The Immune System

1
Primary 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

2
Immunodeficiencies

• 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.
•  

3
PRIMARY 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.

4
Characteristic 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
5
Disorders 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.
6
All T cells are absent in SCID patients
B cell-mediated immunity
X
T cell-mediated immunity
7
X-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.

8
IgA 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.

9
Treatment 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.

10
Secondary 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)

11
A. 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.

12
Figure 9-1
13
B. 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.

14
Variations 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.

15
Epidemic 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.

16
Influenza (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

17
Figure 9-2
Antigenic shift Caused by recombination and
resulting in pandemics
Antigenic drift Caused by mutation and resulting
in epidemics
18
How 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.

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Types, 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.

20
Influenza 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.

21
The 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.

22
Swine flu was type A, H1N1, influenza (the
same type as the Spanish Flue in 1918)This type
of flu virus can cause pandemics.
23
2009 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.
24
TAMIFLU 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.

25
Flu 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.

26
C. 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.

27
Herpes 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.
28
Chickenpox (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.

29
Chicken pox
30
post- herpetic neuralgia
31
D. 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

32
Proviral 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.

33
Isolation 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.

34
2008 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

35
Incidence 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.
36
Transmission 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.

37
Facts 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.
•  

38
HIV/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.

39
HIV is a retrovirus that causes slowly
progressing disease

1. HIV is a single-stranded RNA virus, called
   retrovirus.
2. Retroviruses use an RNA genome to direct
   synthesis of DNA ( a situation backwards, or
   retro from that is used by most organisms).
3. The HIV virus contains RNA nucleoprotein core
   surrounded be a lipid envelope.
4. Gp120 and gp41 are virally encoded envelope
   proteins that mediate the viral entry into human
   cells.

40
Composition 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.

41
HIV 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.

42
Structure of HIV Virus
CCR5/ CXCR4
43
The 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.

44
HIV infection
45
Figure 9-15
46
Early 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.

47
Acute 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.

48
Most 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.

49
After infection with HIV there is a gradual
extinction of CD4 T cells
50
Stages of HIV Infection
51
Function 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.

52
The 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.

53
Mutation 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.

54
HIV 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.

55
Current 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.

56
Anti-HIV treatment strategies
3
AZT
2
4
1
57
Combination 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).

58
HIV 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.

59
Development 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.

60
Vaccination 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.

61
And 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.