HIV Immunopathogenesis Modeling the Immune System May 2, 2007
Question 1 : Explain how HIV infects the host Zafer Iscan Yuanjian Wang Zufferey Abhishek Garg
How does HIV infect the host? HIV infection occurs by transmission of the virus to an uninfected individual by contact with blood or bodily fluids, sexual contact through breast milk
HIV PRESENTATION HIV STRUCTURE
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.
Which viral structures allow entry of HIV into lymphocytes?
Which cells are targeted by HIV and what mediates cell tropism (selectivity)? HIV mainly infects hematopoietic cells that express CD4 and either CCR5 or CXCR4. - T-helper lymphocytes, - macrophages - dendritic cells. Predominantly CD4T Kinetics of HIV infection differs between the different cell types. CD4+ first, followed by CD8+ and CD4+CD8+ thymocytes
Which cell components mediate entry of the virus? The major co-receptors required for entry of HIV- 1 are; - CCR-5 - CXCR-4 In macrophages and in some other cells lacking CD4 receptors, such as fibroblasts, an Fc receptor site or complement receptor site may be used instead for entry of HIV.
How does HIV replicate in the infected cell? Reverse Transcription and Integration Transcription and Translation Assembly, Budding and Maturation
Reverse Transcription and Integration www.thebody.com HIV enzyme reverse transcriptase converts the viral RNA into DNA. This DNA is transported to the cell's nucleus, where it is spliced into the human DNA by the HIV enzyme integrase. Once integrated, the HIV DNA is known as provirus.
Transcription and Translation When the cell becomes activated, it treats HIV genes in much the same way as human genes. First it converts them into messenger RNA (using human enzymes). Then the messenger RNA is transported outside the nucleus, Used as a blueprint for producing new HIV proteins and enzymes. www.thebody.com
Assembly, Budding and Maturation Copies of HIV genetic material gather together with newly made HIV proteins and enzymes to form new viral particles, which are then released from the cell. The enzyme protease plays a vital role at this stage of the HIV life cycle by chopping up long strands of protein into smaller pieces, which are used to construct mature viral cores. The newly matured HIV particles are ready to infect another cell and begin the replication process all over again. www.thebody.com
Which processes drives the natural history of HIV infection? Antigen-driven T cell activation is the principal driving process determining the natural history of HIV infection. HIV enters through a defect or site of inflammation in a mucous membrane and is bound by dendritic or Langerhans cells. Dendritic cells then carry HIV to a lymphoid organ and migrate to the paracortical region, which is rich in CD4+ T cells. These CD4+ T cells are activated by the dendritic cells and are exposed to bound HIV, which leads to their productive infection and to subsequent wide dissemination of virus. Dendritic cells probably also interact with CD8+ T cells in lymphoid organs and initiate an immune response that partially but not completely controls HIV replication.
Question 2 : Explain how the host controls the HIV infection Kremena Diatchka Guillaume Bonnier
Which arms of the adaptive immune system control the infection? 2 forms of response: The humoral response refers to antibody production and activity The cellular response refers to the activity of the CD4+ and CD8+ T-cells (helper and cytotoxic T cells)
How do antibodies work? Antibodies are produced by B cells. TI (Thymus independant) B cells give rise to low-affinity antibody-secreting plasma cells and are not associated with memory cell generation. TD (Thymus dependant) B cells are activated by CD4 T cells and give rise to high-affnity antibody-secreting plasma cells and are associated with memory cell generation.
How do antibodies work? Antibody structure : Heavy chains and light chains. The Fc region (Fragment, crystallizable), binds to various cell receptors and complement proteins. The Fab region (Fragment, antigen binding site).
How do antibodies work? Antibody functions : Agglutination of antibody-antigen products primed for phagocytosis Block viral receptors : Antibodies that recognize viruses can block these by binding them directly. In doing so, the virus will be unable to dock to its preferred receptor on a host cell in order to infect it Stimulate other immune responses, such as the complement pathway
Part 3a: How do CTLs work? Mechanisms by which CTL cells kill target cells Granule exocytosis pathway FasL/Fal pathway Highlight CTL functions which may require presence of CD4 cells
Differentiation of activated T cells
Differentiation of CD8 T cells into CTL Priming of naïve CD8+ T cells may require the presence of Th1 cells Role of Th1 cells in generation of CTLs is not fully understood
CD8 T cell effector functions Effector CD8+ T cells don t produce IL-2 Dependent on the IL-2 produced from CD4+ T cells for further proliferation Duration of cytolytic effect May not be long enough for virus to be cleared completely May be the reason why CTLs can t clear HIV
Part 3b: Why does HIV infect predominantly CD4 T cells? CD4 cells have receptor which interacts with gp120 Other cell surface receptors mannose binding protein on macrophages DC-SIGN on dendritic cells also interact with gp120 on virus particles but do not actively promote fusion and virus entry
Part 4: Why is the immune system inefficient at controlling the infection? Virus replicates persistently Chronic activation of immune system CD4 cells cannot handle continuous T cell turnover CD4 cell population depleted Both cellular and humoral responses depend to some extent on CD4 cells Response becomes ineffective
Question 3 : Explain how HIV induces a CTL response Christopher Burger Alexei Kounine
What is T cell activation? Antigen-presenting cells (APCs) meet T cells in secondary lymphoid organs Activation precedes differentiation into either CTL (cytotoxic T cells) or CD4+ helper cells Signal 1: ligation of the TCR with the MHC/peptide complex of the APC Signal 2: High-affinity IL-2 receptor on the CD8, proliferation in response to its own IL-2.
How do CD8 T cells recognize their cognate antigen? Cognate antigen: antigen the CTL recognizes Where? Anywhere (involves migration) Lymph nodes (main infection sites) How? Antigen-specific TCR of the CTL binds to the peptide/mhc-1 complex (several tests before finding the correct antigen)
Why does T cell activation enhance viral replication? T cell activation precedes T cell differentiation into CD4+ and CD8+ cells. HIV mostly infects CD4+ cells (not naïve T cells).
How is T cell memory induced? Superiority of memory T cells: increased responsiveness to antigen respond to lower concentrations of antigen encountered for shorter periods less dependent on co-stimulatory signals than naive T cells rest in G1 rather than the G0 phase of the cell cycle allowing more rapid cell division (suggested) Th1 can improve CTL memory functions T cells are able to respond to a wider range of antigen presenting cells than naive cells, and can be activated outside lymphoid tissues. 3 suggested pathways for memory cells creation
What are the mechanisms of cell death in HIV infected lymphocytes? 3 different ways for killing cells: Direct viral killing of infected cells Increased rates of apoptosis in infected cells Killing of infected CD4+T cells by CD8 cytotoxic lymphocytes that recognize infected cells
Why does HIV deplete the pool of CD4T cells? How does it happen? CD4+ T cells are infected primarily CTL response to infection: killing CD4+ T cells (sort of autoimmunity) The pool of CD4+ cells is depleted, the body produces more T cells, which will differentiate into CTLs and CD4+ cells. Increase of the number of CTLs How can it contribute to virus progression? Lack of Th1 can lead to a lack of CTL memory functions Any other ideas?
Contributors Kremena Diatchka Alexei Kounine Christopher Burger Guillaume Bonnier Yuanjian Wang Zufferey Abhishek Garg Zafer Iscan