Human Retroviruses Flashcards Preview

Infectious Disease: Unit 2 > Human Retroviruses > Flashcards

Flashcards in Human Retroviruses Deck (19):
1

Human diseases possibly associated with retroviruses

  • Human T-cell lymphotrophic virus 1 (HTLV-1)
    • Leukemia/lymphoma
  • Human foamy virus (HFV)
    • Lymphoblastoid cells
    • Cancer etiology unknown
  • Human endogenous retrovirus K  (HERV-K)
    • CML
    • Breast cancer
    • Prostate cancer
    • Melanoma
    • Autoimmune diseases (MS, RA, psoriasis, T1D)
  • HIV
    • Kaposi's sarcoma
    • Non-Hodgkins lymphoma

2

Retrovirus structure

  • HIV as "prototypical retrovirus"
  • 2 copies of RNA genome packaged inside capsid
  • Surrounding capsid - matrix
  • Outside matrix - envelope, derived from host cytoplasmic membrane
    • 2 membrane proteins: gp120, gp41

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3

3 essential genes in viral genome

  1. Gag
    • Encodes matrix, capsid, nucleic acid-binding proteins
  2. Pol
    • Encodes protease (PR), reverse transcriptase (RT), integrase (IN)
  3. Env
    • Proteins determine host range
    • Derived from host cytoplasmic membrane

4

Proteins encoded by pol gene

  • Protease (PR)
    • Cleaves viral polyproteins
  • Reverse transcriptase (TR)
    • Copies viral RNA genome --> dsDNA that contains long terminal repeats (LTRs)
      • Very inefficient
      • Drug target
  • Integrase (IN)
    • Integrates dsDNA made by RT into host genome = viral persistence
      • Integrated DNA also known as proviral DNA

5

Unique features of retroviruses: reverse transcription

  • Initiation of infectious cycle begins 1 of 2 ways
  • Integration into host chromosome
    • Envelope proteins bind to receptors on host cell and dump contents into cytoplasm OR
    • Endosomes take virus into host cells then dump contents into cell
  • Viral uncoating
  • In cytoplasm: RT makes dsDNA containing necessary LTRs
  • Productive infectious cycle begins when viral DNA enters nucleus, integrates into host DNA
  • Viral mRNAs made by host polymerase
  • Viral mRNAs processed by host splicing and polyadenylating enzymes
  • Retroviruses mature by budding from plasma membrane (just like other enveloped viruses)

6

3 mechanisms by which retroviruses contribute to development of cancer

  1. Acute transforming
  2. Nonacute transforming
  3. Trans-activation

7

Acute transforming mechanism

  • Some onco-retroviruses have a viral oncogene, derived from cellular proto-oncogenes

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8

Non-acute transforming mechanism

  • Addition of virus genome into host's genome
  • 2 types of non-acute transformations:
    • Insertion activation: virus sticking strong promoter/enhancer directly in front of proto-oncogene not normally expressed in host's genome
    • Enhancer activation: genome insertion many thousands of base pairs away
  • Can include growth factors, growth factor receptors, signal transduction proteins, and transcription factors 

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9

Trans-activation

  • Very comple - Not covered well in lecture
  • Rare
  • Involves accessory genes
  • Takes a long time

10

Human T-cell lymphotrophic viruses (HTLV): epidemiology and associated diseases

  • HTLV-1: δ-retrovirus that infects human T lymphocytes
  • Epidemiology:
    • Isolated in Japan, Caribbean countries, South America, Africa, parts of Iran
    • Transmission: sexual contact, blood products, needles, mother --> child during breastfeeding
      • Effective transmission relies on cell to cell contact
  • Associated diseases:
    • Adult T-cell leukemia/lymphoma (ATL)
    • HTLV-1 associated myelopathy (HAM) a.k.a. tropical spastic parapesis 
    • Overall increased susceptibility to other diseases 

11

Adult T-cell leukemia/lymphoma (ATL): types, treatment

  • Lymphoproliferative disorder - poor prognosis, difficult to treat
  • Tumor derived from single transformed cell infected by virus
  • 4 types:
    • Acute (50-60%): most patients die within 6 months of dx
    • Chronic type + lymphoma type (together 20%) - 2 year survival
    • Smoldering is slow and least aggressive (5%)
  • Treatment: all current chemotherapeutic regimens fail to treat ATL - some therapies are promising:
    • Stem cell transplanation
    • Monoclonal Abs against T-cell leukemia cells
    • Anti-virus drugs

12

ATL: clinical characteristics, histologic features

  • Enlargement of peripheral lymph nodes
  • Skin lesions due to leukemic cell infiltration
  • Lytic bone lesions and as a result, hypercalcemia
  • If acute, patients also have:
    • Increased ATL cells
    • Systemic lymphadenopathy
    • Pulmonary lesions
    • Hepatosplenomegaly
    • Immunodeficiency --> opportunistic infections often present, increase with course of disease
  • Histology: flower-like nucleus, easy to distinguish

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13

HTLV-1 associated myelopathy (HAM) a.k.a. tropical spastic parapesis

  • Autoimmune disease
  • Seems to be due to strong immune response to HTLV-1 antigens, including increased chemokine levels
  • Resembles MS:
    • Progressively paralytic disease of CNS
    • Demyelination of spinal cord nerves --> weakness, stiffness, paralysis of legs, resulting in many patients bedridden within 10 years
    • 2:1 ratio F:M
  • Tx: corticosteroids for some symptomatic relief
  • Uveitis: swelling/irritation of uvea (middle layer of eye), provides most of the blood supply to the retina

14

AIDS-defining cancers

  • Increased incidence with decreased CD4 counts
  • Kaposi Sarcoma: HHV-8
  • Non-Hodgkins lymphoma: EBV, HHV-8
  • Cervical cancer: HPV

15

Non-AIDS defining cancers

  • Not affected by CD4 counts
  • HAART increasing survival of people with HIV -- shift in natural spectrum of HIV related disease --> more non-AIDS defining cancers
  • Large range of common cancers

16

"Trends" in HIV-associated cancers

  • Cancer developing at young ages
  • Become more invasive cancers more rapidly
  • Atypical pathology with increased grade
  • More aggressive, worse outcomes
  • Relapse more common

17

Retroviral gene therapy: mechanism

  • Retroviruses used as vector in gene therapy
  • Viral genes (gag, pol, env) replaced with therapeutic gene
    • Human retroviruses not used
  • Areas of backbone homology removed to prevent recombination
  • Has been used to successfully treat 20 patients with SCID 
    • Except for the ones who developed leukemia
  • Highly controversial

18

Retroviral gene therapy: benefits

  • Wide host range
  • Stably integrate into host cell genome
  • Long term expression of transgene
  • Can easily modify genome for use as vector
  • Non-pathogenic in humans

19

Retroviral gene therapy: limitations

  • Capacity for therapeutic genes is small (< 8kb)
  • Infectivity limited to dividing cells
  • Relatively low titers
  • Randomly integrates into genome --> insertion mutagenesis