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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33

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

• Immunology modeling
• Slide 2
• Slide 3
• Slide 4
• Slide 5
• Slide 6
• Comparative immune system
• Innate Immune system
• Adaptive Immune system
• Slide 10
• Importance of the innate Immune System
• Slide 12
• Slide 13
• Slide 14
• Slide 15
• HIV Infection Leads to a state of Generalized Immune Activation
• Subsets of CD4+ Lymphocytes
• CD4+ T-cell Response to HIV
• CTL Responses To HIV
• CTL fail to eliminate HIV
• Slide 21
• Why does the immune response fail to clear HIV
• Mathematical models
• Simple model
• Slide 25
• With Therapy
• Immune Response
• Slide 28
• Immune response
• HIV-1 First Phase Kinetics
• HIV-1 Two Phase Kinetics
• Summary
• Slide 33