HCV and DENV

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Hepatitis

General Background

infection in hepatocytes

blood-borne infection

chronic infection leads to disease

2-26 week incubation period

Acute Symptoms

80% of the time its asymptomatic

The 20%: fever, fatigue; low appetite vomiting and pain

Chronic Outcomes

serious liver damage

75-85% cases hepatitis with fibrosis

2-7% lead to hepatocellular carcinoma (cancer)

Evasion Antibody Responses

Viral mimicry - imitation of LDL

Viral hiding - spread/hide through tight junctions

Shifting Antigens - move glyscoslyation patterns on envelope proteins

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Evasion of Interferon System

NS3/4a protease- cleaves many proteins to block them from meditating interferon induction

NS4b - blocks STING

NS5a - binds to MyD88 so no TLR signalling/ binding to ISGs

Core - prevent STAT1 phosphorylation and activation

Envelope: bind to ISG PKR

Immunopathology: Cytotoxic Cells

NK and CD8+ - kill infected liver cells and produce cytokines

CD8+ - regulated by Tregs to suppress the cytotoxic effects and causes long term persistance to HCV

"" HCV antigen exposure is prolonged and exhausts markers = low proliferation, degranulation and reduced cytotoxicity

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Viral Progression

after incubation period, in the acute infection, HCV RNA in the blood is detected and symptoms are present

both viral load and symptoms digress but viral load never clears

as viral load peaks, in the chronic infection, symptoms as present again (this can happen in waves)

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Dengue Virus

General Background

Acute

4 serotypes (1, 2, 3 and 4)

tropism occurs in immune cells (myeloid)

transmission through A. aegypti and albopictus

Symptoms

Breakbone fever

muscle and joint pain

high fever

headaches

rash

possiblitly of shock and haemorrhage in final days of fever (increasing of IgM) (Antibody-dependent enhancement)

Evasion of Interferon

NS2B/3 - cleave STING

synergy of NS2A,4A,4B, to reduce STAT1 phosphorylation

NS5 - binds and degrades STAT2

replication in membranous regions to avoid immune sensors

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The Risk of Haemorrhage

subsequent infections from new serotypes lead to infection

initial infection and recovery from one serotype will give you life-long immunity

the secondary immune response leads to overwhelming concentrations of antibodies

Enhancing Replication

bound DENV particle by antibodies increases uptake into macrophages

virus continues to replicate and Mφ releases cytokines (storm)

vasdilatory cytokines like TNFα

Virion Structure

ssRNA+

envelope for cell fusion and entry

Entry and Uncoating

receptor-mediated endocytosis

E protein unburies itself from the virion surface

E protein inserted into the host cell membrane

Trimerisation of E protein on viral membrane

hemifusion to full fusion between viral and host membrane

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