project inform © 2005 1 immune pathogenesis of hiv pathogenesis: the way that something causes...

Project Inform © 2005 1

Immune Pathogenesis

of HIV

Pathogenesis:The way that something causes disease.Immune pathogenesis is how the virus (HIV) interacts with the immune system, what happens to the immune system and how.

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Information, Inspiration and Advocacy for People Living with HIV/AIDS.

Project Inform

© Project Inform 2005 2

HIV Disease

Caused by Human Immunodeficiency Virus (HIV) Disables the immune system in many complex

ways HIV infects CD4+ (T4) and other immune cells CD4+ cells are important immune cells

Key ‘mediator’ of immune responses’ Communicating through chemicals (called ‘cytokines’)

CD4+ cells mediate humoral (antibody) and cellular immune responses


CD4+ Cells:Mediators of Immune Responses

BB B

B

B

B

T

T

T

T

T

ThymusT-cells (e.g. CD4+ and CD8+)

Bone MarrowB-cells CD4

Th0

CD4Th1

CD4Th2

IL-2IL-12INF-gamma

IL-4IL-6

IL-10

Humoral• B-Cells• Antibodies• Attacks “critters” outside of Cell

(e.g. free virus in blood)

Cellular• CD8+ cells, NK

cells• Cell to Cell killing• Attacks “critters”

inside of cells(e.g. HIV infected cells)


Infected CD4+ cells may die or become dysfunctional

HIV also infects other immune cells (e.g. antigen presenting cells)

Virus reproduces, infecting cells throughout the body Immune system is gradually weakened Body loses the ability to fight off infections

HIV Disease (continued)

IL-4IL-6IL-10

IL-2IL-12INF-g

Humoral Cellular

Antigen Presenting CellAntigen Presenting Cell(e.g. dendritic cell, macrophage)CD4+ T-CellCD4+ T-Cell


HIV Disease (continued)

Co-factors may further weaken the immune system Other sexually transmitted diseases and active infections

Active infection can increase HIV replication (HIV RNA increases 100 fold+)

StressChemicals released destroys (involutes) thymus and weaken cell walls

Poor nutritionEarly signs of nutritional deficienciesDeficiencies have similar symptoms as early signs of HIV disease

Lifestyle Factors (e.g. substance use, poor sleeping habits, etc.)

Acquired Immune Deficiency Syndrome (AIDS) is the advanced stage of HIV disease


CD4+ Cell Ranges

1500 and up

500

200100 50 0

NormalNormal RangeRange

PredictPredictiveive

RangeRange

LowestLowest RangeRange

Normal Range (500-1500+) Predictive Range (below 500)

Changes in CD4+ counts become ‘meaningful’ Data supports intervention (200 to 350)

Gray Zone For Therapy (350+) Guidelines suggest either Tx or no Tx

depending on HIV RNA & preference Limited data on use of Tx in this range

Lowest Range (below 200) Increased Risk for opportunistic infections

*Note: Trends are most important*Note: Number does not equal function


Immunopathogenesisof HIV Infection

Early

Intermediate

High Burst ofHigh Burst ofViral ActivityViral Activity

Development of Antibodies (seroconversion))

EarlyIntermediate

CD4+ > 500

CD4+ 200-500

AdvancedCD4+ <200

Onset of SymptomsOnset of SymptomsInfection with HIVInfection with HIV TIME

Viral ActivityCD4+ Count

Acute SyndromeAcute Syndrome


Immune Pathogenesis

Population-based information provides insights into disease, but each person experiences HIV disease uniquely


Early Infection/Acute Syndrome

Burst of viral replication Wide distribution of virus “Seeding” of virus in lymph tissue

Some believe that this early stage is very important and may determine the course of disease in each individual

Control of virus is probably not only due to immune response (cellular and humoral) but also to ‘sequestration’ of virus in lymph tissue

Early

High Burst ofHigh Burst ofViral ActivityViral Activity

Infection with HIVInfection with HIV

Development of Antibodies(seroconversion))


Early Intermediate (CD4+ >500)Clinical Latency?

EarlyIntermediate

CD4+ > 500

Virus is ‘trapped’ in follicular dendritic cells (FDC)

Dendritic cells act as a filter and central clearing house for ‘antigen presentation’ Unfortunately, HIV collects in large number

and use FDC as a ‘central’ infection center CD4+ cells, macrophages and monocytes

become infected when traveling through the lymph nodes

Virus levels in lymph tissue are generally much higher than what is seen in the blood/plasma


Follicular Dendritic Cells The “string mops” of the immune system, sweeping up ‘dirt’

that needs to be dealt with

“Critters” moving through lymph nodes and are ‘caught’ in FDC network

CD4+ and other cells also move through lymph nodes to see what kind of “critters” need to be dealt with


Intermediate (CD4+ 200-500)

IntermediateCD4+ 200-500

Structure and function of lymph nodes begin to degrade due to high level of viral activity

Beginning to lose follicular dendritic cells Are “strings” falling off the mop? Do FDCs become infected by HIV? Do FDCs die for unknown reasons?

Clinically: Minor problems begin to worsen (e.g. herpes, genital warts, thrush), blood tests begin to show abnormalities.


Lymph Node “Architecture”

Healthy lymph node:Healthy lymph node: Arranged like an egg FDC form the yolk in an intricate ‘network’ Network is like a cotton ball

Deteriorated lymph node:Deteriorated lymph node: FDC are scattered throughout Cotton ball network is ripped apart Decrease number of FDCs


Advanced DiseaseOnset of Severe Symptoms

AdvancedCD4+ <200

Onset of SymptomsOnset of Symptoms

Complete ‘burn out’ of lymph node centers? Some studies say no, even in advanced

disease. Much that is not wholly understood Loss or dysfunction of many cell types

CD4+ and CD8+ cells, FDC, B cells, macrophages, others

Virus levels similar in lymph node and blood/plasma

Possible changes in virus (M-tropic to T-tropic, syncitia inducing)

Immune system more resilient than we thought


Diversity of Immune Cells

Active vs. Resting cells HIV is a retrovirus, and can only reproduce from

activated (e.g. actively replicating) cells

T-cell receptor diversity V-beta repertoire (Variable region of the beta chain

of the T-cell receptor, immunologic alphabet)

Naïve vs. Memory Co-receptor expression (e.g. CKR5, CXCR4)


V-Beta RepertoireNaïve and Memory CellsP

A

W

C

P

B

W

C

H

M

Specificity of cell is dependent on the composition of the T-cell Receptor (TCR)

The greater the ‘repertoire’ of TCRs, larger the diversity of cells and function

“Naïve” cells are “rookies” in the immune system army

“Memory” cells are “veterans”, which respond more quickly and potently

P C M F H B P C M F H B


Co-receptors

CD4 receptorCKR5CXCR4Others...

Rantes, MIP1a, MIP1bSDF1, MDC

2 ‘receptors’ are necessary ‘doorways’ for HIV to infect a cell (CD4+ plus chemokine receptors)

Chemokines (chemicals produced by immune cells) block the doorways

Genetic alterations in receptors may inhibit HIV from using them to infect cells (CCR5 32bp-delta)

NSI virus uses R5; SI virus uses X4


Plasma HIV RNACD4+ T cell count

CD4+ cells in GALTViral Divergence from “founder strain”

Viral Diversity

CXCR4 or “X4” virus

Dual tropic – X4/R5 virus

Immune activation (esp CD8+ cell activation)

EmergingEmerging Information Information


Acute Infection/Early Disease (Emerging Information)

Within weeks of initial infection: ~75% depletion of “memory” CD4+ cell in gut Destruction of gut-associated lymphoid tissue

(GALT) “architecture” ~50% loss of total body “memory” CD4+ cells

Initial infection typically with CCR5 or “R5” type of virus

Virus closely resembles “founder strain” Virus population not diverse

Plasma HIV RNACD4+ T cell count

CD4+ cells in GALT Viral Divergence from “founder strain”

Viral DiversityImmune activation (esp CD8+ cell activation)


Early Intermediate and Intermediate(Emerging Information)

Rising levels of immune activation (not viral load) predicts rate of CD4+ cell loss

Continued destruction of GALT Increased divergence from initial

infecting strain Increased viral diversity (believed

to be due to escape from cellular immune responses)

Possible rise of dual tropic virus

Plasma HIV RNA

CD4+ T cell count

CD4+ cells in GALT

Viral Divergence from “founder strain”

Viral Diversity


Dual tropic – X4/R5 virusImmune activation (esp CD8+ cell activation)


Advanced Disease(Emerging Information)

High levels of immune activation increasingly believed to be responsible for immune deficiency/AIDS

Rise and disappearance of X4 virus (re-emergence of R5 virus?)

Decrease in viral diversity (possibly due to loss of CTL, no pressure on virus to “escape”)

Plasma HIV RNA

CD4+ T cell count

CD4+ cells in GALT

Viral Divergence from “founder strain”

Viral Diversity


Dual tropic – X4/R5 virusImmune activation (esp CD8+ cell activation)


Future Directions in AIDS Research

Project Inform


Immune Restoration: Rationale

AIDS is a disease of PRIMARY IMMUNE DEFICIENCY caused by a virus (HIV)

Anti-HIV Therapies alone do not appear to fully restore the immune system

Strategies that build on advances in anti-HIV therapy and enhance immune recovery and restoration are critical

Treatment for the major defect in HIV/AIDS, the primary immune deficiency/dysfunction


Immune Restoration:Areas of FocusEnvironmentEnvironment NumberNumber ProtectionProtection FunctionFunction

School

Virus

Cell

Bone Marrow

ThymusSpleenLymph tissue


Addendum Materials:Immune Pathogenesis of HIV

Project Inform


The Immune Response

B-cell

CD8+ T-cell

Antigen Presenting cells - Cells of the immune system that bring intruders to CD4+ T cells. (e.g. macrophages and dendritic cells )

CD4+ T-cells (also may be called “T4 helper cells”, “T4 cells”, or less accurately “T-cells”. CD4+ T cells mediate the immune system response.

CD4+T-cell

CD8+ T-cells - Some CD8+ T cells, when ordered by CD4+ cells will specifically seek out and destroy infected cells.

B cells - During an immune response B-cells make antibodies.

Antibodies - Antibodies are made by B-cells, they attach to “critters”, marking them for destruction by the immune system. Antibodies are specific to the “critter” (bacteria, virus, or other harmful toxins).


Immune Deficiency in HIV Disease Decreased number of lymphocytes

Initial decrease then stabilization of CD4+ cell number Increase in activated CD4+ Depletion of CD4+ naïve cells

Initial increase in CD8+ cell number Increase in activated CD8+ cells (CD8+CD38+/DR+) Despite increase CD8+ cell number, poor anti-HIV responses Decrease in CD8+ naïve cell parallels loss in CD4+

Impairment of Cell Function Decreased ability to produce cytokines, respond to antigens, loss

of TCR diversity & APC function, loss of B-cell function Increased risk of opportunistic infection

Impairment of Immune Environment Damage to immune tissues (LN architecture, FDC Network), status

of thymus Evidence of immune activation

Increased CD38+/DR+ expression, increased TNF-alpha

project inform © 2005 1 immune pathogenesis of hiv pathogenesis: the way that something causes...

Documents

immune cells cd4

cells virus

hiv infected cells

resting cells hiv

infecting cells

nk cells cell

infected cd4

tcell slide