Slide 1 HIV Pathogenesis and Natural Course of the Disease Unit 4 HIV Care and ART: A Course for Physicians Unit 4 should take approximately 2 hours.

HIV Pathogenesis and Natural Course of the Disease Unit 4 HIV Care and ART: A Course for Physicians Unit 4 should take approximately 2 hours to implement: Step 1 Overview of Learning Objectives (Slides 1 – 2) – 5 minutes Step 2 Virology of HIV (Slides ) – 55 minutes Step 3 Immunology and HIV Infection (27 – 65) - 55 minutes Step 4 Key Points (66 – 67) – 5 minutes

Learning Objectives Discuss HIV molecular biology and virology
Slide 2 Discuss HIV molecular biology and virology Describe immunological response against infections Explain the effect of HIV on the immune system and how HIV establishes a chronic infection Identify characteristics that make HIV disease chronic and incurable Understand the natural course of the disease Step 1 Overview of Learning Objectives (Slides 1 – 2) – 5 minutes Begin by reviewing the unit aim and objectives. The aim of this unit is to better understand the course of HIV disease, including the molecular biology and virology of HIV, the human immunological response, and the viral dynamics of the disease. These topics are essential in order to understand other topics related to prevention, diagnosis, staging and treatment of HIV. Pathogenesis and Natural Course of the Disease

Virology of HIV Slide 3 Pathogenesis and Natural Course of the Disease
Step 2 Virology of HIV (Slides ) – 55 minutes Pathogenesis and Natural Course of the Disease

Characteristics of HIV
Slide 4 Classification Family of retroviruses (RNA -> DNA -> RNA) Subfamily of lente (slow) viruses Cytopathic to cells that replicate it Infects many cells types and is latent in some cells Infects and depletes CD4 lymphocytes Causes cell-mediated immunosuppression HIV belongs to a family of HIV retroviruses that possess the reverse transcriptase enzyme. This enzyme enables the RNA virus to transform itself to DNA provirus and integrate itself into the nucleus of the activated T-cell lymphocyte. The virus is cytopathic to the T-cells that replicate or produce new HIV virus. The death and depletion of these infected T-cells cause immunosuppression. HIV can infect other cell types and remain latent in these cells, thus providing a reservoir of HIV. Once HIV infects a cell, it is part of the cell for life. Pathogenesis and Natural Course of the Disease

HIV Strains HIV-1 Group M (main), the cause of the AIDS epidemic
Slide 5 HIV-1 Group M (main), the cause of the AIDS epidemic HIV-2, a less virulent retrovirus causing an epidemic in West Africa Pathogenesis and Natural Course of the Disease

HIV-1 and HIV-2 Differ in Multiple Ways
Slide 6 Accessory genes HIV-1 vpu HIV-2 vpx Distribution HIV-1 – global pandemic HIV-2 – West Africa Rate of progression of severe immunosuppression HIV-1 – median time to AIDS = 10 years HIV-2 – median time to AIDS = longer, but ? Beyond the gag, env and pol genes, HIV-1 contains six RNA genes that code for regulation. These are tat, rev, nef, nif, vpr and vpu. In HIV-2, the vpx gene replaces the vpu gene of HIV-1. They also differ in their molecular weight. HIV –2 is found in western Africa. It takes a more chronic course and is less aggressive than HIV-1. HIV-1 is far more common globally than HIV-2. Some people who may be infected with both serotypes. Pathogenesis and Natural Course of the Disease

Classification of HIV-1
Slide 7 Groups M (major) with 9 subtypes (clades) O (outlier) N (reported only in Cameroon) Group M’s clades (related viruses) Named with letters A to K, with many recombinants between parts of HIV from two clades Differ in geographic distribution Differ from each other by about 30% in the env coding sequences and 14% of the gag code sequences There are three groups of HIV-1. M is the most common. It is possible to identify the clades by gene sequencing. The clades vary in their infection progress and infectivity. There also are differences in the geographic distribution of the clades. Clade C, which is present in Ethiopia, causes a fast-progressing infection and is the most infectious. Therefore, it is important to be aggressive in prevention and treatment. Pathogenesis and Natural Course of the Disease

HIV Clades HIV rapidly evolves by two mechanisms:
Slide 8 HIV rapidly evolves by two mechanisms: Mutation - changes in single nucleosides of the RNA Recombination – combinations of long RNA sequences from two distinct HIV strains Distinct genetic subgroups, or clades, of the M group of HIV have evolved and become dominate in specific geographic regions A in Central Africa B in North American and Europe C in Southern and Eastern Africa Several clades (e.g., A/G ad A/E) are recombinants Although there are distinct clades that are based on geography, with time and increased travel there are now several recombinant clades. Over time it is likely that there will be more of the recombinants. This will present interesting challenges to prevention and treatment. Pathogenesis and Natural Course of the Disease

Geographic Distribution
Slide 9 As you can see, Africa has a wide variety of clade distribution At present, most geographic areas have a predominate clade. The distribution can be expected to evolve over time to a more heterogeneous representation of clades. Pathogenesis and Natural Course of the Disease

Structure of HIV Slide 10 This slide shows a model an HIV vision particle structure. Familiarity with this structure will enable you to understand how the virus can infect the CD4 lymphocyte, how we can attack and kill the virus, and how the various antiretroviral agents work in preventing attachment and replication of HIV. Pathogenesis and Natural Course of the Disease

Slide 11 HIV infect cells that express CD4 receptor molecules CD-4 receptor molecules are expressed by T-helper cells and monocyte-macrophage cell lines Successful entry of the virus to a target cell also requires cellular co-receptors Viruses need a receptor on a cell surface in order to attach themselves and get access to inside of a cell. In order for a cell to be infected by HIV, there must be CD4 receptor molecules present. These receptors occur on CD4 cells and on other cells in the monocyte-macrophage cell lines. Once HIV attaches, there also needs to be a cellular co-receptor to facilitate entry into the CD4 cell (or other cell). Pathogenesis and Natural Course of the Disease

Characteristics of HIV (2)
Slide 12 A fusion co-receptor is designated CXCR5 for T-cell tropic stain and CCR4 for monocyte-macrophage tropic strains The receptor and co-receptors of CD4 cells interact with HIV’s gp-120 and gp-41 proteins during entry into a cell Fusion co-receptor CXCR5 or CCR4 is needed for entry. In some people with naturally occurring genetic defects at this cellular level, HIV infection can be prevented or lessened. For most, however, this co-receptor allows HIV to enter the CD4 cell (or other cell). The gp-120 and gp-41 (glycoprotein layer that we saw on the diagram of the AIDS virus) are needed for entry into the CD4 cell (or other cell). Pathogenesis and Natural Course of the Disease

HIV and Cellular Receptors
HIV Receptors HIV Receptors HIV and Cellular Receptors Slide 13 This diagram illustrates the HIV virus’s attachment and entry into a host cell. The gp-120 protein attaches itself to a CD4 receptor. Then the gp-41 is exteriorized for attachment to the host cell, and the process of fusion starts. These glycoproteins form the connection and bridge, facilitating the attachment and entry of HIV into the CD4 (or other) cell. Levy JA, NEJM, 335(20); Pathogenesis and Natural Course of the Disease

Role of Chemokine Receptors in HIV Entry Host Cell Membrane Fusion Via CXCR4
Slide 14 This slide illustrates the way the HIV virus uses its gp-41 and gp-120 to attach to the receptors for these epitopes on the surface of the CD4 cell. Note in a figure A how the glycoproteins line up perfectly to the receptors. In figures B and C the attachment occurs. With the aid of the fusion domain and CCR5 and CXCR4, the entry to the CD4 cell starts in picture D. Entry into the CD4 cell is completed in picture E. This results in an infected CD4 cell that will be used to manufacture the HIV virus, resulting in the death of the CD4 cell itself.

Pathogenesis and Natural Course of the Disease
Slide 15 This photomicrograph shows how the HIV viral particle attaches to the surface of the CD4 cell. Pictured on the right are the CD4 receptors vulnerable to attachment by the glycoproteins on the HIV viral surface. On the left you see the virus attaching to the receptors on the CD4 cell as “a perfect fit.” The chemokine co-receptors, CCR5 and CXR4, assist in the fusion or entry of the virus into the CD4 cell. Pathogenesis and Natural Course of the Disease

Slide 16 This photomicrograph illustrates the HIV virus after it has entered the CD4 cell. At this time, the virus is uncoated, and its viral RNA is exposed and converted to DNA. The process of reverse transciptase takes place within 4 to 6 hours of infection. Pathogenesis and Natural Course of the Disease

Slide 17 The final products of reverse transcriptase are double-stranded molecules. It is during this process that the backbone ARV drugs work the nucleosides, nucleotides and non nucleoside ARV. A new class of ARV called integrase inhibitors is under development and may be available in the future. Following entry the reverse transcription complex is formed. This pre-integration complex contains the newly made viral DNA and several HIV proteins: The matrix protein p17 Integrase Reverse transcriptase Viral protein R (vpr) Pathogenesis and Natural Course of the Disease

These double-stranded DNA are transported to the nucleus of the CD4 cell, where the HIV viral DNA is integrated into to DNA of the CD4 cell. The final product’s provirus remains a part of the CD4 genetic material until the death of the cell.

Cell cytoplasm Cell nucleus Slide 19
The primary transcripts of the provirus are made by the CD4 RNA and are spliced and made ready for assembly. Transcription starts and is completed with full-length transcripts that are spliced and translated. Cell nucleus Pathogenesis and Natural Course of the Disease

Slide 20 Assembly occurs when the gag proteins put together viral proteins and CD4 cells into mature viral particles. The assembly takes place at the cell membranes, making possible the release of the viral particle. It is during these final steps of assembly and maturation that the potent ARV protease inhibitors are effective. Without the interruption of this final step, the newly released infectious virus will proceed to infect new CD4 cells. Pathogenesis and Natural Course of the Disease

Life Cycle of HIV: Replication
Slide 21 Reverse transcription converse HIV RNA into proviral DNA Importation to cell nucleus Integration of proviral to host-cell DNA Cellular activation causes transcription (copying) of HIV DNA back to RNA Some RNA translated to HIV proteins Other RNA moved to cell membrane HIV assembled under cell membrane and budded from cell Proteases convert immature to infectious HIV Although HIV in vivo and vitro can infect both resting and activated CD4 T-cells equally well, its ability to replicate in T-cells is strictly dependent on the state of activation of the cells. Furthermore, efficient viral replication in monocytes or macrophages depends on both the activation and the differentiation states of these cells. This slide reviews the complicated steps that it takes for the free HIV virus to infect, replicate in and destroy the CD4 cell. Remember that it is this destruction of the CD4 cell that causes the immune deficiency that allows AIDS to occur. Pathogenesis and Natural Course of the Disease

Summary of Life Cycle of HIV and Sites of Drug Action
HIV life cycle Summary of Life Cycle of HIV and Sites of Drug Action Slide 22 Fusion-Inhibitors Once a virus gets inside a CD4-expressing cell, the viral DNA can become part of the CD4 cell’s DNA within the nucleus. It can transform the cell into a factory for making more HIV. The viral DNA combined with the host cell’s DNA is like a complete blueprint for making new virus. The complete DNA (i.e., the blueprint) undergoes translation and creates complex HIV proteins. These new HIV proteins are not infectious until the protease enzyme cuts each complex protein chain into smaller functional proteins that can be used to build the new virus (e.g., the core, the envelope). Once HIV has bound to and invaded the host cell, part of the virus, an enzyme called reverse transcriptase (RT) translates HIV’s genetic material (single stranded RNA) into a form compatible with human DNA (double stranded DNA, the building block of all human cells). These smaller functional proteins are then stuck together to form new HIV virus. These complete virus can then leave the CD4 cell and enter the plasma to infect new host cells. Gray = blood Blue circle = CD4 cell Purple circle = CD4 cell nucleus Fusion Inhibitors Nucleoside, nucleotide and non-nucleosides Protease inhibitors Integrase inhibitors (in development) Pathogenesis and Natural Course of the Disease

Slide 23 Once infection is established, the virus homes itself mainly in the lymphoid and, to a lesser extent, in the circulation. Pathogenesis and Natural Course of the Disease

Early Phases of HIV Entry and Replication at Mucosal Surfaces
Slide 24 Cell free HIV CD40—CD40 T-cell Immature Dendritic cell PEP Skin or mucosa Via lymphatics or circulation Burst of HIV replication If you look carefully at this slide, you see the short length of time that it takes to establish HIV infection. There is less than 72 hours between entry into the skin or mucous membrane and HIV production in the CD4 cell. This information may help scientists to develop better means of PEP (post-exposure prophylaxis) in the case of high-risk contacts or rape. 24 hours 48 hours HIV co receptors, CD4 + chemokine receptor CC5 Mature Dendritic cell in regional LN undergoes a single replication, which transfers HIV to T- cell Selective of macrophage-tropic HIV Pathogenesis and Natural Course of the Disease

Spread of HIV in Host Tissues
Slide 25 Early Events in Transmucosal HIV-1 Infection The arrows indicate the path of the virus. The viral-envelope protein binds to the CD4 molecule on dendritic cells. Entry into the cells requires the presence of CCR5, a surface chemokine receptor. Dendritic cells, which express the viral co-receptors CD4 and CCR5, are selectively infected by R5 (macrophage-tropic) strains. Within two days after mucosal exposure, virus can be detected in lymph nodes. Within another three days, it can be cultured from plasma.

Enhanced: Dendritic Cell’s HIV Infectivity to CD4 T-cell
Slide 26 The recruitment of virus (green-fluorescent-protein–labeled HIVLAI, depicted as green dots) to sites of cell–cell interaction suggests a mechanism by which dendritic cells enhance viral infectivity as virus particles cluster along the surface between the dendritic cell and the CD4+ T cell. (Blue areas denote DNA, and red areas actin.) At the same time, HIV receptors travel to this site, enabling HIV particles to travel between cells. The large surface area of the dendritic cells may enable as many particles as possible to gather at the interface. CD4 Pathogenesis and Natural Course of the Disease

Immunology and HIV Infection
Slide 27 Immunology and HIV Infection Step 3 Immunology and HIV Infection (27 – 65) - 55 minutes We have just finished the section on the virology of the HIV virus. In this next section we will discuss the human immune system and its role in HIV infection. This section is particularly important because the virus does not cause human death, but the destruction of the immune system allows opportunistic infections to kill the patient. Pathogenesis and Natural Course of the Disease

Types of Normal Immune Responses
Slide 28 Innate – non-specific, “natural,” no prior contact required Mediated through neutrophils, macrophages, circulating binding proteins, and natural killer lymphocytes Acquired – specific, learned from contact with pathogens Mediated through T (cellular signalizing) and B (antibody producing) lymphocytes and macrophages Humans are equipped with an inherent ability to “fight off” insults to our body. All health humans are born with these defense mechanisms, which include various cells in circulation and in tissue, including white blood cells, neutrophils, lymphocytes, macrophages, and substances such as circulating binding proteins. In other cases this protection is acquired by the immune system from exposure to these “insults” or pathogens. The T and B lymphocytes and macrophages once exposed to these pathogens become “educated” to recognize and produce antibody. Pathogenesis and Natural Course of the Disease

The Normal Immune Response
Slide 29 Normal host defense in response to a foreign antigen culminates in a rapid and efficient elimination of a non-self substance The process of elimination of a foreign antigen involves effector-cell activity and their interaction through soluble cellular secretions (cytokines) The specific or adaptive immune system may take days to respond to a primary invasion (that is, infection by an organism that has not hitherto been seen). In the specific immune system, we see the production of antibodies (soluble proteins that bind to foreign antigens) and cell-mediated responses in which specific cells recognize foreign pathogens and destroy them. In the case of viruses or tumors, this response is also vital to the recognition and destruction of virally infected or tumorigenic cells. The response to a second round of infection is often more rapid than to the primary infection because of the activation of memory B and T cells. Pathogenesis and Natural Course of the Disease

Specific Normal Immune Response
Slide 30 Dendritic cells and macrophages are major antigen-presenting cells. In HIV infection, extensive viral replication takes place in these cells. They also secrete IL-1, IL-12 and TNF-Alfa, which stimulate proliferation of T-cells and B-cells. B- and T-lymphocytes may be regarded as the principal effector cells of antigen-specific immune responses, but their function is under the control of dendritic cells, which are able to pick up antigens in the periphery. These antigens are processed and expressed on the cell surface, together with co-stimulatory molecules that initiate T-cell activation. B-cells may recognize an antigen after binding to the B-cell receptor. Recognition of antigen by T-cells requires previous processing and presentation of antigenic peptides by dendritic cells. This slide shows the central role played by the T-helper (TH) cell. Pathogenesis and Natural Course of the Disease

Normal Immune-Cell Interaction
Slide 31 plasma CD-4-4 CTL CTL CD4 T-cells have essential helper/inducer functions in both the cellular and humoral arms of specific immunity. By cell-to-cell contact and local release of regulatory cytokines (IL-2, INF-gamma, etc.), antigen-responsive CD4 T-cells transmit activating signals to cytotoxic CD8 T-cells, antibody-producing B-cells, and macrophages. Pathogenesis and Natural Course of the Disease

Specific Immune Response
Slide 32 CD-4 cells remain as memory cells after infection is controlled. CD-8 cells transform themselves into cytotoxic T-cells. B-cells change to IG-secreting plasma cells. Pathogenesis and Natural Course of the Disease

Peculiar Characteristics of HIV
Slide 33 HIV is a unique infection in that: The virus is not cleared, except partially in the early period of infection A chronic infection is established, and it persists with varying degrees of viral replication. The viral replication continues for about eight to ten years before bringing in significant immuno-suppresion There is no virological latency Although there may be a period of time when the person appears well after the initial HIV infection with its acute manifestations, the virus is ALWAYS active. This false sense of security that patients may feel during this time (if they even know that they are infected) is due to the fact that for some time, even many years, they may feel and act healthy. Eventually, however, the immune system will become so severely damaged that it will be unable to protect the infected person from opportunistic infections. Over time the virus continues replication of itself and destruction of CD4 cells to the extent that the person is left with significant immune destruction. Remember there is no virologic latency. Pathogenesis and Natural Course of the Disease

Infected CD4 T-lymphocyte
Slide 34 HIV In HIV infection, infected CD4 T-cell and macrophages are turned into HIV-producing machines. The viruses that are released to the cells perpetuate continuous stimulation of the immune system, resulting in a vicious cycle. This slide illustrates what happens with perpetual production of HIV and immune system stimulation in the face of established HIV infection. This vicious cycle continues until death, or until antiviral or immune system stimulation occurs. Modified; South Carolina Medical Library

Viral Dynamics of HIV Infection
Slide 35 Viral replication is continuous in all stages (early, during clinical latency and in advanced stages) Half life of a virion is about 6 hours, while an infected cell has a life span of 1.6 days Daily about 1010 virions are produced and cleared from the circulation Average generation time of HIV is 2.6 days It is difficult to imagine the magnitude of the viral replication that occurs at all stages of HIV infection. It is relentless, regardless of HIV stage. The absence of symptoms has no relation to this continuous replication of virus. Everything in viral replication occurs quickly and in huge doses of virus. The free virion lives only about 6 hours, but 10 billion (10,000,000,000) virions are produced and cleared from circulation daily. Once a CD4 cell becomes infected, it is dead in less than two days. It takes just over two days from the release of a “new” virion to attachment, entry and manufacture into an infectious circulating virion. Although the CD4 cells replace themselves on a regular basis, the virus eventually “wins” because of sheer numbers as it destroys the CD4 cells and the immune system that protects the individual from opportunistic infections. Pathogenesis and Natural Course of the Disease

Viral Set Point Slide 36 The level of steady-state viremia (set-point) at six months to one year after infection has and important prognostic implication for progression of HIV disease Those with a high viral set-point have faster progression to AIDS, if not treated At the time of acute infection, there is an aggressive burst of viremia with an extremely high viral load. This viremia is controlled initially by the immune system, and a temporary steady state is achieved. At this time, 6-12 months after infection, the viral load is established for each patient. The measurement of the viral load at this time can be important in predicting the rapidity of progression of AIDS in the individual Pathogenesis and Natural Course of the Disease

Reasons for Persistent Viremia
Slide 37 Despite robust immune reaction, HIV evades elimination by the immune system due to: High level of viral mutation Large pool of latently infected cells that cannot be eliminated by viral-specific CTLs Virus homes in lymphoid organs, while antibody is in the circulation Exhaustion of CD8 T-lymphocytes by excessive antigen stimulation As described earlier, once the immune system detects the HIV virus, there is an immune reaction. However, the virus has characteristics that make control by the immune system impossible over time. For each generation (approximately 48 hours), there are high levels of mutations that make it impossible for the immune system to detect the virus. Additionally, the large population of virus that remains “hidden” in latently infected cells cannot be eliminated by the immune system. Similarly, virus that is “hidden” in lymphoid tissue and organs escapes detection by the immune system. Pathogenesis and Natural Course of the Disease

Reasons for Persistent Viremia (2)
Slide 38 Down regulation of HLA-1 molecule in HIV infected cells HIV attacks CD-4 T-cells, which are central to both humoral and-cell mediated immunity HIV seeds itself in areas of the body where sufficient antibodies might not reach, e.g., the central nervous system Although the excessive viremia present at the time of initial infection is somewhat modulated over the early months of infection, eventually there is a decrease in the CD8 population and down regulation of HLA-1. Over time, the immune system deteriorates as the CD4 cells become depleted by percentage and absolute count. The ratio of CD4 to CD8 cells becomes inverted, showing extensive immune system defect. While the humoral and cell-mediated immunity is being damaged, HIV viral infection is established in other compartments inaccessible to the immune system, namely the central nervous system, gastrointestinal tract, and lymphoid and other tissue. Pathogenesis and Natural Course of the Disease

Pathogenesis of HIV Slide 39 HIV infection is a disease characterized by a profound immunodeficiency from progressive decline of T-helper cells The pathogenetic mechanism of HIV disease is multifactorial and multiphasic and it differs in different stage of the disease Next we will discuss how these characteristics of the virus enable it to attack and disable the immune system causing immune deficiency disease. Pathogenesis and Natural Course of the Disease

Effects of Cellular Activation
Slide 40 Quiescent but infected CD4 T-cells start to transcript, making viral spread more efficient Cellular activation induces expression of receptors for HIV Chronic stimulation favors programmed cell death (apoptosis) to CD4, CD8 and B-cells Significant increase in the release of cytokines As HIV becomes established the previously described events become honed to efficiency making continuous production of the virus a reality. Pathogenesis and Natural Course of the Disease

Effects of Cellular Activation (2)
Slide 41 Brings about up-regulation of viral expression and cellular activation Initiates auto-immune phenomena Brings about compromised immune response to broad spectrum of antigens Co-infection (TB, CMV, etc.) also induces viral replication Co-infections result in increased release of cytokines, which induce viral cell replication. As the immune system is “turned on” to fight off bacterial, fungal, parasitic and viral infections, it is stimulated to “step up” HIV viral replication. This increases the viral load with an associated decrease in CD4 cells. In a step-wise fashion, the immune system continues to suffer increased destruction from which it cannot recover. Pathogenesis and Natural Course of the Disease

Cytokines in HIV Slide 42 The immune system is regulated by a complex of immuno-regulatory cytokines Cytokines are cellular products that induce or suppress cellular activity Inducers of HIV expression include: IL-1, IL-2, IL-3, IL-6, IL-12, TNF-Alfa, TNL-beta, M-CSF and GM-CSF The most potent inducers are pro-inflammatory cytokines, TNF-Alfa, IL-1and IL-6, which are products of macrophages Cytokines are capable of regulating the induction of HIV expression from the state of latent or chronic infection to active viral expression77. Many of the cytokines involved in the homeostatic regulation of the human immune response, such as interleukin-1, interleukin-3, interleukin-6, tumor necrosis factor (TNF)- and TNF- , interferon , granulocyte-macrophage colony-stimulating factor, and macrophage colony-stimulating factor, stimulate HIV replication in cell lines of monocyte-macrophage lineage with chronic infection and in primary infection of cells of the same lineage. In addition, TNF- and TNF- may induce the expression of HIV in T-cell lines with chronic infection. Interferones alfa and beta suppress HIV replication. This activity further destroys the immune system by using latently infected T-cells, macrophages, monocytes and other tissues to further increase viral production. These new virions are then free to infect remaining uninfected CD4 cells, continuing the downward spiral toward complete immune depletion of CD4 cells. Pathogenesis and Natural Course of the Disease

Cytokines in HIV (2) Slide 43 T-helper cells are classified as TH-1 and TH-2 based on the type cytokines they release TH-1 type secrete IL-2 and INF-Alfa, which favor cell-mediated immune response TH-2 type secrete IL-4, IL-5 and IL-10, which favor humoral immune response HIV-infected individuals show decreased TH-1 type response in relation to TH-2 In general HIV-infected persons have marked susceptibility to infections that require cell-mediated immune response compared to those requiring humoral immunity. TH-1 primarily produce cytokines that support the effector functions of the immune system (CTL, NK-cells, macrophages). TH-2 cells predominantly produce cytokines that favor the development of a humoral immune response. Since TH-1 cytokines are critical for the generation of CTLs, an HIV-1-specific TH-1 response is regarded as a protective immune response. Pathogenesis and Natural Course of the Disease

Effect of IL-2 Slide 44 Pathogenesis and Natural Course of the Disease
This diagram shows the effect of a single Cytokine IL-2 on different types of cells. IL-2 is secreted by CD4 T-cells and results in: Proliferation of CD4 T-cells Activation of B-cells for division and antibody production Activation of CD8 T-cells, which proliferate and act as CTLs Change in macrophages to activated forms that produce different cytokines Pathogenesis and Natural Course of the Disease

T-cell Abnormalities Slide 45 Late in the course of illness, there are qualitative and quantitative abnormalities T-cell abnormalities detected in the course of the illness are manifested as CD4 and CD8 abnormalities As the disease progress inexorably toward complete destruction, the CD4 (T-cells) decrease in number, and their quality may also diminish. The CD8 cells are likewise diminished, and the ratio continues its inversion as the disease progresses. A ratio greater than 1 can deteriorate to less than 0.1. Pathogenesis and Natural Course of the Disease

CD4 Cell Abnormalities Slide 46 Defective T-cell cloning and colony-forming efficiency Impaired expression of IL-2 Defective IL-2 and INF-Alfa production Decreased help to B-cells in production of immunogloblins Marked reduction in their number There are naïve CD-4 and CD-4 memory cells based on previous exposure to an antigen. CD-4 memory cells that are latently infected with HIV can live as long as 4 to 7 years. Pathogenesis and Natural Course of the Disease

CD8 Cell Abnormalities Slide 47 Remain high after primary infection and throughout the latent period In advanced stage, there is marked reduction HIV-specific clones of CD8 CTLs that are present in the early phase of illness disappear in advanced period In the face of depleting CD4, the homeostatic mechanism responsible for maintaining total T-cells in a normal range replaces CD8, leading to CD8 lymphocytosis The stimulation of CD8 T-lymphocytes and the formation of antigen-specific cytotoxic T-cells (CTL) depend on the presentation of a peptide together with MHC class I antigens. Pathogenesis and Natural Course of the Disease

Mechanism of CD4 Cell Depletion
Slide 48 HIV-mediated direct cytopathicity (singe cell killing) HIV-mediated syncytia formation Defect in CD4 T-cell regeneration in relation to the rate of destruction Maintenance of homeostasis of total T-lymphocytes (decreased CD4, increased CD8) HIV continues its single-cell invasion and destruction of CD4 cells throughout the course of disease. In advanced disease, however, syncytia-forming HIV develops and speeds up the destruction of CD4 cells. Think of the syncytia-forming virus as “gangs” or groups of HIV virus that “gang up” on the CD4 cells. With this increased assault, the CD4 cells can no longer regenerate fast enough to replace the CD4 cells that are destroyed. As a result, the viral load becomes higher and the CD4 count continues to decline. The balance of the viral set point has been destroyed. Pathogenesis and Natural Course of the Disease

Mechanism of CD4 Cell Depletion (2)
Slide 49 HIV-specific immune response (killing of virally infected and innocent cells) Auto-immune mechanism Programmed cell death (apoptosis) Soluble viral proteins might bind to gp-120 of non-infected cells. The HIV-specific immune response is conducted by HIV-specific CTLs and antibody-dependent cellular cytotoxicity (ADCC). ADCC is mediated by the activity of natural killer cells (NKC). Autoimmunity is directed against gp-120 and gp-41, which share similarity with the MHC class 1 of host cells. Pathogenesis and Natural Course of the Disease

Apoptosis (Programmed Cell Death)
Slide 50 This slide shows apoptosis in HIV Infection. In this model, the cross-linking of CD4 molecules to one another by gp-120 alone or gp-120 in complex with anti-gp120 antibodies provides the first of two signals required for programmed cell death. The second signal is the activation of the cell through the T-cell antigen receptor by either conventional antigen or superantigen. Guisoppe et.al. NEJM 328,1993

B-cell Activity in HIV There is no quantitative abnormality
Slide 51 There is no quantitative abnormality Has abnormal activation with spontaneous proliferation and IG, IL-6 and TNF-Alfa secretion B-cells are defective for antigen stimulation HIV can directly stimulate B-cells leading to hypergammaglobulinemia Cannot mount sufficient humoral immunity to common bacterial antigen The B-cell lymphocytes are not destroyed in HIV disease, and their numbers remain normal. Abnormal activation does occur, however, because of the immune system stimulation. These cells can become defective over time, resulting in hypergammaglobulinemia (may manifest as elevated total protein on SMAC lab tests) or defects in humoral immunity for common bacterial antigens. Pathogenesis and Natural Course of the Disease

Monocyte Macrophage Activity
Slide 52 Circulating monocytes are generally normal in HIV infection Cytopathic effect of HIV to monocyte macrophage is low HIV can intensely replicate in monocyte macrophage cell line There is defective function, like in antigen presentation, chemotaxis, secretion of IL-1 and in induction of T-cell response Although the number of monocytes is usually normal in HIV disease, the monocytes do not destroy HIV, and HIV can replicate in the monocyte macrophage cell line undetected by the immune system. As a result, the macrophage can become depleted in function (though not in number), further compromising the normal immune response. Pathogenesis and Natural Course of the Disease

Humoral Immune Response
Slide 53 Neutralizing antibodies appear following primary viremia with CTLs Antibodies are produced to multiple epitopes of HIV HIV antibodies are used as diagnostic tool Generally their preventive role is unknown The role of antibodies in containing HIV disease is not well established, but they are useful for diagnostic purposes. Antibodies directed against some regions of the envelope of HIV may have a protective function related to their ability to mediate antibody-dependent cellular cytotoxicity after binding to natural killer cells, leading to the killing of HIV-infected cells that express viral-envelope proteins on their surfaces. Antibody appears after the initial infection at 6 to 8 weeks, sometimes earlier sometimes later. It is detected by antibody tests that are used to screen for HIV disease. The tests usually are positive by 6 to 8 weeks after infection, although in rare cases it can be a few weeks longer. Pathogenesis and Natural Course of the Disease

Primary HIV Infection Slide 54 Following primary infection there is initial viremia The phenomena of dissemination of virus to lymphoid organs is the major factor in establishment of chronic and persistent infection Whatever the route of entry the virus, it reaches a lymphoid organ, where it bases itself and replicates extensively Intense replication brings about a burst of viremia which triggers HIV-specific antibody This viremia that occurs at the time of initial infection is the highest viral load during the course of disease. It is at this time that the person might complain of the flu-like symptoms that are the hallmark of acute HIV infection. This viremia stimulates the immune system and causes the person to show HIV antibody, which can usually be detected at 6 to 8 weeks after infection. By this time, infection is already established. Viral replication is already occurring in infected T-cells, T-cells are dying and latent virus is already hidden in the sanctuaries of the lymphoid organs, the central nervous system, and latent CD4 cells. Chronic and persistent infection has been established, and without intervention the patient will die. Pathogenesis and Natural Course of the Disease

Primary HIV Infection (2)
Slide 55 Primary viremia lasts several weeks The set-point (steady state) plasma viremia at six months to one year correlates with disease progression (those with low set point develop advanced disease slowly) It is possible to diagnose HIV infection at this time. In developed countries, and with a high level of skepticism, it is possible to monitor viral load for acute infection and at 6 to 8 weeks to test for serum antibody. In developed countries it also is possible to find the viral set point early in infection in order to predict the rapidity with which the disease will progress. Pathogenesis and Natural Course of the Disease

Pathogenesis of HIV Infection: No Progression with Low-level Viremia
Slide 56 Primary HIV Chronic Non-progressive HIV Infection CD4 RNA Set Point ~ 103 RNA This graph illustrates the course of disease that can be expected in a long-term non-progressor. This HIV-infected patient shows a normal (or fairly normal) CD4 count that does not decrease over years, and a low viral set point that allows for the replacement of the CD4 cells that are killed on a daily basis by a low number of HIV virions. This kind of low-level progression can go on for more than 10 years. There may be genetic, immune system or viral factors that allow for this benign course in an individual. Pathogenesis and Natural Course of the Disease

Pathogenesis: Average Progression with Median-Level Viremia
Slide 57 Primary HIV Slowly Progressive HIV AIDS RNA Set Point ~104 RNA CD4 This graph shows the course of the disease in an average progressor. Note the burst of viremia with flu-like symptoms and the decrease in CD4 cells. The viral set point is established at a moderate level and increases gradually over years. The CD4 count remains steady for a few years, but gradually decreases to zero, leaving the host vulnerable to all kinds of opportunistic infections. Symptoms occur with increased frequency as the CD4 count drops below 200. 1 5 10 Years Pathogenesis and Natural Course of the Disease

Pathogenesis: Rapid Progression with High-Level Viremia
Slide 58 Primary HIV AIDS RNA RNA Set Point ~ 106 This abbreviated graph illustrates the course of disease in a rapid progressor. In this case, the CD4 count takes a deep fall at the initial viremic burst. The CD4 count recovers briefly only to fall precipitously as the high viral set point takes its toll. Note that in this case the viremic set point is extremely high and never decreases. This puts more pressure on the immune system than it can handle, resulting in a rapid progression of disease. There is a very short symptom-free period before end-stage symptoms and death occur. Rapid progression may be due to clade C, the host immune system, genetics, or other factors. CD4 2 3 Years Pathogenesis and Natural Course of the Disease

HIV RNA Levels Predict Progression to AIDS
Slide 59 HIV RNA viral loads after infection can be used to assess the viral set point and to predict the likelihood of progression to AIDS in the next 5 years. The higher the viral set point the more rapid the CD4 count fall and the more rapid the disease progression to AIDS. With levels between 1,000 and 10,000 viral copies, the likelihood of AIDS in 5 years is 8%. At 10,000 to approximately 50,000, the likelihood is 26%. At 50,000 to <100,000 it is 49%. Between 100,000 to <1,000,000 the likelihood is 62% at 5 years. Pathogenesis and Natural Course of the Disease

Relating Disease Progression to Plasma HIV-1 RNA Level and CD4 Cell Count
Slide 60 Viral Load 1,000 100 10,000 200 100,000 300 Information available to date suggests that CD4 cell counts are useful as an indicator of current immunologic status and for determining when opportunistic infection prophylaxis should be initiated. However, CD4 cell counts are less useful as prognostic markers of future clinical progression in healthy patients. Plasma HIV-1 RNA level provides information about the speed of disease progression and how actively the virus is replicating. Together, these measures can be used to determine when to start therapy, whether or not treatment is effective and when to change therapy. The CD4 count also predicts when people will develop opportunistic conditions that can be fatal if not diagnosed and treated early. 400 1000 900 800 700 600 500 CD4 COUNT + Adapted with permission from Coffin. AIDS. 1996;10(suppl 3):S75-S84. Pathogenesis and Natural Course of the Disease

Chronic and Persistent Infection
Slide 61 HIV-specific antibody partially clears the virus There is clinical latency Initial clones of CD8 lymphocytes CTLs, which partially control viremia, are later lost There is progressive drop in CD4 T-cells Early in the establishment of HIV disease, the HIV-specific antibody is able to partially clear the virus. During this time, there is an asymptomatic period. The CD8 lymphocytes also are able to assist in the control of the viremia. Over time, however, these defenses are lost and there is a progressive loss of CD4 cells as the viremia persists. This stage of disease can be long (long-term non-progressor) or short (rapid progressor) and depends on the viral set point or viral load. Without treatment (ARV), the patient will progress to advanced disease and immune system failure and death. Pathogenesis and Natural Course of the Disease

Advanced HIV Disease Slide 62 CD4 cells fall below critical level: <200cells/ml Patients present with OIs or malignancy Higher degree of viremia due to destruction of lymphoid organs Advanced disease represents the final stages of immune destruction. This stage of the disease lasts months to years and, if untreated, results in death. Pathogenesis and Natural Course of the Disease

Natural History of HIV Disease from HIV Transmission to Death (no ARV)
Slide 63 The initial event after infection with HIV is acute retroviral syndrome, which is accompanied by a precipitous decline in CD4 cell counts (closed squares), high plasma viremia (closed circles), and high concentrations of HIV RNA in plasma (closed triangles). Clinical recovery is accompanied by a reduction in plasma viremia, reflecting development of cytotoxic T-cell (CTL) response. The CD4 cell count gradually declines over several years, with a more accelerated decline 1.5 to 2 years before an AIDS-defining diagnosis. HIV RNA concentrations in plasma show an initial “burst” during acute infection and then decline to a “set point” as a result of seroconversion and development of an immune response. The viral load correlates with the rate of CD4 decline (4 percent decline/yr/log10/copies/ml). With continued infection, HIV RNA levels gradually increase. Late-stage disease is characterized by a CD4 count <200 cells/mm3 and the development of opportunistic infections, selected tumors, wasting, and neurological complications. In an untreated patient, the median survival after the CD4 count has fallen to <200 cells/mm3 is 3.7 years; the median CD4 count at the time of the first AIDS-defining complication is cells/mm3; the median survival after an AIDS-defining complication is 1.3 years. Source: Fauci AS, Pantaleo G, Stanley, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med 1996;124: Galens Curriculum, Module 8, p. 17. Fauci AS, Pantaleo G, Stanley, Weissman D. Immunopathogenic mechanisms of HIV infection. Ann Intern Med 1996;124:

Window Period: Untreated Clinical Course
Slide 64 antibody Primary HIV infection Acute HIV syndrome Asymptomatic viremia PCR P24 ELISA The window period begins at the time of infection and can last 4 to 8 weeks. During this period, a person is infected, infectious and viremic, with a high viral load and a negative HIV antibody test. The point when the HIV antibody test becomes positive is called the point of seroconversion. Source of graph: S Conway and J.G Bartlett, 2003 Time from a to b is the window period a b 2 3 4 Weeks since infection years Source: S Conway and J.G Bartlett, 2003 Pathogenesis and Natural Course of the Disease

Laboratory Markers of HIV Infection – Immune Suppression
Slide 65 Markers of immunologic damage by HIV: subsets of T-lymphocytes Functional surface proteins (CD4 and CD8) used to count Normal Values Helper / CD4 + cell count = Suppressor/ CD8 + cell count = CD4 counts or lymphocyte subsets can be used to assess the status of the immune system. In particular the CD4 count can be used to assess the need to start ARV, opportunistic infection prophylaxis and to assess the success of ARV. It has become a very important tool in the successful treatment and staging of HIV disease. Pathogenesis and Natural Course of the Disease

Key Points HIV infection is a chronic disease
Slide 66 HIV infection is a chronic disease The immune system is the target of HIV Clinically there are different stages based on immunocompetence During clinical latency, there is no virological latency Step 4 Key Points (Slide ) – 5 minutes Summarize the presentation, review Key Points covered in the unit, and answer final questions. Pathogenesis and Natural Course of the Disease

Key Points (2) Slide 67 The effect of immune system delays the onset of clinical disease HIV can be suppressed, but there is no cure Ultimately the immune system is destroyed, with a few exceptions Pathogenesis and Natural Course of the Disease

Slide 1 HIV Pathogenesis and Natural Course of the Disease Unit 4 HIV Care and ART: A Course for Physicians Unit 4 should take approximately 2 hours.

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Slide 1 HIV Pathogenesis and Natural Course of the Disease Unit 4 HIV Care and ART: A Course for Physicians Unit 4 should take approximately 2 hours.

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Presentation on theme: "Slide 1 HIV Pathogenesis and Natural Course of the Disease Unit 4 HIV Care and ART: A Course for Physicians Unit 4 should take approximately 2 hours."— Presentation transcript:

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