Immunology modeling
Abdessamad Tridane
MTBI summer 2008
HIV virus HIV STRUCTURE
HIV-1 infection of a target cell Figures 187 and 1810 in the 6th and 7th Edition of Campbell amp Reece (2002 2005) respectively
HIV Structure
HIV has just nine genes
Three of the HIV genes called gag pol and env contain information needed to make structural proteins for new virus particles
The other six genes known as tat rev nef vif vpr and vpu code for proteins that control the ability of HIV to infect a cell produce new copies of virus or cause disease
HIV ENTRY
Phenotype Tropism Coresptor
NSI Macrophage CCR-5
CCR-3
SI T-Cell Line CXCR-4
CCR-5
Comparative immune system
Innate Adaptive
Quick response
(min days)+ -
Delay response - +
Antigen-specific - +
Memory response - +
Gene- Re-arragement - +
Conserved through
evolution++ +
Innate Immune system
bull Dendritic cells
bull Macrophages
bull NK-cells
bull Interferon-producing cells (IPC)
bull Chemokines
bull Defensism
Adaptive Immune system
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Innate
bull Dendritic cellsbull Macrophagesbull NK-cellsbull Interferon-producing
cells (IPC) bull Chemokineshellip
Adaptive
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Importance of the innate Immune System
Innate Immunity Cytokines
MHC expression
NK cell activity
Lymphocyte response
Anti-microbial responses (Interferon)
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
HIV virus HIV STRUCTURE
HIV-1 infection of a target cell Figures 187 and 1810 in the 6th and 7th Edition of Campbell amp Reece (2002 2005) respectively
HIV Structure
HIV has just nine genes
Three of the HIV genes called gag pol and env contain information needed to make structural proteins for new virus particles
The other six genes known as tat rev nef vif vpr and vpu code for proteins that control the ability of HIV to infect a cell produce new copies of virus or cause disease
HIV ENTRY
Phenotype Tropism Coresptor
NSI Macrophage CCR-5
CCR-3
SI T-Cell Line CXCR-4
CCR-5
Comparative immune system
Innate Adaptive
Quick response
(min days)+ -
Delay response - +
Antigen-specific - +
Memory response - +
Gene- Re-arragement - +
Conserved through
evolution++ +
Innate Immune system
bull Dendritic cells
bull Macrophages
bull NK-cells
bull Interferon-producing cells (IPC)
bull Chemokines
bull Defensism
Adaptive Immune system
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Innate
bull Dendritic cellsbull Macrophagesbull NK-cellsbull Interferon-producing
cells (IPC) bull Chemokineshellip
Adaptive
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Importance of the innate Immune System
Innate Immunity Cytokines
MHC expression
NK cell activity
Lymphocyte response
Anti-microbial responses (Interferon)
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
HIV Structure
HIV has just nine genes
Three of the HIV genes called gag pol and env contain information needed to make structural proteins for new virus particles
The other six genes known as tat rev nef vif vpr and vpu code for proteins that control the ability of HIV to infect a cell produce new copies of virus or cause disease
HIV ENTRY
Phenotype Tropism Coresptor
NSI Macrophage CCR-5
CCR-3
SI T-Cell Line CXCR-4
CCR-5
Comparative immune system
Innate Adaptive
Quick response
(min days)+ -
Delay response - +
Antigen-specific - +
Memory response - +
Gene- Re-arragement - +
Conserved through
evolution++ +
Innate Immune system
bull Dendritic cells
bull Macrophages
bull NK-cells
bull Interferon-producing cells (IPC)
bull Chemokines
bull Defensism
Adaptive Immune system
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Innate
bull Dendritic cellsbull Macrophagesbull NK-cellsbull Interferon-producing
cells (IPC) bull Chemokineshellip
Adaptive
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Importance of the innate Immune System
Innate Immunity Cytokines
MHC expression
NK cell activity
Lymphocyte response
Anti-microbial responses (Interferon)
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
HIV ENTRY
Phenotype Tropism Coresptor
NSI Macrophage CCR-5
CCR-3
SI T-Cell Line CXCR-4
CCR-5
Comparative immune system
Innate Adaptive
Quick response
(min days)+ -
Delay response - +
Antigen-specific - +
Memory response - +
Gene- Re-arragement - +
Conserved through
evolution++ +
Innate Immune system
bull Dendritic cells
bull Macrophages
bull NK-cells
bull Interferon-producing cells (IPC)
bull Chemokines
bull Defensism
Adaptive Immune system
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Innate
bull Dendritic cellsbull Macrophagesbull NK-cellsbull Interferon-producing
cells (IPC) bull Chemokineshellip
Adaptive
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Importance of the innate Immune System
Innate Immunity Cytokines
MHC expression
NK cell activity
Lymphocyte response
Anti-microbial responses (Interferon)
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Comparative immune system
Innate Adaptive
Quick response
(min days)+ -
Delay response - +
Antigen-specific - +
Memory response - +
Gene- Re-arragement - +
Conserved through
evolution++ +
Innate Immune system
bull Dendritic cells
bull Macrophages
bull NK-cells
bull Interferon-producing cells (IPC)
bull Chemokines
bull Defensism
Adaptive Immune system
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Innate
bull Dendritic cellsbull Macrophagesbull NK-cellsbull Interferon-producing
cells (IPC) bull Chemokineshellip
Adaptive
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Importance of the innate Immune System
Innate Immunity Cytokines
MHC expression
NK cell activity
Lymphocyte response
Anti-microbial responses (Interferon)
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Innate Immune system
bull Dendritic cells
bull Macrophages
bull NK-cells
bull Interferon-producing cells (IPC)
bull Chemokines
bull Defensism
Adaptive Immune system
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Innate
bull Dendritic cellsbull Macrophagesbull NK-cellsbull Interferon-producing
cells (IPC) bull Chemokineshellip
Adaptive
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Importance of the innate Immune System
Innate Immunity Cytokines
MHC expression
NK cell activity
Lymphocyte response
Anti-microbial responses (Interferon)
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Adaptive Immune system
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Innate
bull Dendritic cellsbull Macrophagesbull NK-cellsbull Interferon-producing
cells (IPC) bull Chemokineshellip
Adaptive
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Importance of the innate Immune System
Innate Immunity Cytokines
MHC expression
NK cell activity
Lymphocyte response
Anti-microbial responses (Interferon)
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Innate
bull Dendritic cellsbull Macrophagesbull NK-cellsbull Interferon-producing
cells (IPC) bull Chemokineshellip
Adaptive
bull Dendritic cellsbull Macrophagesbull B-Lymphocytesbull CD4+ Lymphocytesbull CD8+ Lymphocytes
Importance of the innate Immune System
Innate Immunity Cytokines
MHC expression
NK cell activity
Lymphocyte response
Anti-microbial responses (Interferon)
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Importance of the innate Immune System
Innate Immunity Cytokines
MHC expression
NK cell activity
Lymphocyte response
Anti-microbial responses (Interferon)
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
The time course of an HIV-1 infection Figure 4320 in Campbell amp Reece (2002)
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Impact of HIV
CD4+ T-Cells
Reservoir
B-cells
NK cells
Macrophages
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
HIV Infection Leads to a state of Generalized Immune Activation
HIV Induced Immune
Activation
Increased T- cell turnover
(Production and destruction)
Increased activation-induced
death of T- cells
A decline in the size of the CD4+ T Cell pool
A state of activation-induced
immunodeficiency
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Subsets of CD4+ Lymphocytes
Subset Cytokine Produced
Function
Th1 IL-2IFN-gamma
Cell-mediated immunity
Th2 IL-4IL-10
AntibodyProduction
HIV
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
CD4+ T-cell Response to HIV
bull In some individuals CD4+ T-cell responses remain relatively normal
bull These individuals do not appear to progress to disease even though they are infected These individuals are termed Long-term non-progressors (LTNP)
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
CTL Responses To HIV
CTL responses are measured bybull 51Cr release assay (Killing)bull ELISpot (Cytokine release)
Antigen specific CD8+ T-cells can be quantified by tetramer staining (Number of specific cells)
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
CTL fail to eliminate HIV
bull Many chronically infected individuals havevigorous HIV-1-specific CTL responses yetthey almost always fail to adequately
suppressthe virus
Whybull 1048766Epitope escapebull 1048766CTL Exhaustionbull 1048766Suboptimal CTL
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Why does the immune response fail to clear HIV
bull HIV integrates into the host genome Therefore to eliminate HIV infected cells must be killed
bull Host factors can paradoxically enhance HIV replication Therefore by responding to HIV CD4+ T-cells can be destroyed
bull HIV can mutate and escape immune mediated opposition
bull Suboptimal CTL responses can be elicted
bull APCrsquos may exhibit altered functions diminishing their ability to elicit immune responses
bull Antigen presenting cells can act as trojan horses spreading HIV to CD4+T-cells as they begin to respond to antigen
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Mathematical models
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Simple model
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
With Therapy
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Immune Response
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Immune Response
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Immune response
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
HIV-1 First Phase Kinetics
Perelson et al Science 271 1582 1996
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
HIV-1 Two Phase Kinetics
Perelson et al Nature 387 186 (1997)
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Summary
bull Models of viral infections and immune reactions strongly resemble ecological models
bull The fact that the viral generation time can be estimated by a simple linear regression proves that simple models sometimes allow for important new interpretations
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson
Using techniques from physics ndash modeling large scale computation scaling laws network models new optical techniques (2-photon microscopy) etc ndash will allow new insights into the population biology of hosts insights and pathogens allow development of new therapeutics and vaccines optimize response to biothreats and most importantly generate new understanding of how complex biological systems work
Summary
Alan S Perelson