Title: Immune Basis of HIV Pathogenesis
1Immune 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.
3The Classical Model of AIDS Pathogenesis
HAART Anti-HIV CTL, Neutralizing Abs,
CD4T cell pool
Progressive exhaustion.... AIDS
4Embracing the complexity of AIDS pathogenesis
Okoye et al., J Exp Med 2007
5Two 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?
6Two 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.
7T-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
8T-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
9T-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
10T-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
11In 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?
12The 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.
13In 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). -
14Immune Activation Predicts Disease Progression
Even in Elite Controllers (i.e., with
undetectable viral load)
Hunt et al, J. Infect. Dis. 2008
15In 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) -
16Natural 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
17Sooty 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.
18The 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
19Limited 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
20Direct 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
21The 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.
22SIV 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
23Similarities 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
24The 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
25TWO 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?
26T-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
27The Merck STEP Trial
28CONCLUSIONS
- 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?
29Acknowledgments
- 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