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Transcript
The branch that breaks Is called rotten, but Wasn’t there snow on it? Bartolt Brecht Haiti after a hurricane Your body has evolved complex mechanisms of recognizing “non-self” and fighting against it The Immune System is the Third Line of Defense Against Infection Antibodies are Produced by B Lymphocytes (B cells to their friends) T Lymphocytes (T cells) provide “cell based” immunity Overview of Human Immunity: Adaptive and Innate Lymphocyte Origins 16-22 Let’s start with the role of B cells and antibodies in the immune response Some definitions are in order Antigen A substance produced by a pathogen (e.g., protein, complex sugar) capable of producing an immune response Some definitions are in order Antibodies Protein molecules (immunoglobulins) produced by B lymphocytes to help eliminate an antigen B cells Make Antibodies In response to antigens Molecular Biology of the Cell Alberts et al These antibodies can bind to and “neutralize” Viruses or can direct immune attack of virus-infected cells Molecular Biology of the Cell Alberts et al Antibodies can also direct phagocytosis of pathogens Molecular Biology of the Cell Alberts et al Cytotoxic (Killer) T Cells Recognize, Attack and Kill Virus-Infected Cells CELLS alive! Let’s focus first on antibodies Molecular Biology of the Cell Alberts et al Antibodies are proteins that have evolved to recognize molecules from pathogens Molecular Biology of the Cell Alberts et al These molecules from pathogens are called Antigens The variable and constant regions of antibodies are related = Ig domains Molecular Biology of the Cell Alberts et al Let’s use as an example an antibody that recognizes a protein on the surface of flu (influenza) virus Antigen Binding Region Hypervariable Region Heavy Chain Light Chain Constant Region courses.washington.edu/medch401/pdf_text/401_07_lect2.ppt Here is the antibody Bound to the “antigen” = influenza hemagglutinin Hemagglutinin Human antibody The antibody recognizes the antigen by a lock-and-key fit Rotate ~90 Add all atoms This interaction is VERY specific Antigen residues at the interface = epitope Epitopes are typically ~5 residues long This interaction is VERY specific hemagglutinin antibody Space-filling mode Grey now = mainchain of hemagglutinin Epitopes reside in turns and loops You can generate antibodies against HIV like you do against other viruses Given thousands of pathogens each of which is constantly evolving how do we generate antibodies against each? Molecular Biology of the Cell Alberts et al We cannot dedicate all 25,000 genes in the genome just to make antibodies. What’s the solution? Molecular Biology of the Cell Alberts et al We cannot dedicate all 25,000 genes in the genome just to make antibodies. What’s the solution? Put antibodies together by a mix-and match approach! Molecular Biology of the Cell Alberts et al requires rearranging the DNA Molecular Biology of the Cell Alberts et al requires rearranging the DNA Molecular Biology of the Cell Alberts et al The result: an antibody light chain Molecular Biology of the Cell Alberts et al Since there are multiple types of each gene segment, there are thousands of possible V-D-J combinations Each B cell gets a unique combination Since there are multiple types of each gene segment, there are thousands of possible V-D-J combinations Each B cell gets a unique combination Other mechanisms further increase antibody diversity Molecular Biology of the Cell Alberts et al When a pathogen enters the body it stimulates proliferation of the specific B Cells that recognize its Antigens Once you are exposed to an antigen your B cells “remember” this OK, that explains antibodies and B cells but what about us? CELLS alive! T cells carry antibody-related proteins on their plasma membranes called T cell receptors Molecular Biology of the Cell Alberts et al T cell receptors are also assembled by gene rearrangement, creating great diversity Molecular Biology of the Cell Alberts et al However, T cell receptors (unlike antibodies) cannot recognize antigens from pathogens all by themselves!! T Cells Only Recognize Antigen when it is presented by another cell Antigen presentation is done by another family of proteins called MHC proteins Viral or bacterial proteins are digested by Cellular proteases inside the cell and pieces of them bind the MHC proteins Molecular Biology of the Cell Alberts et al This allows T cells to recognize HIV infected cells, for example, and even internal proteins like reverse transcriptase can serve as antigens Molecular Biology of the Cell Alberts et al Here is where our old friend CD4 comes into the picture Molecular Biology of the Cell Alberts et al Let’s come back to the immune response to HIV People initially mount a strong immune response However, this response ultimately fails for five reasons However, this response ultimately fails for five reasons Integration and latency Destruction of CD4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC We already discussed two of these Integration and latency Destruction of CD4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC First, the ability to integrate into the host genome allows HIV to lurk undetected Second, by killing CD4+ Helper T Cells HIV ultimately disables both antibody production and Killer T cells What about the other three means HIV uses for immune evasion? Integration and latency Destruction of CD4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC One way HIV “hides” is by hiding its most “antigenic” regions Integration and latency Destruction of CD4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC Most antibodies against the virus do not block viral entry Why not? Regions of gp120 and gp41 key for viral entry are hidden until after the shape change we discussed Natural selection also shapes the sequence of viral proteins Integration and latency Destruction of CD4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC Remember that while reverse transcriptase is an amazing Enzyme, there was something it lacks—which was…. Remember that while reverse transcriptase is an amazing Enzyme, there was something it lacks—which was…. This has major consequences RT makes 1 error /10,000 bp =1 error per replicated genome And since the viral generation time Is 2.5 days and one infected cell produces ~1010–1012 new VIRIONS each day….. Do the numbers! Do the numbers! Given that billions of cells are infected per day There will be thousands of copies of EVERY possible mutation Present in the gene pool!! Recombination adds to the amount of variation Many cells are co-infected by two or more viral variants and RT can switch between viral templates when copying the genome Remember these sequence based “trees” we used to study the evolution of different HIV and SIV strains? We can use the same approach to study the evolution of a single virus after it infects a single person HIV rapidly evolves into different “strains” after the initial infection Viral diversity in 9 AIDS patients How could That happen? Can you say Natural selection? We start with the tremendous amount Of viral variation caused by RT errors + Now we add the selective pressure Exerted by the immune response In response to antibody selection Viruses with mutations in gp120 and gp41 accumulate T cell selection selects for changes in peptide “epitopes” so they no longer bind to MHC proteins The result: despite high levels of anti-HIV antibodies viral variants escape from the immune response HIV also has another trick Integration and latency Destruction of CD4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC Remember our discussion of Long-term non-progressors: Some are infected with a mutant HIV virus lacking the accessory gene Nef What does Nef do? Nef prevents infected cells from putting MHC proteins on their cell surface! Without MHC proteins infected cells become Invisible to T cells HIV has even one more trick Integration and latency Destruction of CD4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC Blocking Cytosine Deamination Cytosine Deamination Causes Mutations Dr. Weiguo Cao website, Clemson U. APOBEC3G is a Cytosine Deaminase Present in Resting T cells, which HIV doesn’t infect well APOBEC3G APOBEC3G is incorporated into HIV virions and inhibits viral replication by inducing hypermutation Dr. Warner Greene's laboratory at the Gladstone Institute of Virology and Immunology The viral accessory protein vif blocks APOBEC3G function Vif blocks APOBEC3G incorporation into virions and targets it for proteolytic destruction This formidable array of defense mechanisms Allows HIV to avoid being suppressed by our immune system Integration and latency Destruction of CD4+ T cells Inaccessible epitopes Antigenic escape Downregulating MHC Blocking Cytosine Deamination