can be immunized
with a cell-based vaccine.
26C. Some viruses enter a dormant state and cannot
be recognized by the immune system
- In contrast to flu virus, some other viruses are
difficult to clear because they enter a quiescent
(resting) state within human cells, in which they
neither replicate nor generate enough
virus-derived peptides to assemble the MHC class
I complexes. - Very often these viruses hide in the brain, which
does not express any MHC class I molecules, and
therefore viruses are not recognized there. - Development of this dormant state, called
latency, does not cause disease. After the
initial immune response subsides, the virus
reactivates, causing a disease.
27Herpes virus persists in human hosts by hiding
from the immune response Herpes simplex virus,
the cause of cold sores, first infects epithelial
cells and then spreads to sensory neurons in the
brain. In the neurons, the virus persists in a
latent state, and is re-activated by various
stresses (hormonal changes, bacterial infection,
sunlight). Re-activated virus travels down the
neurons and re-infects the epithelium, causing
cold sores again.
28Chickenpox (Varicella) and Shingles (Herpes
Zoster)
- Shingles and chickenpox were once considered
separate disorders. It is now known that they are
both caused by a single virus of the Herpes
family known as Varicella-Zoster Virus (VZV). - Varicella the primary infection that causes
chickenpox. - Herpes zoster the reactivation of the virus that
causes shingles. - Varicella (Chickenpox). When patients with
chickenpox cough or sneeze, they expel tiny
droplets that carry the virus, which in this
early form is referred to as varicella virus. If
a person who has never had chickenpox or been
vaccinated inhales these particles, the virus
enters the lungs. From here it passes into the
blood stream. When it is carried to the skin it
produces the typical rash of chickenpox. - Herpes Zoster (Shingles). The virus also travels
to nerve cells called dorsal root ganglia. These
are nerves that transmit sensory information from
the skin to the brain. Here, the virus can hide
in the latent form from the immune system for
years, often for a lifetime. - If the virus becomes active after being latent,
it causes the disorder known as shingles. The
virus in this later form is referred to as herpes
zoster. The virus spreads in the ganglion and to
the nerves connecting to it. Those nerves most
often affected are those in the face or the
trunk. The virus, however, can also spread to the
spinal cord and into the blood stream. - It is not clear why the virus reactivates in some
people and not in others. In many cases, the
immune system has become impaired or suppressed
from certain conditions such as AIDS. Aging
itself may increase the risk for shingles.
29Chicken pox
30post- herpetic neuralgia
31D. Destruction of the immune system (HIV-AIDS)
- Acquired immune deficiency syndrome (AIDS) was
first described by physicians in the early 1980s - The disease is characterized by a marked
reduction in CD4 T cells, and accompanied by
severe infections - In 1983, the virus known to cause AIDS, the human
immunodeficiency virus (HIV), was first isolated
by Gallo at NIH, and Montagnier in France - Two types of HIV are now distinguished HIV-1 and
HIV-2 - In most countries, HIV-1 is the principle cause
of AIDS. HIV-2 is less virulent, has a slower
progression, and spreads widely through Asia
32Proviral DNA of a retrovirus, human T-cell
leukemia virus, in two patients with
AIDS.Gelmann EP, Popovic M, Blayney D, Masur H,
Sidhu G, Stahl RE, Gallo RC.Science. 1983 May
20 220 862-865.
- The acquired immune deficiency syndrome (AIDS)
is characterized by T-lymphocyte dysfunction and
is frequently accompanied by opportunistic
infections and Kaposi's sarcoma. Human T-cell
leukemia virus (HTLV) is associated with T-cell
malignancies and can transform T lymphocytes in
vitro. In an attempt to find evidence of HTLV
infection in patients with AIDS, DNA from samples
of peripheral blood lymphocytes from 33 AIDS
patients was analyzed by Southern
blot-hybridization with a radiolabeled cloned
HTLV DNA probe. Analysis of DNA from both the
fresh (uncultured) lymphocytes and from T cells
cultured with T-cell growth factor revealed the
presence of integrated HTLV proviral sequences in
lymphocytes from two of the patients, both of
whom had antibody to HTLV. The proviral sequences
could not be detected in blood samples obtained
from these individuals at a later date,
consistent with the possibility that the
population of infected cells had become depleted.
33Isolation of a T-lymphotropic retrovirus from a
patient at risk for acquired immune deficiency
syndrome (AIDS). Barre-Sinoussi F, Chermann JC,
Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet
C, Axler-Blin C, Vezinet-Brun F, Rouzioux C,
Rozenbaum W, Montagnier L.Science. 1983 May 20
220 868-871.
- A retrovirus belonging to the family of recently
discovered human T-cell leukemia viruses (HTLV),
but clearly distinct from each previous isolate,
has been isolated from a Caucasian patient with
signs and symptoms that often precede the
acquired immune deficiency syndrome (AIDS). This
virus is a typical type-C RNA tumor virus, buds
from the cell membrane, prefers magnesium for
reverse transcriptase activity, and has an
internal antigen (p25) similar to HTLV p24.
Antibodies from serum of this patient react with
proteins from viruses of the HTLV-I subgroup, but
type-specific antisera to HTLV-I do not
precipitate proteins of the new isolate. The
virus from this patient has been transmitted into
cord blood lymphocytes, and the virus produced by
these cells is similar to the original isolate.
From these studies it is concluded that this
virus as well as the previous HTLV isolates
belong to a general family of T-lymphotropic
retroviruses that are horizontally transmitted in
humans and may be involved in several
pathological syndromes, including AIDS.
342008 Nobel Prize in Medicine for HIV Discovery
- In 1986, Dr. Gallo and Dr. Montagnier shared a
prestigious Lasker award, given in the United
States Dr. Montagnier was cited for discovering
the virus and Dr. Gallo for determining that it
caused AIDS. - In 1987, President Reagan and Prime Minister
Jacques Chirac of France signed an agreement to
share royalties and credit for the discovery. - 2008 Nobel Prize in Medicine was awarded to
Montagnier and other two European scientists for
discovery of HIV and HPV viruses, while Robert
Gallo was omitted
35Incidence of HIV infection
The human immunodeficiency virus (HIV) is now
known to have originated from chimpanzees.
Transmission from chimps to humans probably
occurred while animals were killed for food in
sub-Saharan Africa, with animal blood
contaminating wounds of humans. The WHO
estimates that there are 60 million people
infected today.
36Transmission of HIV
- HIV is stopped by innate defenses. HIV cannot
penetrate unbroken skin. HIV is transmitted
through direct exchange of body fluids (blood,
semen, breast milk). Infected mothers can pass
HIV to their infants during pregnancy, birth and
breastfeeding. - These body fluids must have direct access to the
bloodstream in order to cause an infection. - Saliva, tears, sweat, and urine can contain HIV,
but in such small concentrations that nobody has
ever been infected through contact with these
fluids. - HIV is NOT transmitted through any form of casual
contact. HIV is NOT transmitted through shaking
hands, hugging, or living in the same house with
someone who is HIV. - HIV is not transmitted through insect bites.
37Facts about HIV (from Nature 410 968, 2001)
- By the end of 1997, 8.2 million children had lost
their mother to AIDS before they turned 15. - More than 4 million children under the age of 15
have been infected. HIV infection in children
progresses more quickly to AIDS, leading to
death. - Around 1/3 of the 42 million people living with
HIV in the world are young people aged 15-24. - In 2000, 5 million people became infected with
the virus more than seven men and women every
minute of the day (14,000/day). - Where they have access to appropriate knowledge,
skills, and means, today's young people show a
remarkable propensity to adopt safer behaviors
better than previous generations or older
adults. -
38HIV/AIDS History
- 1926-46 - HIV possibly spreads from monkeys to
humans. - 1959 - A man dies in Congo in what many
researchers say is the first proven AIDS death. - 1981 - The Centers for Disease Control and
Prevention (CDC) notices high rate of otherwise
rare cancer - 1982 - The term AIDS is used for the first time,
and CDC defines it. - 1983/84 - American and French scientists each
claim discovery of the virus that will later be
called HIV. - 1985 - The FDA approves the first HIV antibody
test for blood supplies. - 1987 - AZT is the first anti-HIV drug approved by
the FDA. - 1991 - Basketball star Magic Johnson announces
that he is HIV-positive. - 1996 - FDA approves first protease inhibitors.
- 2000 - An estimated 1,000,000 Americans living
with HIV/AIDS. - 2010 10,000 people die of AIDS every day.
39HIV is a retrovirus that causes slowly
progressing disease
- HIV is a single-stranded RNA virus, called
retrovirus. - Retroviruses use an RNA genome to direct
synthesis of DNA ( a situation backwards, or
retro from that is used by most organisms). - The HIV virus contains RNA nucleoprotein core
surrounded be a lipid envelope. - Gp120 and gp41 are virally encoded envelope
proteins that mediate the viral entry into human
cells.
40Composition of HIV virus
- When HIV infects a cell, the RNA genome is first
copied into a complementary DNA cDNA, by reverse
transcriptase. - The viral integrase then integrates the viral DNA
into the genome of the host cell, to form a
provirus. - The HIVs RNA genome consists of nine genes
flanked by repetitive DNA sequences called long
terminal repeats (LTR), which facilitate
integration of the virus into the host genome. - Proviruses use the transcriptional and
translational machinery of the host cell to make
viral proteins which assemble into new infectious
virions.
41HIV infects CD4 T cells, macrophages and
dendritic cells
- The HIV virus infects cells expressing the CD4
glycoprotein receptor CD4 T cells, macrophages
and dendritic cells. - Chimpanzees, which are closest to humans, are
resistant to HIV because of a small difference in
the CD4 glycoprotein primary structure. - In addition to CD4, HIV virus also binds through
the viral gp120 glycoprotein to two chemokine
receptors expressed on the surface of macrophages
and T cells CCR5 and CXCR4.
42Structure of HIV Virus
CCR5/ CXCR4
43The life cycle of HIV in human cells
- Macrophages and dendritic cells present at the
site of virus entry are the first cells to be
infected. - Subsequently, the virus produced by macrophages
infects also the CD4 T cells, which is followed
by a rapid decline in CD4 T cells and progression
to AIDS. - The synthesis of viral proteins in the infected
CD4 T cells is regulated at the level of
transcription by the transcription factor NFkB.
44HIV infection
45Figure 9-15
46Early stages of HIV infection
- Infection with HIV occurs after transfer of body
fluids from infected person to an uninfected
recipient. Immediately after HIV infection, a
person can be either asymptomatic, or experience
a transient flu-like symptoms. This is
accompanied by viral presence in the blood, and
the rapid decline in CD4 T cells. - This is associated with activation of an
HIV-specific immune response, in which anti-HIV
antibodies are produced, and CD8 T cells become
activated to kill the virus-infected cells. - First appearance of anti-HIV antibodies in the
blood serum is called HIV seroconversion, and
occurs 2-6 weeks after infection.
47Acute HIV diagnostic timeline
- The diagnostic challenge in acute HIV infection
is made more difficult by the fact that routine
HIV antibody tests will typically remain negative
for 2-6 weeks following infection. - While HIV nucleic acid amplification assays are
now extremely sensitive and can reliably detect
HIV by days 911 of infection, they are
vulnerable to false-positive rates as high as 1.
Such tests remain relatively expensive and have
not traditionally been used for routine clinical
HIV screening.
48Most people who become infected with HIV progress
in time to develop AIDS
- The initial phase of infection is followed by an
asymptomatic period, called clinical latency,
which can last 2-15 years. - When the amount of CD4 T cells drops below a
critical level, a period of increased
immunodeficiency starts, which is the onset of
AIDS. - Patients with AIDS are susceptible to
opportunistic infections and some cancers this
is also the cause of death in AIDS patients.
49After infection with HIV there is a gradual
extinction of CD4 T cells
50Stages of HIV Infection
51Function of CCR5 chemokine receptor in HIV
- Some people who are heavily exposed to HIV never
become infected they are resistant to HIV. - This resistance is conferred by a mutation in the
CCR5 co-receptor. - CCR5 is a chemokine receptor only individuals
who are homozygous for the mutation (CCR5 genes
on both chromosomes are mutated) are resistant to
HIV. - On average, about 0.2 of population carries this
resistance. - In some parts of Europe, it can be up to 10, and
this is thought to be associated with the
previous selection for this mutation during the
Black Death, the pandemic of plague that
occurred in Europe during the Middle Ages
(causing up to 30 mortality), or with the small
pox pandemic.
52The black death and ccr5 (from Nature, March 11,
2005)
- Devastating epidemics that swept Europe during
the Middle Ages seem to have had an unexpected
benefit - leaving 10 of today's Europeans
resistant to HIV infection. - But epidemics of which disease? Some researchers
claim that plague helped boost immunity to HIV,
but rival teams are arguing that the credit
should go to smallpox. - What is clear is that something has boosted the
prevalence of a mutation that helps protect
against the virus. The mutation, which affects a
protein called CCR5 on the surface of white blood
cells, prevents HIV from entering these cells and
damaging the immune system, if inherited from
both parents. - Around 10 of today's Europeans carry the
mutation, a significantly higher proportion than
in other populations. The incidence is only 2 in
central Asia. The mutation is completely absent
among East Asians, Africans, and American
Indians.
53Mutation that Protects Against HIV Infection May
Raise Risk of West Nile Virus Illness(Journal
of Experimental Medicine, 2005)
- People who lack a cell surface protein called
CCR5 are highly resistant to infection by HIV but
may be at increased risk of developing West Nile
virus illness when exposed to the mosquito-borne
virus, report researchers from the NIH. - The findings may have cautionary implications for
physicians who are treating HIV-positive
individuals with experimental CCR5-blocking
drugs, say the scientists. - This is the first genetic risk factor to be
identified for West Nile virus infection, says
NIH Director Elias A. Zerhouni, M.D. While
infection does not always lead to illness, the
virus can sometimes cause serious problems and,
according to the Centers for Disease Control and
Prevention, there were 102 deaths in the United
States from West Nile virus infection in 2005.
54HIV escapes the immune response and develops
resistance to antiviral drugs by rapid mutations
- HIV and other retroviruses (flu virus) have high
mutation rates because their reverse
transcriptase introduces many errors during the
reverse transcription of RNA into cDNA? gives
rise to new mutant strains. - This high mutation rate complicates development
of an effective vaccine, as well as effectiveness
of anti-viral therapy.
55Current anti-HIV therapy
- Based on inhibition of
- 1. Inhibition of HIV entry into the cell
- 2. Inhibition of reverse transcriptase
(zidovudine, AZT) - 3. Inhibition of viral integrase
- 4. Inhibition of viral protease
- Currently, combination therapy (or highly active
anti-retroviral therapy HAART) is the most
successful (several antiviral drugs are used
together). This therapy does not stop virus
production by cells that are already infected,
but prevents infection of new cells.
56Anti-HIV treatment strategies
3
AZT
2
4
1
57Combination therapy reduces HIV virus in the
blood to below detectable levels.
- Two weeks after combination therapy, the amount
of virus in the blood drops to 5 of the original
amount. - However, the virus never becomes completely
eliminated, since it persists in dormant CD4
cells and macrophages (that are not replicating
and therefore are not affected by the therapy).
58HIV infection leads to immuno-deficiency and
death from opportunistic infections
- As the number of CD4 cells decreases,
HIV-infected people become progressively
susceptible to opportunistic infections (caused
by pathogens that are usually present in healthy
people, but can be effectively kept under
control). - Opportunistic pathogens include Candida (fungi),
Mycobacterium tuberculosis (bacteria), Herpes
simplex (viruses) and Toxoplasma species
(parasites). - With the collapse of the immune system, the
opportunistic infections associated with HIV,
eventually cause death.
59Development of HIV vaccines
- There have been many experimental trials aimed at
developing HIV vaccine. - In 2007, Merck stopped a study of its
experimental vaccine after seeing it did not
prevent HIV infection analysis suggested the
vaccine might even raise the risk of HIV. - In September 2009, WHO announced a development of
new vaccine - a combination of two previously
unsuccessful vaccines that cut the risk of
becoming infected with HIV by more than 31 in
Thailand. - They are ALVAC, from French drugmaker
Sanofi-Aventis and AIDSVAX, developed by Vaxgen. - ALVAC uses canarypox, a bird virus altered so it
can't cause human disease, to carry synthetic
versions of three HIV genes into the body.
AIDSVAX contains a genetically engineered version
of gp 120 developed by Vaxgen . The vaccines are
not made from whole virus dead or alive and
cannot cause HIV. - The study used strains of HIV common in Thailand.
Whether such a vaccine would work against other
strains in the U.S., Africa or elsewhere in the
world is unknown.
60Vaccination with ALVAC and AIDSVAX to Prevent
HIV-1 Infection in Thailand
October 2009
- ABSTRACT
- Background The development of a safe and
effective vaccine against the human
immunodeficiency virus type 1 (HIV-1) is critical
to pandemic control. - Methods In a community-based, randomized,
multicenter, double-blind, placebo-controlled
efficacy trial, we evaluated four priming
injections of a recombinant canarypox vector
vaccine (ALVAC-HIV) plus two booster injections
of a recombinant glycoprotein 120 subunit vaccine
(AIDSVAX). The vaccine and placebo injections
were administered to 16,402 healthy men and women
between the ages of 18 and 30 years in Thailand. - Results In the intention-to-treat analysis
involving 16,402 subjects, there was a trend
toward the prevention of HIV-1 infection among
the vaccine recipients, with a vaccine efficacy
of 26.4. - Conclusions This ALVAC-HIV and AIDSVAX B/E
vaccine regimen may reduce the risk of HIV
infection in a community-based population with
largely heterosexual risk. Although the results
show only a modest benefit, they offer insight
for future research.
61And the Band Played On
- Chronicles the discovery and spread of HIV and
AIDS with a special emphasis on government
indifference and apathy, which allowed the spread
of the disease to become much worse. - Although NIH officials spoke publicly about the
epidemic, calling it in 1983 its "Number One
Health Priority" no extra funding was given to
the CDC or the NIH for research.