Project Inform © 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 th Street #2001 San Francisco, CA Website: Hotline: or Information, Inspiration and Advocacy for People Living with HIV/AIDS. Project Inform

© Project Inform 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

© Project Inform CD4+ Cells: Mediators of Immune Responses B B B B B B T T T T T Thymus T-cells (e.g. CD4+ and CD8+) Bone Marrow B-cells CD4 Th0 CD4 Th1 CD4 Th2 IL-2 IL-12 INF-gamma IL-4 IL-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)

© Project Inform 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-4 IL-6 IL-10 IL-2 IL-12 INF-g Humoral Cellular Antigen Presenting Cell (e.g. dendritic cell, macrophage) CD4+ T-Cell

© Project Inform 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+)   Stress Chemicals released destroys (involutes) thymus and weaken cell walls   Poor nutrition Early signs of nutritional deficiencies Deficiencies 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

© Project Inform CD4+ Cell Ranges 1500 and up Normal Range Range Predictive Range Range Lowest Range Range Normal Range ( ) 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

© Project Inform Immunopathogenesis of HIV Infection Early Intermediate High Burst of Viral Activity ) Development of Antibodies (seroconversion) Early Intermediate CD4+ > 500 CD Advanced CD4+ <200 Onset of Symptoms Infection with HIV TIME Viral Activity CD4+ Count Acute Syndrome

© Project Inform Immune Pathogenesis Population-based information provides insights into disease, but each person experiences HIV disease uniquely

© Project Inform 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 of Viral Activity Infection with HIV Development of Antibodies ) (seroconversion)

© Project Inform Early Intermediate (CD4+ >500) Clinical Latency? Early Intermediate 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

© Project Inform 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

© Project Inform Intermediate (CD ) Intermediate CD 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.

© Project Inform Lymph Node “Architecture” Healthy lymph node: Arranged like an egg FDC form the yolk in an intricate ‘network’ Network is like a cotton ball Deteriorated lymph node: FDC are scattered throughout Cotton ball network is ripped apart Decrease number of FDCs

© Project Inform Advanced Disease Onset of Severe Symptoms Advanced CD4+ <200 Onset 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

© Project Inform 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)

© Project Inform V-Beta Repertoire Naïve and Memory Cells P 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

© Project Inform Co-receptors CD4 receptor CKR5 CXCR4 Others... Rantes, MIP1a, MIP1b SDF1, 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

© Project Inform Plasma HIV RNA CD4+ T cell count CD4+ cells in GALT Viral Divergence from “founder strain” Viral Diversity CXCR4 or “X4” virus Dual tropic – X4/R5 virus Immune activation (esp CD8+ cell activation) Emerging Information

© Project Inform 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 RNA CD4+ T cell count CD4+ cells in GALT Viral Divergence from “founder strain” Viral Diversity Immune activation (esp CD8+ cell activation)

© Project Inform 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 CXCR4 or “X4” virus Dual tropic – X4/R5 virus Immune activation (esp CD8+ cell activation)

© Project Inform 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 CXCR4 or “X4” virus Dual tropic – X4/R5 virus Immune activation (esp CD8+ cell activation)

Project Inform © Future Directions in AIDS Research Project Inform

© 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

© Project Inform Immune Restoration: Areas of Focus

Project Inform © Addendum Materials: Immune Pathogenesis of HIV Project Inform

© 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).

© Project Inform 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