Bi1_2009_Final_Review_full - • • • • • • •...

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Unformatted text preview: • • • • • • • – – – • 5’-ATGGGCTACGAAATTTCGAAACGGT-3’ 3’-GCCA-5’ 5’-ATGG-3’ 3’-TACCCGATGCTTTAAAGCTTTGCCA-5’ • • – – • • – – – – – • • • • – – • • • – – • – – • • • • • • • • • • • – – • D’Souza & Summers, 2005, Nature Reviews 3: 643-655 • – – • – – • – – – – – • – – • • • • • • • – – – • • • • • • • • • • Cellular Kills cells directly without using antibodies Infected cells will display viral peptides on MHC I Macrophages, Natural Killer cells, and Cytotoxic/Killer T cells (T cells with CD8) will recognize foreign peptides on MHC I and kill the infected cells directly Intracellular pathogens – Fights off infected “self”-cells. I.e. cells infected with virus, intracellular bacteria, cancer, or against small pathogens Humoral Use antibodies and the complement system to eliminate the pathogen Antigen presenting cells will digest foreign cells and present peptides on MHC II Helper T cells (T cells with CD4) will recognize foreign peptides on MHC II and activate B cells to make antibodies against the pathogen Extracellular pathogens – Fights off invading foreign cells like bacterial infections as well as some viruses (especially membrane bound viruses) • • • • • • • • • • • • • • • • • • • • • – – • • • • • • • • – – – • • • • • • • – – 3 • – – • – • • • – – – • – • – • – • – • • • – – • • – – • – – VACCINES Yvonne Pao Branches of Immune Response • Cellular • Directly kills infected cells without antibodies Uses antibodies and the complement system to eliminate the pathogen • Humoral • Cellular Humoral Infected cells display viral peptides Antigen presenting cells (APC’s) on MHC class I molecules digest foreign cells and present peptides on MHC class II molecules Macrophages, natural killer cells, and cytotoxic/killer T cells (CD8+ T cells) recognize foreign peptides on MHC I and kills infected cells directly Helper T cells (CD4+ T cells) recognize foreign peptides on MHC II and activate B cells to make antibodies against pathogen Targets extracellular pathogens: Targets intracellular pathogens: Fights off invading foreign cells Fights off infected “self”-cells (bacterial infections and some (i.e., cells infected with virus, viruses, especially membraneintracellular bacteria, cancer, or bound viruses) small pathogens) Types of Vaccines Whole-killed virus vaccines • Live-attenuated virus vaccines • Whole-killed virus vaccines Method Inject an inactivated virus Live-attenuated virus vaccines Inject an active virus that is not as strong as the dangerous virus MHC The inactivated virus will not infect the cell so it cannot be displayed on MHC I but will be displayed on MHC II MHC II presentation induces antibody production, leading to humoral immunity (antibodies only) The active virus infects the cell and will be displayed on both MHC I and MHC II Immunity MHC I and II induce cellular and humoral immunity (antibodies + CTL activation) Polio Vaccines Polio epidemics in 1950s affected >50,000 people in the U.S. Polio Vaccines Salk Vaccine Whole-killed virus Prevented spread of virus to the nervous system but allowed infection of gastrointestinal tract Sabin Vaccine Live-attenuated virus Eradicated polio virus completely Conclusion: Humoral immunity was insufficient to completely eradicate polio. Both cellular and humoral immunity were required. Flu Vaccines The World Health organization annually specifies the contents of the vaccine that contain the most likely strains of viruses that will attack the next year. Recap: Influenza Infection 1. HA binds sialic acid on host glycoproteins Virus is internalized into acidic endosomes Low pH triggers conformational change in HA Fusion of viral and endosomal membranes then occurs 2. 3. 4. Recap: Hemagglutinin fusion 1. 2. 3. HA1 binds to sialic acid on the host membrane Low pH induces a conformational change that exposes the fusion peptide attached to HA2 HA2 mediates fusion of the viral and host membranes Recap: Neuraminidase Cleaves sialic acid to allow newly formed influenza viral envelope to bud from host cell Recap: Influenza Two surface glycoproteins: Neuraminidase (N) 9 possible subtypes Hemagglutinin (H or HA) 15 or more possible H subtypes (not to be confused with the types of hemagglutinin HA1 and HA2) Multiple subtypes leads to antigenic drift and antigenic shift If we make a vaccine against one type of influenza (e.g., H1N1), antigenic drift/shift can cause the influenza to mutate to a different type, thus rendering the vaccine ineffective towards the new strain. HIV Vaccine Anti-retroviral therapy has not eradicated HIV and is expensive, complex, and has some serious side effects. Why isn’t there a HIV vaccine yet? Problems Safety Logistics Whole-killed virus Is the virus really dead? There are many different strains of HIV, so killed versions of all of these would need to be injected. Live-attenuated virus Obvious safety concerns. Cannot be tested in humans. A vaccine against one strain of SIV worked, but did not protect against other strains. Mutation rate As HIV mutates, new vaccines must be made to keep up with HIV’s antigenic drift. Other Problems HIV rapidly mutates, quickly rendering antibodies ineffective HIV’s spike protein (gp160) are heavily glycosylated which are poorly or non-immunogenic Antibodies are too large to access some regions of spike proteins (gp160) Possible DNA Vaccine? DNA vaccine: Inject DNA coding for HIV protein Transient expression of HIV proteins will lead to presentation by MHC class I molecules to activate CTL’s Problem: Cannot prevent infection—CTL’s only kill cells already infected with HIV Benefit: If DNA vaccine could elicit a strong anti-HIV CTL response, it could potentially eliminate virally-infected cells and reduce viral load. Broadly Neutralizing Antibodies to HIV Recall from your homework that several “broadly” neutralizing antibodies (NAb’s) have been isolated e.g., 4E10, 2F5, etc. Can we reprogram a human immune system to make broadly neutralizing anti-HIV reagents? Possible HIV Gene Therapies Use retroviral or lentiviral vectors containing gene for NAb to infect cells. Infected cells will transcribe the gene and produce the NAb. Zinc finger endonuclease-mediated gene targeting uses the cell’s homology-directed gene-editing process rather than gene addition. Recall that zinc fingers are small protein domains that coordinate 1 or more zinc ions to stabilize folds Zinc fingers can be engineered to target desired DNA sequences, enabling nucleases to target a unique sequence within a complex genome Possible HIV Therapies ...
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