Comprehensive Notes – RNA & Oncogenic Viruses

III. RNA Viruses – Core Concepts

• Learning outcomes
  • $\textbf{Students should be able to:}$
  • $1.$ List aetiology of common RNA viral infections.
  • $2.$ Explain pathogenesis / pathogenic mechanisms.
• Genome polarity
  • $\textbf{ssRNA}$ (single-stranded) & $\textbf{dsRNA}$ (double-stranded) classes.

Orthomyxoviridae – Influenza A, B, C

• Virion structure
  • Segmented $\textbf{ssRNA}$, enveloped, helical capsid.
  • Only RNA viruses that replicate in the $\textbf{host nucleus}$.
• Transmission & epidemiological terms
  • Respiratory droplets, fomite contact.
  • $\textbf{Endemic}$ = constant baseline in a region.
  • $\textbf{Epidemic}$ = regional outbreak.
  • $\textbf{Pandemic}$ = global outbreak, often due to species jump.
• Envelope glycoproteins
  • $\textbf{Hemagglutinin (H)}$
  • Binds sialic-acid receptors on epithelial cells ⇒ fusion & entry.
  • Laboratory: agglutinates RBCs (hemagglutination test).
  • $\textbf{Neuraminidase (N)}$
  • Cleaves sialic acid ⇒ release of progeny & mucus detachment.
• Genome segmentation $\,(7-8\,segments)$ ⇒ genetic variation.
• Variability mechanisms
  • $\textbf{Antigenic drift}$ = gradual point mutations (all strains).
  • $\textbf{Antigenic shift}$ = reassortment in co-infected host ⇒ novel $H/N$, sudden pandemic (Influenza A only).
• Pathogenesis
  • Infection of respiratory epithelium ⇒ apoptosis & shedding ⇒ inflammation.
  • Clinical: chills, malaise, fever, myalgia, coryza, cough; severe → bronchitis, interstitial pneumonia.
  • Complications: secondary bacterial pneumonia (Strep. pneumoniae, Staph. aureus, H. influenzae); rare CNS involvement (meningitis, encephalomyelitis, polyneuritis).
• Prevention
  • Annual vaccine (strain-updated); no protection against secondary bacterial disease.

Hepatitis Viruses (A-G) – Overview

• Transmission summary
  • $A,E$: faecal-oral (acute only).
  • $B,C,D$: parenteral/sexual (chronic potential).
  • $D$ requires $B$ (incomplete virion).
• Clinicopathologic syndromes
  • Acute asymptomatic (serology only).
  • Acute symptomatic – anicteric or icteric.
  • Chronic hepatitis ⇒ ±cirrhosis.
  • Fulminant hepatitis (massive necrosis) mainly HBV.

Hepatitis B Virus (HBV)

• Classification & genome
  • Hepadnavirus; partially double-stranded circular DNA (relaxed-circular) converted to $\textbf{cccDNA}$ template.
• Transmission: injection, sexual, perinatal.
• Cell entry: binds heparan-sulfate proteoglycans then $\textbf{NTCP}$ & $\textbf{EGFR}$ on hepatocytes.
• Immune response dictates outcome
  • Strong CD4⁺/CD8⁺ IFN-$\gamma$ response ⇒ resolution.
  • Impaired / tolerant immunity ⇒ chronicity.
  • Hepatocyte injury predominantly CTL-mediated.
• Clinical
  • Incubation $\approx60-90\,\text{days}\;(45-180)$.
  • Acute: self-limited, fatality $0.5-1\%$, mild / non-specific (anorexia, fever, RUQ pain, jaundice).
  • Chronic infection probability: $30-90\%$ if infected $\le5\,$yrs; $2-10\%$ if >5\,yrs.
  • Premature mortality chronic liver disease $15-25\%$.
• Chronic HBV definitions & outcomes
  • Persistence >6\,months, lymphocytic inflammation, apoptotic hepatocytes.
  • Non-progressive: asymptomatic, no anti-HBs, mildly damaged yet infectious.
  • Progressive: cirrhosis ⇒ liver failure, HCC.
• Vaccine available.

Hepatitis C Virus (HCV)

• Flaviviridae; enveloped $\textbf{ssRNA}$, $6$ genotypes (1 most common).
• Transmission: parenteral (IVDU, transfusion), sexual, vertical.
• Virology special points
  • Error-prone RNA polymerase ⇒ quasispecies ⇒ immune evasion; E2 highly variable.
  • Anti-HCV IgG not protective ⇒ reinfections.
• Clinical course
  • Acute infection asymptomatic in $85\%$, milder than HBV; strong T-cell response ⇒ self-limited.
  • Chronicity in $80-85\%$; cirrhosis in $20-30\%$ of chronic.
• Therapy: direct-acting antivirals (oral, $$ cost).

Hepatitis D Virus (HDV)

• Defective RNA virus using HBsAg.
• Coinfection (acute HBV+HDV): mimics acute B, usually self-limited.
• Superinfection in chronic HBsAg carrier: severe acute, $80-90\%$ chronic HDV, suppresses HBV during acute, later reciprocal ⇒ rapid cirrhosis / HCC.

Flaviviridae – Dengue Virus

• Four serotypes $DEN\,1-4$; small enveloped.
• Transmission: $Aedes\,aegypti$ & $A. albopictus$ bites.
• Immunity: lifelong to infecting serotype, none cross-protective.
• Cell tropism & receptors: monocytes & endothelial cells via MR, DC-SIGN; CLEC5A (signalling).
• Clinical spectra
  • Dengue fever: mild, fever, lymphadenopathy, myalgia (“break-bone”), rash.
  • DHF/DSS: secondary heterologous infection ⇒ antibody-dependent enhancement ⇒ ↑cytokines, vascular leak, thrombocytopenia, haemoconcentration, shock.
• Diagnostics: IgM, NS1 antigen.

Picornaviridae – Poliovirus

• Three serotypes $PV1-3$ (PV2 $2015$ & PV3 $2019$ eradicated).
• Transmission: faecal-oral; $95\%$ subclinical; <$1\%$ paralytic.
• Pathogenesis
  • Viraemia ⇒ CNS (motor neurons, spinal cord, brain stem, motor cortex) via BBB crossing, retrograde axonal transport, or infected leukocytes.
  • Neuron destruction ⇒ flaccid paralysis (days–weeks permanent).
  • Prodrome: muscle pain & spasms.
• Vaccine preventable (IPV & OPV).

Retroviridae – Human Immunodeficiency Virus (HIV-1)

• Reverse-transcribing $ssRNA$ retrovirus; makes DNA provirus.
• Transmission: sexual (main), blood.
• Life cycle highlights
  • Prolonged latency; provirus hidden from drugs.
  • Progressive CD4⁺ decline.
• AIDS criteria: CD4 <$200\,\text{cells mm}^{-3}$ or opportunistic infections.
• Pathogenesis
  • Direct cytopathic: lysis, membrane permeability, protein-synthesis shutoff.
  • Bystander apoptosis: soluble gp120 binding; CTL kill gp120-coated uninfected cells.
  • Loss of precursors; macrophage transport to brain.
  • CNS injury via infected macrophages/microglia & soluble gp120.
• Clinical stages
  • Acute viraemia ⇒ lymphoid seeding.
  • Clinical latency: ongoing replication, immune containment.
  • Gradual CD4 erosion ⇒ opportunistic disease.

Coronaviridae – Common Cold & Severe Strains

• Largest RNA genome $\le32\,\text{kb}$; crown-like S-spikes.
• Human CoVs
  • 229E, NL63, OC43, HKU1 (colds)
  • SARS-CoV $(2001-2003)$, MERS-CoV $(2012-2015)$, SARS-CoV-2 $(2019-)$.
• Structure proteins: Spike (S), Nucleocapsid (N), Membrane (M), Envelope (E).
  • S binds $ACE2$ ⇒ fusion/entry.
• SARS-CoV-2 disease spectrum
  • Asymptomatic → pneumonia/COVID-19 → ARDS (cytokine storm).
  • Risk factors: age, CVD, DM, HTN, lung/kidney disease, obesity, smoking, cancer.

Togaviridae – Rubella (German Measles)

• Transmission: respiratory droplets; replication in respiratory tract & lymphoid tissues.
• Signs: fever, maculopapular rash (immune complexes), lymphadenopathy, arthropathy.
• Congenital Rubella Syndrome (CRS)
  • Infection timing & risks
  • $0-12\,\text{wks}$: $100\%$ major defects, $20\%$ spontaneous abortion.
  • $13-16\,\text{wks}$: $15\%$ deafness & retinopathy.
  • >16\,\text{wks}: slight risk deafness/retinopathy.
  • Defects: deafness, cataracts, heart disease, intellect disability, hepatosplenomegaly, low birth weight, “blueberry muffin” rash.
• Vaccine (MMR) protects mother/foetus.

Other RNA Viruses – Fast Table

• Astrovirus, Calicivirus (Norovirus, Sapporo), Rotavirus → acute viral gastroenteritis (faecal-oral).
• Paramyxovirus: Measles, Mumps, RSV (bronchiolitis, croup) – aerosol.
• Rhabdovirus: Rabies – animal bite.
• Flavivirus: Zika (microcephaly), Dengue (above).
• Togavirus: Chikungunya (myositis-arthritis) – vector.
• Filovirus: Ebola haemorrhagic fever – blood/body fluids.
• Enteroviruses: Coxsackie A (HFMD), Coxsackie B (pleurodynia), EV71, Rhinovirus/Echovirus (common cold) – faecal-oral or respiratory.

IV. Transforming (Oncogenic) Viruses – Generalities

• About $15-20\%$ of worldwide cancers are virus-related.
• Features
  • Virus alone insufficient; long-term persistent infection.
  • Host immunity may protect or promote.
• Mechanisms
  • $\textbf{Direct}$: viral oncogene expression inactivates p53/pRb; insertional mutagenesis near proto-oncogenes; tumour-suppressor disruption.
  • $\textbf{Indirect}$: chronic infection & inflammation → ROS, cytokines, regenerative proliferation.

Human Papillomavirus (HPV)

• Non-enveloped icosahedral dsDNA; >$200$ types; >$40$ mucosal/STD.
• Low-risk $6,11$ ⇒ anogenital/oral warts.
• High-risk $16,18$ (others) ⇒ cancers (>$80\%$ cervical; $16$ most other sites).
• Risk factors: multiple partners, HIV, smoking/chewing tobacco (oropharynx), poor oral hygiene, many births, long OCP use, immunosuppression, chronic inflammation.
• Life cycle & wart formation
  • Entry via micro-abrasions ⇒ basal keratinocytes; latent circular episome (low copy).
  • Differentiation migration ⇒ replication burst in keratinised layer ⇒ shedding with exfoliated cells ⇒ cutaneous/mucosal warts (condylomata acuminata, smooth/flat papules, keratotic lesions).
• Cancer progression
  • Persistent infection ⇒ CIN1-3 ⇒ $\approx30\%$ CIN3 → invasive cervical cancer over $10-30\,$yrs.
• Molecular carcinogenesis
  • Viral DNA integrates ⇒ constitutive E6 & E7.
  • $E6$ binds p53 ⇒ ubiquitin-mediated degradation.
  • $E7$ binds pRb ⇒ releases E2F ⇒ proliferation.
  • Result: uncontrolled growth, genomic instability, blocked apoptosis.
• Vaccine (bivalent, quadrivalent, 9-valent) prevents high-risk & low-risk types.

HBV & HCV in Hepatocellular Carcinoma (HCC)

• Chronic infection over decades ⇒ inflammation, regeneration, fibrosis, cirrhosis, dysplasia, HCC.
• HBV
  • Integration into host genome ⇒ viral-human fusion, copy-number changes, instability.
• HCV
  • Core & non-structurals promote survival/growth, inhibit DNA repair, induce breaks, increase mutations ⇒ instability; more efficient cirrhosis promoter (>80\% chronicity).
• Common tumour mutations: p53, $\beta$-catenin, etc.

Epstein–Barr Virus (EBV)

• Herpesvirus; $\approx90\%$ seropositive adults.
• Spread: saliva, blood, semen, transplants.
• Primary childhood infections asymptomatic; young adults ⇒ infectious mononucleosis.
• Latency with reactivation in immunosuppressed.
• EBV-associated tumours
  • $\textbf{Burkitt\,Lymphoma}$ (endemic African): t$(8;14)$ C-myc next to IgH, driven by EBNA 1; cofactor chronic malaria.
  • $\textbf{Nasopharyngeal\,Carcinoma}$ (South China/Asia): EBNA1, LMP1 activates NF-$\kappa$B & pro-angiogenic genes $\rightarrow$ oncogenesis; cofactors nitrosamines (salted fish/meat), genetics, smoking, alcohol.

Kaposi’s Sarcoma-Associated Herpesvirus (KSHV/HHV-8)

• Transmission: saliva, sexual.
• Latent in B cells; disease on immunosuppression (AIDS, therapy, aging).
• Kaposi’s Sarcoma (KS)
  • Multicentric endothelial tumours; cutaneous purple-brown lesions; may involve mucosa, lymph nodes, lung, liver, GI tract.
  • Leading AIDS-related cancer.
• Oncogenesis: latent viral proteins drive proliferation, survival, transformation.