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4. HDS Multisystem > Latent Viruses > Flashcards

Latent Viruses Flashcards

1
Q

Persistent/Latent Viruses

A
  • Remain for the life of their immunocompetent hosts
  • Often w/o causing any sx
  • Virus–host balance can be disrupted by imbalances in immune response, genetic or environmental factors
  • Major source of morbidity and mortality
  • Cause a variety of pathologies including virus-associated cancers
  • Cause life-threatening viral replicative infections in immunocompromised
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2
Q

Epstein-Barr Virus (EBV)

Overview

A
  • EBV is a human herpes virus (HHV)
  • EBV infection has 3 potential outcomes:
    1. Replicate in B-cells or epithelial cells
    2. Latent infection of memory B-cells in the presence of competent T-cells
    3. Stimulate growth and immortalize B-cells
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3
Q

Epstein-Barr Virus (EBV)

Classification and Morphology

A
  • Human herpes viruses (HHV-4)
  • Enveloped, icosadeltahedral nucleocapsid symmetry w/ linear dsDNA
  • Classified into 3 subfamilies based on genomic structure, tissue tropism, cytopathology, site of infection, and pathogenesis/symptomology
  • Gamma herpes viruses
    • Very restricted host range
    • Intermediate replication time
    • Latently infect cells of the lymphoid system
    • EBV is the only human virus in this group
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4
Q

Epstein-Barr Virus (EBV)

Lifecycle

A
  • Replicates in permissive cells in the oropharynx ⇒ lytic EBV replication
    • Infectious virus is detected in the saliva
  • Human disease generally ass. w/ 1° infection of EBV is mononucleosis
  • After OP infection, naive resting B-cells in the tonsils are infected
  • Latent infection in long-lived memory B-cells
  • Host cells and type of infection linked:
    • Mucosal epithelial cells ⇒ lytic infection
    • B-cells ⇒ latent infection
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5
Q

Epstein-Barr Virus (EBV)

Immune Response

A
  • T-cells stimulated by infected B-cells ⇒ kill and limit B-cell outgrowth
    • T-cells required for controlling infection
    • Host T-cell surveillance important for preventing EBV pathogenesis
  • ↑ Incidence of potentially fatal lymphoproliferative lesions in pts receiving immunosuppressive therapy s/p organ transplants
  • Can be reversed by infusion of EBV-specific immune T-cells
  • Ab role is limited
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6
Q

Epstein-Barr Virus (EBV)

Epidemiology and Transmission

A
  • EBV carried by > 90% of adult human population worldwide
  • EBV infection transmitted in saliva ⇒ “kissing disease”
  • EBV-specific immunity is lifelong
  • Co-factors for EBV-associated neoplasms are suggested by epidemiological findings
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7
Q

Epstein-Barr Virus (EBV)

Pathogenesis

A
  • EBV infection of B-cells ⇒ viral shedding ⇒ host-to-host transmission and viremia
  • Viral gene expression ⇒ ⊕ B-cell growth, ⊗ apoptosis ⇒ B-cell immortalization
  • T-cells limit B-cell outgrowth
  • Absence of T-cell regulation ⇒ lymphoproliferative disease
  • Diseases of EBV result from either:
    • An overactive immune response ⇒ infectious mononucleosis
    • Lack of effective immune control ⇒ lymphoproliferative diseases and cancers
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8
Q

Epstein-Barr Virus (EBV)

Clinical Presentation

A
  • Infectious mononucleosis is rarely fatal
    • Milder in children vs adults
  • EBV-associated lymphoproliferative diseases
    • Generally d/t B-cell proliferation w/o T-cell control
  • EBV ass. w/ several tumors of B-cell origin & other cell types including:
    • Post-transplant lymphoproliferative disease
    • Burkitt’s lymphoma
    • Hodgkin’s lymphoma
    • T/NK cell lymphomas
    • Nasopharyngeal carcinoma, Hairy cell oral leukoplakia
    • Gastric carcinoma
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9
Q

Infectious Mononucleosis

Overview

A
  • B-cell overgrowth controlled by a normal T-cell response to B-cell proliferation and EBV antigenic peptides
  • B-cells present EBV Ag on both MHC I and MHC II
  • Activated T-cells appear as atypical lymphocytes ⇒ Downey cells
    • ↑ # in peripheral blood during 2nd week of infection
      • 10-80% of total WBCs at this time
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10
Q

Infectious Mononucleosis

Clinical Manifestations

A

Sx results mainly from activation and proliferation of T-cells:

Classic triad: lymphadenopathy, splenomegaly, and exudative pharyngitis

  • Classic lymphocytosis ⇒ ↑ mononuclear cells
  • Swelling of lymphoid organs (lymph nodes, spleen, and liver)
  • Malaise and fatigue ⇒ a large amount of energy is required to power the T-cell response
  • Sore throat ⇒ response to EBV-infected epithelium and B-cells in the tonsils and throat
  • ± Rash, esp. after ampicillin tx (for a possible strep throat)
  • Children w/ less active immune response to EBV infection ⇒ mild disease
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11
Q

Epstein-Barr Virus (EBV)

Lymphoproliferative Diseases

A
  • EBV infection in pts w/o T-cell immunity ⇒ polyclonal leukemia-like B-cell proliferative disease and lymphoma, instead of mononucleosis
  • Transplant pts on immunosuppressive tx @ high risk for post-transplant lymphoproliferative disease
    • New exposure to EBV or reactivation of latent virus
  • Disease dissipates on reduction of immunosuppression
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12
Q

Epstein-Barr Virus (EBV)

Chronic Diseases

A
  • African Burkitt Lymphoma
    • Poorly differentiated monoclonal B-cell lymphoma of the jaw and face
    • Endemic in children living in the malarial regions of Africa
  • Burkitt Lymphoma
    • Tumor cells derived from lymphocytes
  • Hodgkin’s Lymphoma
  • Nasopharyngeal Carcinoma
    • Endemic in adults in Asia
    • Tumor cells are epithelial in origin
  • Hairy Cell Oral Leukoplakia
    • Unusual manifestation of a productive EBV infection of epithelial cells
    • Characterized by lesions of the tongue and mouth
    • Opportunistic manifestation in pts w/ AIDS
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13
Q

Epstein-Barr Virus (EBV)

Diagnosis

A
  • Based on sx, blood work, heterophile Ab, and EBV-specific Ab
  • Sx include HA, fatigue, fever, and classic triad of lymphadenopathy, splenomegaly, and exudative pharyngitis
  • CBC
    • Leukocytosis
    • Downey cells (atypical lymphocytes)
      • Appear w/ onset of sx
      • Disappear w/ resolution of disease
  • Heterophile Ab ⇒ IgM
    • Made by nonspecifically-activated, proliferating B-cells
    • Reacts w/ Paul-Bunnell Ag on sheep, horse, and bovine RBCs
    • Can usually be detected by end of 1st week of illness
    • Lasts for as long as several months
    • Basis for Monospot agglutination test
    • Often not present in children w/ infectious mononucleosis
  • EBV-specific Ab
    • Appear at different times post-infection
    • Used to distinguish b/t 1° infection and reactivation
    • ⊖ VCA Ab ⇒ no infection & person is susceptible
    • ⊕ Anti-VCA IgM ⇒ early EBV infection
      • Appears early in EBV infection and usually disappears w/in 4-6 weeks
    • ⊕ IgG vs viral capsid antigen (VCA) and Epstein Barr Nuclear Antigen (EBNA) ⇒ previous infection
  • Anti-VCA IgG
    • Appears in the acute phase of EBV infection
    • Peaks at 2-4 weeks after onset
    • Declines slightly then persists for the rest of a person’s life
  • Ab to EBNA
    • Not seen in the acute phase of EBV infection
    • Slowly appears 2-4 months after onset of sx
    • Persists for the rest of a person’s life
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14
Q

Epstein-Barr Virus (EBV)

Treatment/Prevention

A
  • No specific tx available for EBV infection
  • Vaccines specific to gp350 and EBV-specific CTL epitopes under development
  • Ubiquitous nature & potential for asymptomatic shedding makes control difficult
  • Infection elicits lifelong immunity
  • Exposure to virus early in life better b/c disease is more benign in children
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15
Q

Human T-Cell Lymphotropic Virus Type 1 (HTLV-1)

Overview

A
  • Leukemia virus characterized by a long latency period (> 30 years)
  • Associated with:
    • Tropical spastic paraparesis (TSP) ⇒ degenerative neurologic disorder
    • Adult T-cell leukemia/lymphoma (ATLL)
    • HTLV-1-associated myelopathy (HAM)
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16
Q

HTLV-1

Morphology

A
  • Retrovirus
    • Genus Deltaretrovirus, family Retroviridae, subfamily Orthoretrovirinae
  • In vivo tropism for CD4+ T-cells
  • Has also been shown to infect CD8+ T-cells, immature bone marrow cells, monocytes, cells of neural origin, and dendritic cells
  • Replication cycle characteristic of retroviruses:
    • Receptor-mediated entry via binding to glucose transporter GLUT-1
  • HTLV-1 genome is typical of complex retroviruses encoding:
    • Structural proteins (Envelope, Gag)
    • Enzymatic proteins (Reverse transcriptase, Integrase)
    • Regulatory proteins (Tax, Rex)
    • Accessory proteins
17
Q

HTLV-1

Epidemiology

A

Endemic to southern Japan, the Caribbean, and Central Africa

18
Q

HTLV-1

Transmission

A

Routes of transmission include:

  • Vertical transmission
  • Consumption of infected breast milk (predominantly Japan)
  • Sexual intercourse
  • IV drug use (US)
  • Blood transfusion (US)
19
Q

HTLV-1

Clinical Presentation/Pathogenesis

A
  • ~ 90% of infected individuals remain asymptomatic carriers during their lives
  • HTLV-1 causes two distinct diseases:
    • Adult T-cell leukemia/lymphoma (ATL) in ~4% over 30-50-year period
    • HTLV-1-associated myelopathy / tropical spastic paraparesis (HAM/TSP) in < 2% of infected individuals
  • Factors contributing to pathogenesis include:
    • Viral strain
    • Viral load
    • HLA haplotype
    • Route of infection
    • Host immune response
20
Q

Adult T-cell Leukemia/Lymphoma (ATLL)

Overview

A

Malignant lymphoma/leukemia of CD4+ T-cells

  • Progression to ATLL can take 30-50 years
  • Can be acute or chronic
  • Incidence of ATLL is greater in males
  • Characterized by leukemic T-cells, skin lesions, and abnormal lymph nodes
  • Usually monoclonal but can be polyclonal
  • Malignant cells called “flower cells” ⇒ pleomorphic w/ lobulated nuclei
  • Usually fatal w/in 1 year of dx, regardless of tx
21
Q

Adult T-cell Leukemia/Lymphoma (ATLL)

Subtypes

A

Differentiated as acute, lymphocytosis, chronic, and smoldering:

  • Acute (60%) ⇒ rapidly progressive skin lesions, pulmonary involvement, hypercalcemia, and immunodeficiency
    • Median survival is 6 months
  • Lymphocytosis (20%) ⇒ similar to acute except that circulating abnormal cells are rare
    • Pts have skin lesions and hypercalcemia
  • Smoldering (≤ 5%) ⇒ malignant cells have monoclonal pro-viral integration
    • No involvement of CNS, bone, or GI tract
    • Median survival is 5 years or longer
22
Q

HAM/TSP

Overview

A

HTLV-1-Associated Myelopathy (HAM) & Tropic Spastic Paraparesis (TSP)

  • Chronic inflammation w/ demyelination
  • Debilitating disease of the CNS
  • Lesions in the brain and spinal cord
  • Infected cell infiltrates into CNS tissue
  • Incidence of HAM/TSP is greater in females
23
Q

HAM/TSP

Clinical Manifestations

A
  • Weakness or stiffness in legs
  • Back pain
  • Urinary incontinence
  • Thoracic myelopathy
  • Spastic paraparesis or paraplegia
  • 30% of pts are bedridden w/in 10 years of Dx
  • 50% of pts are unable to walk w/in 10 years of Dx
24
Q

ATLL vs HAM/TSP

Immune Response

A

Cytokine profile in the serum differs b/t ATLL and HAM/TSP:

  • ATLL
    • ↑ IL-10, ↓ Treg cells
    • CTL response impaired
    • Manifests as lymphoproliferation
    • Pts considered immunosuppressed
  • HAM/TSP
    • ↑ Pro-inflammatory cytokines and chemokines
      • IFN-γ, TNF-α, CXCL9, and CXCL10
    • CTL response activated
    • Manifests as chronic inflammation
25
Q

HTLV-1

Diagnosis

A
  • HTLV-1-specific Ag in serum or CSF detected by ELISA
  • HTLV-1-specific nucleic acids detected by RT-PCR
  • PCR or ELISA w/ virus-specific synthetic peptides is necessary to distinguish b/t HTLV-1 and HTLV-2
  • ELISA can also be used to detect antiviral Ab
26
Q

HTLV-1

Treatment/Prevention

A
  • AZT (zidovudine) and IFN-α w/ efficacy in ATLL
  • Some success w/ oral corticosteroids or gamma-globulins to treat HAM/TSP
  • Interferon-α also has limited effectiveness in HAM pts
  • Vaccines specific to HTLV-1 under development

4. HDS Multisystem (43 decks)

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