1. Antigen Processing and Presentation Ag processing: degradation of proteins into peptides Ag presentation: binding of peptide by MHC molecule and displaying the complex on the cell surface Cytosolic (endogenous) pathway Endocytic (exogenous) pathway Class IClass II 11 22 33 2m2m 11 22 11 22

3. Two compartments of the cell Extracellular pathogens Endocytic vesicles (exogenous) Class II CD4 T cells Degraded in Peptides bind to Presented to Intracellular pathogens Cytosol (endogenous) Class I CD8 T cells Cytosol: continuous with nucleus Vesicular system (ER, golgi, endosomes, lysosomes): continuous with extracellular fluid

5. nucleusER Cytosolic pathway 1. Site of peptide generation 2. Site of membrane protein synthesis 3.Transport of peptides into ER 4.Loading of peptide onto nascent class I molecules in ER 5.Display the complex on the cell surface Golgivesicle Plasma membrane

6. Cytosolic pathway nucleusERGolgivesicle Plasma membrane

7. Pathogen exploitation nucleusERGolgivesicle Plasma membrane Human Cytomegalovirus (HCMV): US2 and US11 bind and remove nascent class I  chain from ER US18 mimics HLA-E X US3 prevents class I from egress from ER US6 blocks TAP

9. Endocytic pathway 1.Site of peptide generation 2.Site of MHC class II synthesis 3.Loading of peptide into class II molecules 4.Surface expression Plasma membrane Y Y Y Y

10. Endocytic pathway Y Y Y Plasma membrane Y

11. Influenza A Virus Segmented RNA virus 8 RNAs 10 proteins 15 HA 8 NA H5N1

12. vRNA (-)Virion cRNA (+) mRNA (+) protein Virion RNA Complementary RNA Messenger RNA RNA pol RNA polymerase No proof-reading No repair High mutation rate 1.5 x 10 -5 /nt/cycle Antigenic Drift: a series of mutations that occur over time and cause a gradual evolution of the virus Seasonal Influenza Epidemics

13. HA and NA are highly variable

14. Antigenic Shift: an abrupt change in the HA and/or the NA proteins resulting in a new subtype of the virus Influenza Pandemics Cell Co-infection Reassortment

16. Interferons inhibit protein synthesis and therefore virus replication

17. CD8CD4BClearance (days)% Survival Role of T and B cells in responses to influenza virus infection +++7-10100 -++10-14100 +-+10-1490 ++-10-1435-85 --+>200 -+->200 +-->1420 --->200

18. Host-Influenza Virus Interaction HostInfluenza virus 5’ triphosphate5’ cap TLR7, RIG-IdsRNA, NS1 APOBEC NK cells AntibodyHA and NA (antigenic shift) CTLEpitope change (antigenic drift)

19. Principles of adaptive immunity TCR recognition Antigen presentation and processing Host defense against viruses