L14- Immune Response to Viruses

Question 1

How does Human papilloma virus infect cells?

Answer 1

Infect epithelial cells though microabrasions (or other epithelial trauma) causing genital warts and/or cancerous lesions

Question 2

How is human papilloma virus spread?

Answer 2

Spread by direct contact and by autoinoculation via scratching

Question 3

What is the main interferon responses to viruses?

Answer 3

Induce resistance to viral replication in all cells

Increase expression of ligands for receptors on NK cells

Activate NK cells to kill virus-infected cells

Question 4

Which cells produce interferon?

Answer 4

Type I IFN can be produced by most cell types in response to stimulation of an array of transmembrane or cytosolic receptors

Question 5

What distinct RNA ligand based on sequence composition does RIG-1 bind to?

Answer 5

preferentially binds to ssRNA containing a terminal 5′ triphosphate and short dsRNA motifs.

Question 6

What distinct RNA ligand based on sequence composition does MDA-5 bind to?

Answer 6

Detects long dsRNA segments.

Question 7

Negative-sense RNA viruses (measles, rabies, Ebola, influenza, RSV) activate which pathway?

Answer 7

RIG-I–dependent pathway

Question 8

Positive-sense viruses such as picornaviruses turn on the which pathway?

Answer 8

MDA-5 pathway

Question 9

Some viruses activate both RIG-1 and MDA5. Name 3.

Answer 9

DENV, JEV and HCV.

Question 10

Ligation of TLR triggers Type I IFN production. T or F?

Answer 10

True

Question 11

What are TLRs?

Answer 11

The Toll-like receptors (TLRs) are pattern recognition receptors (PPRs), located in the endosome or in the cytoplasm which detect associated molecular patterns.

Question 12

Engagement of RLR and TLRs with their respective ligands drives activation of….?

Answer 12

Engagement of TLRs with their respective ligands drives activation of Nuclear Factor кB (NFкB) and several members of the interferon-regulated factor (IRF) family of transcription factors.

The translocation into the nucleus activates the production of type I interferons IFN-α and IFN-β.

Question 13

TLR3 ligation binds to what type of virus?

Answer 13

double-stranded RNA (dsRNA)

Question 14

TLR7/8 Ligation binds to what type of virus?

Answer 14

single-stranded (ss)RNA

Question 15

TLR9 ligation binds to what type of virus?

Answer 15

unmethylated CpG DNA

Question 16

What is antiviral state?

Answer 16

The antiviral state is the result of a signaling pathway induced by IFN-α/β binding to the IFN receptor on both infected and nearby uninfected cells following viral infection.

Signalling from the IFNR induces transcription of several genes encoding proteins which ultimately inhibit virus replication.

Question 17

The antiviral state induced transcription of several genes encoding proteins to ultimately inhibit viral replication. Name 3.

Answer 17

• PKR kinase phosphorylates eukaryotic synthesis initiation factor eIF-2 and thereby inhibiting viral replication;
• Oligoadenylate synthase activates endonuclease which degrades viral RNA;
• Mx proteins inhibit viral transcription (gene expression and virion assembly) of some RNA virus, but not DNA viruses.

Question 18

How do NK cells mediate direct lysis of infected cells?

Answer 18

Via the perforin/granzyme mechanism.

Question 19

NK cell killing is increased up to 100-fold in the presence of….

Answer 19

Type I IFN or IL-12.

Question 20

How else do NK cells assist the immune system?

Answer 20

Activated NK cells amplify immune responses by producing IFN-γ;

Enhanced macrophage microbicidal activity and IL-12 production;

Enhanced antigen presentation function of dendritic cells

Question 21

NK cells are major effector cells against which virus?

Answer 21

Against herpesviruses, especially MCMV and HCMV.

Question 22

Antibody-coated target cells can be killed by NK cells via which mechanism?

Answer 22

ADCC (antibody-dependent cellular cytotoxicity)

Question 23

Explain ADCC process

Answer 23

The ADCC mechanism is mediated by the NK cell FcγRIII (CD16), and the Fc portion of immunoglobulins presented on the target cell.

Example;
Antibody binds antigen on the surface of target cells

Fc receptors on NK cell recognises bound antibody

Cross-linking of Fc receptors signals the NK cell to kill the target cell

Target cell dies by apoptosis

Question 24

Virus infection can be blocked by neutralizing antibodies. Explain this.

Answer 24

Antibodies bound to viral surface proteins neutralize the virus, inhibiting either initial binding to the cell or its subsequent entry.

Antibodies may be directed against any viral protein – only antibodies against glycoproteins expressed on the virion enveloper on the infected cell membrane are important on controlling infection.

Protection is also dependent on how the virus induces pathology.

Question 25

Why is Sabin a better live attenuated poliovirus vaccine in contrast to Salk polio vaccine?

Answer 25

Sabin is able to elicit a strong mucosal IgA response and provides intestinal immunity. Salk does not provide intestinal immunity and is less effective at preventing the spread of poliovirus in a population.

Question 26

Cells infected by viruses are recognised by CD8+ cytotoxic T lymphocytes by binding to which MHC class?

Answer 26

MHC class I. Cytotoxic T cells (also referred as CD8+ cells) recognise complex of viral peptide with MHC class I and kills infected cells.

Question 27

CTL cells infect cells how?

Answer 27

CTL kill infected cells via perforin and granzymes. CTL responses are effective as they eliminate virus-infected cells without damaging uninfected cells.

Question 28

During a typical cytopathic virus infection, when do you have CTL activity?

Answer 28

During a typical cytopathic virus infection CTL activity appears within 3-5 days after infection, peaks about 1 week, and declines thereafter.

Question 29

What is the CTL response after reactivation of a latent response to a viral infection?

Answer 29

After a viral infection – in this case reactivation of latent CMV – the number of T cells specific for viral antigen increases and then falls back to give a sustained low level of memory T cells.

Question 30

What is a type II interferon?

Answer 30

IFN-γ

Question 31

What cells produce IFN-γ?

Answer 31

IFN-γ is produced by NK cells and by effector TH1 CD4+ and CD8+ T cells.

Question 32

What does IFN-γ do?

Answer 32

Inhibits viral replication directly. Upregulates expression of MHC and components of antigen processing pathway; Activates macrophages, recruiting them to sites of infection as both effector cells and antigen presenting cells.

Question 33

Naïve CD4 T cells activated in the presence of IL-12 and IFN-γ are committed to differentiate into what T cell?

Answer 33

TH1 cells

Question 34

Two types of variation allow repeated infection with Influenza virus A (IVA). What are they?

Answer 34

Antigenic drift and antigenic shift Antigenic shift refers to the gene recombination occurring when Influenza viruses re-assort. Mutations causing minute changes in the Haemagglutinin and Neuraminidase antigens on the surface of the influenza virus is termed antigenic drift.

Question 35

What is antigenic drift?

Answer 35

Antigenic drift: emergence of point mutants with altered binding sites for NAb on the surface HA; Ab and T cell recognition (including previously generated responses) of unaltered epitopes provides a degree of protection.

Question 36

What is antigenic shift?

Answer 36

Antigenic shift: a rare event involving reassortment of segmented RNA genomes of >1 IVA viruses (from birds or pigs). So RNA segments are exchanged between viral strains in a secondary host. No cross- protective immunity to virus expressing a novel HA. Large changes in HA = new virus not previously seen in humans; Ab and memory T cells produced in earlier IVA infections are not protective.

Question 37

Antigenic drift and antigenic shift explained in great detail by CDC website

Answer 37

Antigenic Drift One way influenza viruses change is called “antigenic drift.” These are small changes (or mutations) in the genes of influenza viruses that can lead to changes in the surface proteins of the virus: HA (hemagglutinin) and NA (neuraminidase). The HA and NA surface proteins of influenza viruses are “antigens,”. The changes associated with antigenic drift happen continually over time as the virus replicates. Most flu shots are designed to target an influenza virus’ HA surface proteins/antigens. The nasal spray flu vaccine (LAIV) targets both the HA and NA of an influenza virus. The small changes that occur from antigenic drift usually produce viruses that are closely related to one another, which can be illustrated by their location close together on a phylogenetic tree. Influenza viruses that are closely related to each other usually have similar antigenic properties. This means that antibodies your immune system creates against one influenza virus will likely recognize and respond to antigenically similar influenza viruses (this is called “cross-protection”). However, the small changes associated with antigenic drift can accumulate over time and result in viruses that are antigenically different (further away on the phylogenetic tree). It is also possible for a single (or small) change in a particularly important location on the HA to result in antigenic drift. When antigenic drift occurs, the body’s immune system may not recognize and prevent sickness caused by the newer influenza viruses. As a result, a person becomes susceptible to flu infection again, as antigenic drift has changed the virus enough that a person’s existing antibodies won’t recognize and neutralize the newer influenza viruses. Antigenic drift is the main reason why people can get the flu more than one time, and it’s also a primary reason why the flu vaccine composition must be reviewed and updated each year (as needed) to keep up with evolving influenza viruses. Antigenic Shift The other type of change is called “antigenic shift.” Antigenic shift is an abrupt, major change in an influenza A virus, resulting in new HA and/or new HA and NA proteins in influenza viruses that infect humans. Shift can result in a new influenza A subtype in humans. One way shift can happen is when an influenza virus from an animal population gains the ability to infect humans. Such animal-origin viruses can contain an HA or HA/NA combination that is so different from the same subtype in humans that most people do not have immunity to the new (e.g., novel) virus. Such a “shift” occurred in the spring of 2009, when an H1N1 virus with genes from North American Swine, Eurasian Swine, humans and birds emerged to infect people and quickly spread, causing a pandemic. When shift happens, most people have little or no immunity against the new virus.

Question 38

Which is more common; antigenic shift or antigenic drift? Influenza A or influenza B is most susceptible to this?

Answer 38

While influenza viruses change all the time due to antigenic drift, antigenic shift happens less frequently. Influenza pandemics occur very rarely; there have been four pandemics in the past 100 years. For more information, see pandemic flu. Type A viruses undergo both antigenic drift and shift and are the only influenza viruses known to cause pandemics, while influenza type B viruses change only by the more gradual process of antigenic drift.

Question 39

Neutralizing antibodies (NAb) directed at the viral surface protein haemagglutinin (HA) mediate protection from infection. T or F?

Answer 39

True. Influenza vaccines contain HA

Question 40

HIV evolves rapidly and escapes humoral and cell mediated immune control. How?

Answer 40

HIV Env is a trimeric protein that enables the virus to enter host cells and is the primary target for neutralizing antibodies - glycans on the protein shield the conserved envelope domains from recognition by neutralizing antibodies. Additional N-linked glycosylation sites in the viral E gene confer escape from neutralization.

Question 41

Non-neutralizing antibodies may form immune complexes with viral antigen. What happens to these complexes?

Answer 41

In persistent or chronic viral infection ineffective, non-neutralizing antibodies may form immune complexes with viral antigen. Antigen–antibody complexes are constantly present in the blood of HIV infected patients, for example. These complexes are deposited in kidney or blood vessels where they provoke inflammatory responses leading to tissue damage.

Question 42

Low-avidity, cross-reactive, non neutralizing antibodies generated during a primary viral infection can mediate increased infection of monocytes and macrophages via FcRmediated uptake of antibody-coated virus particles. Explain how this happens.

Answer 42

Non-neutralizing Ab present in the host from a primary infection binds to an infecting viral particle during a subsequent infection but cannot neutralize the virus. Instead, the Ab–virus complex attaches to the FcγR on circulating monocytes, thereby facilitating the infection of FcγR cell types in the body not readily infected in the absence of antibody. The overall outcome is an increase in the overall replication of virus, leading to the potential for more severe disease. This has been described for Dengue virus, Ross-river virus and HIV.

Question 43

What is Lymphocytic choriomeningitis virus (LCMV)?

Answer 43

Lymphocytic choriomeningitis virus (LCMV) can cause meningitis in both human and murine hosts. LCMV is a non-cytopathic virus - the damage induced in the CNS is not caused by the virus, but rather is caused by the subsequent immune response. Removal of T cells from an infected animal protects it from death – brain damage is induced directly by CTL.