Lecture 4: Emerging viruses

Question 1

Emerging virus defintion

Answer 1

newly appeared, notably increasing in incidence or geographic range or has potential to increase in near future

Question 2

2 emerging viruses

Answer 2

Ebola , Sars-2

Question 3

Ebola overview

Answer 3

→ filamentous virus, variable length
→ in DCs and macrophages
→ systemic infection after lymph node
→ impaired T cell activation
→ excessive cytokines
→ neg. ss RNA of 19kb
→ transcriptional sluttering ar polyU where polyermase moves back one nucleotide after each inserted Adenine → 3 products

Question 4

Ebola assembly

Answer 4

Helical viral nucleocapsid containing viral ss neg. RNA
→ NP interacting with VP24
→ P-Protein, VP30 and L-Protein

Matrix protein layer associated to membrane
→ Minor (VP24) and major matrix (VP40) protein, responsible for budding

Lipid bilayer membrane envelope
→ contains glycoprotein GP (trimer)

Question 5

2 vaccines for Ebola

Answer 5

rVSV ZEBOV-GP (Ervebo)
→ recombinant, replication competent vector
→ VSV expressing GP from Zaire Ebolavirus
→ neutralising antibodies induction
→ no cross-protection

Zabdeno and Mvabea
→ kids
→ Adenovirus vector and MVA (Poxvirus) vector vaccine in 2 doses
→ multivalent, but less immunogenic and not used for outbreaks

Question 6

3 Drug targets in Ebola Virus

Answer 6

Entry inhibitors

Transcription and replication inhibitors

Budding inhibitors

Question 7

Ebola Virus entry

Answer 7

GP1 trimer (receptor binding) and GP2 trimer (fusion protein subunit)

→ macropinocytosis
→late endosomes cellular protease Cathepsin B and L cleave GP1
→ Two-pore channels control endosomal movement
→ GP1 subunit acts with NPC-1
→ renders GP2 fusogenic
→ fusion of virus and endosomal membrane

Question 8

Which people are immune to Ebola and which 3 drugs target same step ?

problems of drugs

Answer 8

NPC-1 essential for entry
→ NPC deficiency of cholesterol transporter of endosomal mebrane leads to immunity
→ accumulation of cholesterol leads to disease

Drug:
Two-pore channel inhibitors
→ Tetrandine

GP-related entry inhibitors

→ Sertraline, Toremifene, Bepridil
→ targets Cathepsin B cleavage of GP
→ binds pocket of GP for destabilization

Cationic amphillic drugs
→ Amiodarone, Dronedarone, Clomiphene, Terconazole
→ binds directly to NPC1 (allosteric) and blocks site for function
→ intercalation LE/Lys mebrane to disrupt NPC function
→ binding to another protein that is regulated via NPC-1 and also rerquired for entry

problems
→ only early stages → prophylaxis

Question 9

Transcription and replication process

Inhibitors

Examples

Answer 9

→ RNP: NP, polymerase cofactor VP35, transcription activator VP30, L polymerase

RdRp inhibitors
→ nucleotide delivery disrupted due to phosphate group
→ premature chain termination
→ Cidofovir

Examples
→ BCX4430, Remdesivir (broad spectrum)

Question 10

Assembly process

Inhibitors

Answer 10

VP40 needs to be phosphorylated by host kinases
→ inhibitor blocks tyrosine kinase

Examples
→ Nilotinib, Imatinib

Question 11

Antibody based therapy

Answer 11

ZMapp
→ 3 monoclonal antibodies

mAb 114
→ 1
→ approved

REGN-EB3
→ 3
→ approved

Question 12

Limitations of Ebola Virus drugs

Answer 12

rare disease
not enough patients
BSL4
surrogate models helpful