Future Directions In Immune Reconstitution

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Future Directions In Immune Reconstitution

• By Bruce D. Walker, M.D.
• Harvard Medical School

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INTRO/SUMMARY

• In the 18 years or so since the appearance of
  HIV/AIDS, scientists have
• noticed that some HIV-infected people become sick
  quickly, while others
• remain healthy for years, even without treatment.
  Those who become ill
• soon after infection are referred to as "rapid
  progressors" those who
• stay well for years are called "non-progressors."
  Recent research has
• shown that non-progressors have a naturally
  strong immune response to
• HIV, generating immune cells called helper T
  cells (part of a group of immune cells often
  called "T cells" or "CD4 cells") and cytotoxic T
  lymphocytes (CTL, also called killer T cells),
  to keep the virus in check. Scientists believe
  that early and potent antiretroviral therapy may
  produce a similarly strong and persistent immune
  response in those who aren't non-progressors.

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Development of AIDS is like an impending train
wreck

• The next slide compares the progression of HIV to
  AIDS with the image of a train wreck. (This
  comparison was first used at the 11th
  International AIDS Conference in Vancouver,
  Canada, in 1996.)
• The higher the amount of virus (the faster the
  train speed) and the lower the amount of T cells
  (the shorter the distance from the cliff), the
  sooner an individual will progress to AIDS (the
  sooner the train will crash).

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Development of AIDS is like an impending train
wreck Viral Load Speed of the train CD4
count Distance from cliff
HIV infection
J. Coffin, XI International Conf. on AIDS,
Vancouver, 1996
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Clues to immune control of HIV?

• The next slide shows data for two HIV-infected
  individuals, one a rapid
• progressor and the other a non-progressor. Both
  had similar symptoms (Sx) and ultimately tested
  positive for HIV (Dx). However, subject JP
  experienced a rapid increase in the amount of
  HIV (this is called viral load or VL for
  short) and a drop in the number of CD4 cells (T
  cells), leading to an AIDS diagnosis within 11
  months.
• In contrast, subject 161J maintained a low VL and
  a high CD4 cell
• count without any medication, and was still in
  good health 19 years
• after infection.

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Clues to immune control of HIV?
Subject JP Sx Fever, Rash, Headache Dx
HIV ELISA Neg. HIV RNA gt700,000 F/U
Extensive Rx AIDS at 11 mo. Rapid CD4 cell
decline Viral Load gt750,000
Subject 161J Sx Fever, Rash, Headache Dx
HIV ELISA Neg. HIV ELISA Pos. F/U No
Rx Well at 19 yrs. CD4 1000 Viral Load lt 500
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CTL control of viremia

• The image on the next slide shows how killer T
  cells (cytotoxic T lymphocytes, or CTL) attack
  and kill HIV-infected cells. This has to happen
  before the virus makes new viruses and sends them
  out to infect other immune cells. The entire
  process of making new viruses from infected cells
  takes about 2.6 days, so the killer T cells must
  act quickly.

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CTL control of viremia CTL killing vs. progeny
virus production
CTL attack
HLA class I processing
New virus assembly
HIV
Progeny virus production
2.6 Days
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CTL can eliminate HIV-infected cells

• The graph on the next slide shows how killer T
  cells (CTL) can eliminate HIV-infected cells in a
  lab experiment where virus is added to uninfected
  cells. The x-axis on the graph, labeled "p24 Ag
  (ng/ml)" represents HIV produced by the infected
  cells. (Higher numbers mean larger amounts of
  HIV.) The y-axis, labeled "Days Post Infection,"
  shows the time since HIV infection.
• The yellow line shows what happens if no killer T
  cells (CTL) are added. The light blue line show
  what happens when killer T cells are added HIV
  is blocked from making new viruses and infecting
  the cells.

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CTL can eliminate HIV infected cells
CTL Removed
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T helper cells are the central orchestrator of
the immune system

• The next slide shows the role of helper T cells
  as commander of the immune system, directing
  the function of the following
• cytotoxic T lymphocytes (CTL), which destroy
  specific infected cells,
• B-cells, which produce antibodies
• natural killer (NK) cells, which destroy any
  infected cells,
• antigen-presenting cells (APC), which mark
  infectious agents for destruction, and
• production of antibodies and cytokines
• antibodies mark antigens for destruction
• antigen refers to parts of the virus that
  cause immune response. An antigen-presenting cell
  shows these parts of the virus to helper T cells
  and killer T cells, which then become activated.
• cytokines are chemical messengers that help
  speed up immune response

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T helper cells are the central orchestrator of
the immune system
CTL Function
NK Cell Function
T helper cell
APC Function
B Cell Function
Cytokine production
Antibody Production
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Virus-Specific T Helper Cells Mechanism

• The image on the next slide shows how helper T
  cells work. Like using a key to unlock a lock,
  the antigen-presenting cell (APC) shows part of
  the antigen (in this case HIV) to the helper T
  cells receptor (TCR). This unlocks the
  activity of the helper T cell, causing it to
  secrete lymphokines (chemical signals that speed
  up immune response).
• These helper T cells are also called CD4 cells
  because the receptor (the lock that recognizes
  the APC-HIV key) is partly made up of a CD4
  receptor.

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Virus-Specific T Helper Cells Mechanism
Class II
TCR
Lymphokine Secretion
CD4
Antigen Presenting Cell
CD4 Th Cell
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HIV-1-specific T helper cell responses

• The graph on the next slide shows how helper T
  cells respond to various antigens, including
  gp120 and p24 (two different parts of HIV) and
  tetanus.
• In a rapid progressor, where the virus has
  increased quickly and done much damage, the
  immune system cant respond very well to these
  antigens.
• In a non-progressor, however, the immune system
  functions well and thus can strongly attack these
  infectious agents.
• (The longer lines on the graph indicate a
  stronger immune response.)

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HIV-1-specific T helper cell responses
Rapid Progressor RNA gt 300,000
Non-Progressor RNA lt 400
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The immune system at work against HIV

• The image on the next slide shows two antigen
  presenting cells (APC) presenting different
  antigens to two different kinds of immune cells.
  One transforms a pre Th cell (a baby helper T
  cell) into an activated helper T cell. Another
  APC activates a pre-CD8 CTL (a cytotoxic T
  lymphocyte named for its CD8 receptor). The
  activated helper T cell helps turn the activated
  CTL into a mature CTL, which then attacks and
  kills HIV-infected cells.

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Pre-Th Cell
Virus infected Cell
APC
Activated Th Cell
Mature CTL
Activated Pre-CTL
Pre-CD8 CTL
APC
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How HIV infection progresses

• The flowchart on the next slide shows how HIV
  infection progresses. (Acute HIV infection
  means new infection, when HIV is reproducing
  rapidly and the immune system has not yet started
  to attack it.)
• After infection, the immune system produces
  helper T cells (HIV-1-specific immune CD4 cells)
  to fight the virus. These cells help prepare
  cytotoxic T lymphocytes (CTL, or HIV-1-specific
  killer cells) to attack HIV. Other helper T cells
  are infected by HIV. As HIV infects more and more
  helper T cells, there is less and less help for
  CTL, so they cant remain activated and kill
  infected cells, and HIV disease progresses.

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Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4
cells (Helper cells)
Generation of HIV-1-specific killer cells (CTL)
Infection of activated helper cells
Loss of CTL function due to inadequate
HIV-1-specific helper cells
Loss of HIV-1-specific helper cells
Progression
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HIV-1-specific T helper cells in individuals
treated during acute infection

• The graph on the next slide shows the difference
  in the amount of helper T cells in 7 individuals
  treated in the earliest stages of HIV infection.
  Right after infection, the number of helper T
  cells is small but after two months on anti-HIV
  drugs, most individuals showed increased amounts
  of helper T cells. Thus the slide shows that
  early treatment leads to reconstitution of a
  critical part of the immune system.

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HIV-1-specific T helper cells in individuals
treated during acute infection (n7)
1
0
0
1
0
1
M
B
J
C
K
M
N
D
S
J
D
K
K
S
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The effects of treatment on HIV disease
progression

• The next slide shows another flowchart of HIV
  disease progression, this time with the addition
  of treatment at or near the time of infection.
• If given early enough, these treatments protect
  many helper T cells, enabling them to direct
  cytotoxic T lymphocytes (CTL) to kill
  HIV-infected cells and preserve the immune
  system.

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Acute HIV-1 infection
Stimulation of HIV-1-specific immune CD4
cells (Helper cells)
Antiviral Rx
Generation of HIV-1-specific killer cells (CTL)
Protection of activated helper cells
Maintenance of CTL function due to adequate
HIV-1-specific helper cells
Maintenance of HIV-1-specific helper cells
Nonprogression
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Conclusions

• The term antiretroviral therapy on the next
  slide refers to drugs used to combat HIV.
• HIV is a kind of retrovirus, so antiretroviral
  therapy will help destroy HIV.

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Conclusions

• A small percentage of infected persons
  successfully control HIV without drug therapy,
  indicating that the immune system can contain the
  virus
• These persons have strong virus-specific T helper
  cell responses
• These persons also have strong CTL responses
• Early treatment with potent antiretroviral
  therapy results in the generation of strong and
  persistent immune responses similar to those seen
  long-term non-progressors

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Questions

• Can the immune system be boosted in persons with
  chronic infection?
• Can persons treated in the acute stage of
  infection, who develop strong T helper cells,
  control the virus without drug therapy?
• Can prolonged treatment with potent antiviral
  therapy restore T helper cells?