Immune Basis of HIV Pathogenesis

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Immune Basis of HIV Pathogenesis

• Guido Silvestri, MD
• Departments of Pathology Laboratory Medicine
  and Microbiology
• University of Pennsylvania School of Medicine
• Penn Center for AIDS Research (CFAR)
• Yerkes National Primate Research Center

2

• Major challenges for AIDS research
• Absence of a vaccine or a long lasting
  microbicide.
• Absence of a treatment that can eradicate
  infection.
• Incomplete understanding of the pathogenesis of
  infection.

3
The Classical Model of AIDS Pathogenesis
HAART Anti-HIV CTL, Neutralizing Abs,
CD4T cell pool
Progressive exhaustion.... AIDS
4
Embracing the complexity of AIDS pathogenesis
Okoye et al., J Exp Med 2007
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Two Basic but Still Unresolved Questions

• What causes CD4 T cell depletion and disease
  progression in HIV-infected patients?
• What is the role of HIV-specific immune responses?

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Two Key Features of HIV Infection

• HIV infects activated CD4 T cells, thus every
  anti-HIV immune response results in more targets
  for the virus.
• 2. HIV reverse transcriptase is an error-prone
  enzyme that generates a constantly evolving virus
  population within infected individuals.
• For these reasons, it is not truly surprising
  that HIV-specific immune responses usually fail
  to protect from disease progression.

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T-cell responses to HIV why immunology 101
may not work (1)
Activated CD4 T cells
T helper cells
(Cytokines, co-stimulation, etc)
B cells CD4 T cells CD8
T cells HIV
B cells
CD8 T cells (CTLs)
NAbs
Antiviral activity
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T-cell responses to HIV why immunology 101
may not work (2)
HIV-specific CTLs an exhausting exercise of
futility?
Lower fitness High CTL resistance (escape mutant)
CD8 T cell
Higher fitness Low CTL resistance
Epitope 3
Epitope 4
Epitope 5
Epitope 2
Epitope 1
9
T-cell responses to HIV why immunology 101
may not work (2)
HIV-specific CTLs an exhausting exercise of
futility?
Lower fitness High CTL resistance (escape mutant)
CD8 T cell
Higher fitness Low CTL resistance
Epitope 3
Epitope 4
Epitope 5
Epitope 2
Epitope 1
10
T-cell responses to HIV why immunology 101
may not work (2)
HIV-specific CTLs an exhausting exercise of
futility?
Lower fitness High CTL resistance (escape mutant)
CD8 T cell
Higher fitness Low CTL resistance
Epitope 3
Epitope 4
Epitope 5
Epitope 2
Epitope 1
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In this context, a new question arises

• Could HIV-induced (both specific or non-specific)
  T cell responses be pathogenic by contributing to
  the HIV-associated immune activation?

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The Immune Activation Hypothesis
During HIV infection, a state of chronic,
generalized immune activation is a key
determinant of CD4 T-cell depletion and
progression to AIDS Gottlieb MS et al.
Pneumocystis carinii pneumonia and mucosal
candidiasis in previously healthy homosexual men
evidence of a new acquired cellular
immunodeficiency N. Engl. J. Med.
1981. Monoclonal-antibody analysis of
peripheral-blood T-cell subpopulations revealed
virtual elimination of the Leu-3 / helper/inducer
subset, an increased percentage of the Leu-2
suppressor/cytoxic subset, and an increased
percentage of cells bearing the
thymocyte-associated antigen T10.

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In Support of the Immune Activation Hypothesis

• 1. Immune activation is a strong, INDEPENDENT
  predictor of clinical progression to AIDS.
• (Giorgi et al., J Infect Dis 1999 Leng et
  al., J. AIDS 2001 Giorgi et al. J AIDS 2002
  Sousa et al. J Immunol 2002 Hazenberg et al.
  AIDS 2003 Deeks et al., Blood 2004 Camerini J
  Virol 2007 Hunt J InfectDis 2008)
• 2. Reduction of immune activation may predict
  CD4 T cell increase after ART better than virus
  suppression.
  
• (Hunt et al, J Infect Dis 2003 Anthony J.AIDS
  2003 Paiardini et al. AIDS 2004 Goicoechea et
  al., J Infect Dis 2006)
• 3. Non-pathogenic SIV infection of natural hosts
  is associated with low immune activation (despite
  high viral loads).

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Immune Activation Predicts Disease Progression
Even in Elite Controllers (i.e., with
undetectable viral load)
Hunt et al, J. Infect. Dis. 2008
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In Support of the Immune Activation Hypothesis

• 1. Immune activation is a strong, very
  consistent, and INDEPENDENT predictor of clinical
  progression to AIDS
  (Giorgi et
  al., J Infect Dis 1999 Leng et al., J. AIDS
  2001 Giorgi et al. J AIDS 2002 Sousa et al. J
  Immunol 2002 Hazenberg et al. AIDS 2003 Deeks
  et al., Blood 2004 Camerini J Virol 2007 Hunt J
  InfectDis 2008)
• 2. Correction of immune activation may predict
  CD4 T cell recovery after HAART better than
  suppression of viremia
  (Hunt et al, J Infect Dis 2003
  Anthony J.AIDS 2003 Paiardini et al. AIDS 2004
  Goicoechea et al., J Infect Dis 2006)
• 3. Non-pathogenic SIV infection of natural hosts
  is typically associated with low levels of immune
  activation (despite high viral loads)

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Natural SIV hosts are the origin of HIV-1, HIV-2,
and SIVmac
SIVmac
HIV-2
Sooty mangabey
Sykes monkey
Greater spot-nosed monkey
Mantled guereza
SIV
SIVcpz
HIV-1
Chimpanzee
SIVmnd
Vervet monkey
Red-capped mangabey
Slide courtesy of Beatrice Hahn
Mandrill
LHoests monkey
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Sooty mangabeys a living challenge to the
classical model of HIV pathogenesis

• West African monkeys, infection common in the
  wild and in captivity.
• AIDS is very rare despite chronic high levels of
  viremia.
• SIVsmm is cytopathic for SM CD4 T cells.

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The AIDS-resistance of SIV-infected mangabeys is
independent of cellular immune responses
CD8 T cell responses
SIV-infected SMs (Dunham et al., Blood 2006)
HIV-infected individuals (Betts et al.,
J Virol 2000)
No correlation can be made between magnitude or
breadth of the SIV-specific T cell response and
either SIV viral load or CD4 T cell count See
also Ansari, unpublished observations
Feinberg/Staprans, unpublished observations
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Limited virologic effects after CD8 T cell
depletion in SIV-infected mangabeys
2500
2000
FNg
FZo
FLn
1500
CD8 T cells per ml
FCo
FQk
1000
FUr
FOo
500
FNw
0
-15
-5
5
15
25
35
45
55
Day of experiment
Barry et al., J. Immunol, 2007
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Direct correlation between the number of
activated CD4 T cells and viral load in
SIV-infected sooty mangabeys
(Klatt et al., J Clin Invest 2008)
Availability of target cells, rather than the
strength of the immune response, is the
determinant of virus replication in SIV-infected
sooty mangabeys
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The AIDS-resistance of natural SIV hosts is
independent of cellular immune responses

• A reality check These studies emphasize the
  tremendous challenge of artificially inducing,
  with an AIDS vaccine, a type of protective T
  cell-based immunity that has not been selected
  for in many thousands of years of evolutionary
  pressure posed by lentiviruses on the primate
  immune system.

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SIV infection of natural hosts is typically
associated with low levels of immune
activation (Chakrabarti, J Virol 2000 Bostik, J
Virol 2001 Silvestri, Immunity 2003 Silvestri,
J Virol 2005 Kornfeld, J Clin Invest 2005
Muthukumar, Blood 2005 Paiardini, J Virol 2006
Onanga, J Virol 2006 Pandrea, J Med Primatol
2006 Sumpter, J Immunol 2007 Gordon et al., J
Immunol 2007 Kaur, J Virol 2008)
Hypothesis Attenuated immune activation protects
natural SIV hosts from progression to AIDS
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Similarities and differences between natural SIV
hosts and HIV-infected LTNPs
Natural hosts LTNPs
AIDS NO NO CD4 depletion
NO NO Viral Load HIGH LOW Cellular
responses LOW HIGH to the virus Immune
Activation LOW LOW
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The successful anti-viral immune response all
or nothing?
Strong but ineffective immune response
Extent of immunopathogenesis
Effective immune suppression of virus replication
Low immune response inflammation
AIDS
LTNPs
SMs
Magnitude of virus-specific cellular immune
response
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TWO PRACTICAL QUESTIONS

• Could HIV-infected patients benefit from immune
  modulation?
• Could HIV vaccines do worse by inducing excessive
  immune activation and/or creating more targets
  for the virus?

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T-cell responses to HIV why immunology 101
may not work (1)
T helper cells
Activated CD4 T cells
(Cytokines, co-stimulation, etc)
B cells CD4 T cells CD8
T cells HIV
B cells
CD8 T cells (CTLs)
NAbs
Antiviral activity
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The Merck STEP Trial
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CONCLUSIONS

• The interaction between primate lentiviruses and
  the host immune system is far from being fully
  understood.
• Immune responses to HIV may control viremia, but
  may also damage the immune system by creating new
  targets for virus replication.
• Interventions aimed at boosting HIV-specific T
  cell responses may result in increased virus
  replication (i.e, IL-15, anti-CTLA4, PD-1
  blockade, etc).
• Major breakthroughs may be needed to design an
  effective AIDS vaccine Can we
  induce a strong but CD4-independent antiviral
  immune responses? Can we disconnect CCR5
  expression from CD4 activation? Can we increase
  the flexibility of the CD8 T cell recognition of
  antigens?

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Acknowledgments

• Silvestri Lab
• Mirko Paiardini
• Barbara Cervasi
• Jessica Engram
• Steven Bosinger
• Thomas Vanderford
• Nichole Klatt
• Alex Ortiz
• Jessica Taaffe
• Beth Cramer
• Katrina Nolan
• Emory University
• Cindy Derdeyn
• Francois Villinger
• Tab Ansari
• Yerkes Primate Center

• Tulane Primate Center
• Ivona Pandrea
• Cristian Apetrei
• Ronald Veazey
• Preston Marx
• Pasteur Institute
• Jerome Estaquier
• Univ. of Minnesota
• Ashley Haase
• Oregon Health Sciences Institute
• Louis Picker
• Case Western
• Michael Lederman
• and the CLIC/BBC

• Univ. of Pennsylvainia
• Michael Betts
• Hildegund Ertl
• Ian Frank
• Luis Montaner
• Jim Hoxie
• SBRI Seattle
• Donald Sodora
• Univ. of Alabama Birmingham
• Beatrice Hahn
• Univ. of Ulm
• Frank Kirchhoff
• Michael Schindler
• Los Alamos National Labs
• Alan Perelson