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HSV Flashcards

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1
Q

Herpesviridae is the

  • 2nd most common cause of viral disease in humans (after?
A

Herpesviridae is the

  • 2nd most common cause of viral disease in humans (after flu & cold viruses)
  • Name origin: Greek – herpein (“to creep”)
  • Key feature: Latency with periodic reactivation
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2
Q

What are the Genome & Structure of HSV?

A

Genome & Structure

  • dsDNA virus (125–229 kb)
  • Icosahedral nucleocapsid
  • Tegument layer surrounds the nucleocapsid
  • Envelope derived from host cell membrane
  • Large virion: 120–260 nm
  • Encodes multiple genes for replication, immune evasion, latency
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3
Q

What are the Classification (by behavior, tropism, replication speed)

Subfamily | Features Latency Site Examples

A

Classification (by behavior, tropism, replication speed)

Subfamily | Features Latency Site Examples

| Beta | Slow replication, cytomegalic effect, restricted host range | Glands, monocytes/macrophages | CMV, HHV-6, HHV-7

Gamma | Poor replication, oncogenic potential, narrow host range | B lymphocytes | EBV, HHV-8 (KSHV) |

Alpha | Fast replication, lytic, broad host range | Sensory & cranial ganglia | HSV-1, HSV-2, VZV, Herpes B |

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4
Q

Human Herpesviruses (HHVs)

** Virus** Common Name Subfamily Key Diseases they cause?

A

Human Herpesviruses (HHVs)

** Virus** Common Name Subfamily Key Diseases

HSV-1 | Herpes Simplex Virus 1 Alpha | Oral herpes, encephalitis

HSV-2 | Herpes Simplex Virus 2 | Alpha | Genital herpes

VZV | Varicella-Zoster Virus Alpha | Chickenpox, shingles

CMV | Cytomegalovirus Beta | Congenital CMV, retinitis

HHV-6/7 | Human Herpesvirus 6 & 7
Beta | Roseola infantum (exanthem subitum)

EBV | Epstein-Barr Virus
Gamma | Infectious mononucleosis, Burkitt lymphoma, NPC |

HHV-8 | Kaposi Sarcoma–associated HV |
Gamma | Kaposi sarcoma, Castleman disease

⏩ Note: Herpes B virus infects macaques but causes fatal encephalitis in humans

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5
Q

Epidemiology

  • Universal infections: HSV-1, VZV, EBV, HHV-6/7
  • HSV-2: 15–50% in adults (↑ in developing countries)
  • CMV: 40–70%
  • HHV-8: <5% (↑ in immunocompromised)
  • No sex predilection
A

Epidemiology

  • Universal infections: HSV-1, VZV, EBV, HHV-6/7
  • HSV-2: 15–50% in adults (↑ in developing countries)
  • CMV: 40–70%
  • HHV-8: <5% (↑ in immunocompromised)
  • No sex predilection

Mode | Viruses Involved |
| ——————— | ——————————– |
| Saliva | HSV, CMV, EBV, HHV-6 |
| Sexual contact | HSV, CMV, HHV-8 |
| Intrauterine | HSV, CMV, VZV |
| Transplant | CMV, EBV, HHV-8 |
| Blood transfusion | CMV, EBV |
| Airborne | EBV (unique among herpesviruses) |

  • Entry via:
    • Endocytosis + fusion with endocytic vesicle
    • Direct membrane fusion
  • Receptors involved: Nectin 1/2, PDGFR, EGFR, CD21, CD46, CD134, Integrins, MHC II
  • Replication site: Nucleus
  • Shedding without symptoms: HSV, EBV, CMV, HHV-6/7 (esp. oral mucosa)
  • Symptomatic disease: From lytic replication → skin/visceral lesions
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6
Q

What are the Transmission Routes of HSV?

Mode & Viruses Involved

A

Transmission Routes

Mode & Viruses Involved

Saliva | HSV, CMV, EBV, HHV-6

Sexual contact | HSV, CMV, HHV-8

Intrauterine | HSV, CMV, VZV

Transplant | CMV, EBV, HHV-8

Blood transfusion | CMV, EBV

Airborne | EBV (unique among herpesviruses)

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7
Q

Replication & Pathogenesis

A

Replication & Pathogenesis

  • Entry via:
    • Endocytosis + fusion with endocytic vesicle
    • Direct membrane fusion
  • Receptors involved: Nectin 1/2, PDGFR, EGFR, CD21, CD46, CD134, Integrins, MHC II
  • Replication site: Nucleus
  • Shedding without symptoms: HSV, EBV, CMV, HHV-6/7 (esp. oral mucosa)
  • Symptomatic disease: From lytic replication ➡️ skin/visceral lesions
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8
Q

Latency and Reactivation (Detailed Explanation)

Latency:

  • Herpesviruses establish life-long latency after primary infection.
  • Latency sites vary by virus:
    HSV-1&2
    VZV
    ENV
    CMV
    HHV-6&7
    HHV-8
A
  • HSV-1/2: sensory and cranial ganglia
    • VZV: dorsal root ganglia
    • EBV: B lymphocytes
    • CMV: monocytes/macrophages
    • HHV-6/7: CD4+ T cells
    • HHV-8: B cells and endothelial cells
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9
Q

What’s the Mechanisms of latency:

A

Mechanisms of latency:

  • Viral genome remains episomal (non-integrated circular DNA) inside host cell nucleus.
  • Limited gene expression: avoids immune detection.
  • LAT (Latency-associated transcripts) in HSV suppress apoptosis and regulate reactivation.
  • EBV expresses EBNA-1 for genome maintenance and LMPs for B-cell transformation.
  • Viral microRNAs suppress immediate-early (IE) gene expression ➡️ prevents reactivation signals.
  • Some viral proteins are sequestered in the cytoplasm during latency.
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10
Q

What are the Triggers for Reactivation:

What are the clinical relevance of this latency and reactivation?

A

Triggers for Reactivation:

  • Stress
  • Fever (e.g., other infections)
  • UV light/radiation
  • Immunosuppression (HIV, chemotherapy)
  • Nerve trauma (e.g., dental work)
  • Hormonal changes (e.g., menstruation)

Clinical relevance: Latency explains:

  • Recurrent cold sores (HSV-1)
  • Genital herpes recurrences (HSV-2)
  • Shingles in the elderly or immunosuppressed (VZV)
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11
Q

What are the Clinical Features of these Viruses? (with relevant mechanisms)

A

Clinical Features by Virus (with relevant mechanisms)

HSV-1

  • Acute Gingivostomatitis: Primary infection in children.
  • Herpetic Whitlow: Painful lesion on fingers from inoculation.
  • Keratoconjunctivitis: Involves cornea → risk of blindness.
  • Eczema herpeticum: Generalized HSV infection in eczematous skin.
  • Encephalitis: HSV-1 is the most common cause of sporadic viral encephalitis (temporal lobe involvement).

HSV-2

  • Genital herpes: Painful vesicles, high recurrence.
  • Aseptic meningitis: More common in women.
  • Neonatal herpes: Acquired during delivery.
  • Cutaneous herpes: Vesicles in immunocompromised.
  • Gingivostomatitis: Less common than HSV-1.

VZV

  • Varicella (chickenpox): Primary infection, vesicular rash.
  • Zoster (shingles): Reactivation → dermatomal vesicular rash.

EBV

  • Infectious mononucleosis: Fever, sore throat, lymphadenopathy.
  • Oral hairy leukoplakia: White patches on tongue (seen in AIDS).
  • Hepatitis, pneumonia, encephalitis: Less common.
  • EBV-associated malignancies:
    • Burkitt lymphoma (c-MYC translocation)
    • Nasopharyngeal carcinoma (epithelial cells)
    • Hodgkin lymphoma (Reed-Sternberg cells)

CMV

  • Congenital CMV: Sensorineural hearing loss, intracranial calcifications.
  • Mononucleosis: Heterophile-negative (unlike EBV).
  • Retinitis: Common in AIDS (CD4 <50).
  • Pneumonia: Especially in transplant recipients.

HHV-6 & HHV-7

  • Exanthem subitum (Roseola infantum): High fever → resolves → then rash.
  • Encephalitis: Rare.

HHV-8

  • Kaposi sarcoma: Vascular tumor in AIDS.
  • Castleman disease: Lymphoproliferative.
  • Febrile exanthem: Non-specific.
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12
Q

Herpes B Virus

  • Rare but dangerous zoonosis (monkey bites).
  • Mucocutaneous lesions, encephalitis: Fatal without rapid treatment.
A
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13
Q

What are the Oncogenes of (EBV & HHV-8)

A

Oncogenesis (EBV & HHV-8)

Only two oncogenic herpesviruses:

  • EBV:
    • LMP-1: Mimics CD40 ⏩ B cell proliferation
    • EBNA-1: Maintains viral genome during latency
  • HHV-8:
    • K1, K12, ORF74: Promote angiogenesis and immune evasion

Key insight: These viruses establish latency in immune cells, manipulate signaling pathways, and evade immune detection to promote transformation.

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14
Q

What are the clinical symptoms of HSV?

Samples : for which HSV specie?

What are the ** Laboratory Diagnosis of Herpesvirus Infections**? Which is the Gold Standard & what will you see?

A

Clinical Clue First

  • Many primary infections are diagnosed clinically due to their classic signs:
    • HSV: grouped vesicles, gingivostomatitis, genital ulcers.
    • VZV: dermatomal rash (shingles), chickenpox in children.
    • EBV: sore throat, lymphadenopathy, splenomegaly.

Sample Types (Specimens)

Useful based on clinical context:

  • Vesicular fluid, skin swab ⏩ HSV, VZV
  • Saliva ⏩ EBV, CMV, HHV-6
  • Urine, stool, semen ⏩ CMV
  • CSF ⏩ HSV/CMV encephalitis
  • Brain biopsy → Severe CMV or HSV CNS disease
  • Conjunctival swab → HSV keratitis
  • Blood ⏩ CMV viremia (transplant patients)

Direct Examination Techniques

  • Light Microscopy (LM):
    • Look for cytopathic effects (CPEs):
      • Multinucleation
      • Margination of chromatin
      • Cowdry A intranuclear inclusion bodies
  • Electron Microscopy (EM):
    • Visualizes virions directly (used mainly in research).
  • Fluorescent Microscopy (FM):
    • Immunofluorescent staining detects viral antigens in tissue or cells.

Viral Culture (Gold Standard but Slow)

  • Cell lines: Human fibroblasts, Vero cells, umbilical cord lymphocytes.
  • HSV/VZV: Ballooning of cells, syncytia.
  • CMV: “Owl’s eye” inclusion bodies in fibroblasts.

Serology

  • Detect virus-specific antibodies (IgM, rising IgG):
    • Complement fixation, neutralization, ELISA.
    • Useful in primary infection or congenital CMV.
    • Less helpful in reactivation (antibodies already present).

PCR – Gold Standard for CNS Herpesvirus Infections

  • High sensitivity and specificity.
  • Uses:
    • HSV/CMV/EBV DNA in CSF (encephalitis, meningitis).
    • CMV/EBV viral load in transplant patients.
    • HHV-6/7 in febrile seizures or encephalitis.
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15
Q

What are the Treatment of Herpesvirus Infections?

A

2. Treatment of Herpesvirus Infections

Key Principles

  • Most drugs inhibit viral DNA polymerase.
  • All act only on replicating virus, not latent forms.
  • Most require activation by viral kinases (except a few).

Drugs That Require Viral Enzyme Phosphorylation

  • Acyclovir, Valacyclovir, Famciclovir, Penciclovir:
    • First phosphorylated by HSV/VZV thymidine kinase.
    • Then activated by host kinases.
    • Use: HSV-1/2, VZV.
  • Ganciclovir:
    • Activated by CMV protein kinase UL97.
    • Use: CMV infections.

Drugs That Do NOT Require Phosphorylation

  • Foscarnet: Directly inhibits DNA polymerase. Use when resistance develops (e.g., thymidine kinase-deficient HSV).
  • Cidofovir: Already monophosphorylated → active against CMV, adenovirus, etc.

Special Cases

  • Alpha Interferon: Used in Kaposi’s sarcoma (HHV-8).
  • Vinblastine: Used for severe or disseminated Kaposi’s sarcoma.
  • Steroids: For severe EBV-related complications (e.g., airway obstruction in mononucleosis).
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16
Q

What are the Clinical Limitation?

Study These Flashcards
A

Clinical Limitation

  • No proven clinical benefit of antivirals for:
    • HHV-6, HHV-7
    • HHV-8 (except in Kaposi’s)
    • EBV (except oral hairy leukoplakia)
17
Q

3. Latency & Future Therapeutic Strategies

Current Antivirals = No Effect on Latency

What are the Emerging Approaches?

Study These Flashcards
A

3. Latency & Future Therapeutic Strategies

Current Antivirals = No Effect on Latency

Emerging Approaches

  1. Histone Deacetylase (HDAC) Inhibitors
    • Drugs: Trichostatin A, Trapoxin B, Vorinostat, Belinostat.
    • Mechanism: Reactivate latent virus so it becomes susceptible to antivirals.
    • Concept: “Shock and kill” (used in HIV research too).
    • Research stage, not routine clinical use yet.
  2. HLA-Matched Cytotoxic T Cell Infusion
    • Adoptive immunotherapy.
    • Especially for EBV- or CMV-related disease in immunocompromised patients (e.g., post-transplant).
    • Provides specific immunity.
18
Q

Clinical Integration Tips

  • Recurrent genital ulcers ⏩ Start acyclovir empirically.
  • Temporal lobe encephalitis in adult ⏩ Send CSF PCR for HSV-1 and start acyclovir immediately.
  • Congenital CMV suspicion ⏩ PCR from urine, consider ganciclovir.
  • HIV patient with vision loss ⏩ Think CMV retinitis, treat with ganciclovir or foscarnet.

MCB 1 (11 decks)

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