week 7 and 8 Flashcards
evasion of the immune system, general
large DNA viruses in particular have many strategies for immune evasion. these include HSV, chickenpox, cytomegalovirus (CMV)and epstein barr (EBV), also poxviruses. they employ two strategies to evade the immune system, for one by not being recognized and also by interfering with the function of particular immune mechanims.
general mechanisms that the viruses employ to evade the immune system
- latency
- antigenic variation in epitopes
- blocking priming of dendritic cell by t cell by mechanisms: blocking TLR signalling, DC maturation and interaction with naive t cells
- decreased production of MHC class 1
- cytokine receptor homolouges
etc.
persistant infections
the most common example is latency were the virus evades detections because the viral genome is repressed. there are almost no viral proteins for the cell or immune system to react to. other ways for a virus to remain persistant chronic infection caused by hep B or C. they remain chronic because they cause immune exhasion by production of decoy antigens. HPV also delays or avoids immune response because of non-cytopathic infection of inaccessible site.
neutralizing antibodies and evasion
when b cells encounter an antigen they become activated and differentiate to plasma cells. these plasma cells secrete a high quantity of this specific antibody. these antibodies will then move around freely in the blood and tissues and bind to the pathogen. they are our biggest defence against virus infection and the epitopes they bind usually has a function in entry of the host cell, which binding can inhibit. they can also induce aggregation and immune clearence. this is evaded by antigenic drift which is the genetic drift on viruses to change their epitopes by mistakes produced by rdrp. antigenic drift can either occur on a population (influenza) or single patient scale (HIV)
evasion of t cells
t cells have a unique receptor (TCR) that recognizes antigens that are presented on the surface of APC cells using MHC molecules. when a t cell binds antigen it undergoes clonal expansion. antigenic drift can result in changes of the anhor residues so the antigen can no longer bind well to the MHC or to the TCR. in HCV, mutations in the TCR ocntacts residues have been described.
inhibition of t cell priming by dendritic cells
dendritic cells are APCs that present antigens to t cells causing them to undergo clonal expansion and differentiation upton binding to t cell receptor. viruses can inhibit the maturation of dendritic cells. DC relies on PPR such as TLRs to recognize viral components and initate maturation. viruses can block the signal transduction of PRRs. HSV blocks signal transduciton in immature DC and vaccinia virus encodes a homolouge of TLR4 that does not cause response. vaccinia and HCV blocks cytokine induced maturation
evasion of CD8 t cell recognition, how iit works and what methods different viruses employ
some viral proteins in the cytoplasm will be degradeed by the proteosome. the peptides will then be transported back to the ER via TAP complex. will then be transported via golgi to plasma membrane where the epitope is shown to t cells. will activate killing of the cell. many steps where virus can intervene. for example,
- CMV protein US6 binds to luminal side of TAP transporter and prevents peptide translocation to ER.
- HSV protein ICP47 binds to cytosolic side of TAP transporter and prevents peptie translocation to ER.
- adenovirus E3 binds MHC peptide complex and retains it in the ER so it wont be inserted in the plasma membrane.
- HIV and RV decreases transcription of MHC class 1
- epstein barr in latent cells evades proteosome degradation so viral components cant be presented on MHC.
evasion of natural killer cell recognition
NK cell activity is controlled by a balance of stimulatory and inhibitory signals. NK cells detects the level of MHC molecules and i MHC is not presented the cell is killed. so viruses that evade t cells by inhibiting insertion of MHC molecules may become more suceptible to NK killing.
NKG2D is a ligand that is expressed on cell surface if the cell is stressed or infected which causes the cell killing by NK. CMV encodes a protein m152 which retains the NKG2D ligand in the ER. CMV also encode a MHC1- like molecule that is presented on cell surface and delivers a negative (inhibitory) signal to NK cell to evade killing.
interfering with cytokine function
- poxviruses encode homolouges of cytokine receptors that does not cause response in cells
- epstein barr encodes a IL-10 homolouge which is a cytokine that repress the t cell response and redirects it to other places.
- intracellular blocking of cytokine synthesis: pox encodes crmA protein which inhibits the cleavege of IL-1beta precursor
- intracellular interference with cytokine function: adenovirus encode proteins that interfere with pathway of TNF alpha mediated killing of the cell. tnf alpha is a proinflammatory cytokine and also induce antiviral effects when it binds to its receptor on infected cells and cause apoptosis.
modulation of apoptosis
many viruses needs to inhibit apoptosis to complete replication but some induce apoptosis in the late stages to release virions. the cell
modulation of autophagy
autophagy is a process where cells degrade organelles or proteins by forming a double membrane autophagosome containing the material and fusing with a lusosome to degrade. it has antiviral functions to degrade viral components or virions. some viruses encode proteins to block autophagy and some viruses utilize components of this machinery for their replication or non-lytic cellular release.
evasion of the complement system
the complemeent system is part of the bodies innate immune defence. it consists of a group of proteins found in blood or tissue that can promote inflammation by attracting other immune cells or directly kill pathogens. the complement pathways (classical, lectin and alternative) are normally carefully controlled by control proteins that can stop the complement cascade by binding to complement rpoteins. pox and herpes encode proteins that are homologes of control proteins to stop immune activation.
herpes general
“battleship” of viruses bc encodes many proteins. there are 8 types in humans, all establishing life long latency. shows periodic reactivation, normally following immunosuppression. has a linear dsDNA
herpes subtypes and site of latency
- alpha: HSV 1 and 2 and varicella zoster virus that cause chickenpox and shingles. is latent in neurons.
- beta: cytomegalovirus (CMV) and human herpesvirus 6 that seems to form latency in monocytes or secretory glands.
- gamma: epstein-barr and kaposi sarcoma virus. latent in lymphocytes
herpes genes
- early genes: made before DNA replication. involves encymes such as HSV thymidine kinase that is a drug target, regulatory genes that interfere with host gene expression.
- structural genes: made after replication
- limited gene expression during latency, produces some latency-associated transcripts (LATs). Epstein barr is latent in lymphocytes whihc divides and therefore the virus needs to replicate when latent compared to HSV that are latent in neurons which generally dont divide.
