Micro Test 4: Retroviruses & Cancer

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Micro Test 4: Retroviruses & Cancer
2013-02-03 15:49:13
Micro Test Retroviruses Cancer

Micro Test 4 Retroviruses & Cancer
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  1. Only retrovirus from an animal that has been linked to cancer
  2. 4 Types of Oncogenic Retroviruses
    • Type 1:  Replication competent w/o vONC (gag-pol-env...avian leukovirus)
    • Type 2:  Replication competnet w/ vONC (gag-pol-env-vONC... Rous sarcoma virus)
    • Type 3:  Replication defective + vONC (gag-vONC-env...AEV)
    • Type 4:  Replication competent - vONC+TAX (HTLV-1)
  3. Aberrant versions of normal genes that control growth and development.
    Cellular oncogenes
  4. Cellular genes that have been captured by the virus and in the process have become oncogenic
  5. Both ____ and ______ changes in gene expression can lead to tumor development
    qualitative and quantitative
  6. v/c-erb-b
    Cellular/viral homolog of the epidermal growth factor receptor
  7. Lost the extracellular domain and this presumably leads to disregulation

    Intracellular domain is the autophosphoryation site (site w/ tyrosine kinase activity- can turn genes on and off by phosphorylating them.  Losing the extracellular receptor causes the intracellular portion to be constantly expressed)
  8. Oncongenic when overexpressed; mutations within the TK-domain noted in tumors
  9. Mechanisms of Oncogenesis:  Type I
    Promoter Insertion (integration of the proirus within, or upstream of, cellular genes leads ot aberrant gene expression)

    *Because integration is a random process, tumors develop in infected animals months after infxn
  10. Mechanisms of Oncogenesis:  Types 2 & 3
    Expression of viral oncogene leads to unrestrained growth in certain cell types.

    (Type 2 viruses= replication competent, Type 3 viruses= require co-infxn w/ a helper virus, e.g. ALV.  Because th evirus already contains the oncogene, tumors develop within weeks of infxn)
  11. Mechanisms of Oncogenesis:  Type 4
    Lack vONCs and preferred integration sites:  Unknown mechanism, but may involve transactivation of growth promoting lymphokines (e.g. IL-2) or activation of NFkB.

    ATL (causative agent of HTLV-I) tumors are monoclonal, but tumors from different pts show different sites of HTLV-1 integration.
  12. HIV had exponential growth in what time period?
    Early 1980s
  13. How many people are currently infected with HIV worldwide?
    34 million

    1.1 million in US

    (Currently the rates of infxn are dropping)
  14. Why has the rate of AIDs infxn dropped?
    • Sexually active ppl have fewer partners
    • Condom use has increased
    • Delay in age of onset of sexual activity
    • Increase in male circumcision in Kenya
    • 48% of HIV+ pregnant women have access to therapy to prevent infxn of their child
  15. Humans were first infected with HIV-1 (group M) about 70 years ago, and with HIV-2 about 60 years ago.
    Marked diversity between these two isolates suggests that HIV-1 was circulating long before the recognition of the AIDS pandemic.
  16. HIV-1 derived from?
    HIV-2 derived from?
    • HIV-1:  chimpanzees
    • HIV-2:  mangabeys
  17. Seen in individuals with direct contact with fresh primate bushmeat (1-3 million tons consumed/yr)
    Simian foamy virus
  18. Seen in persons who hunt, butcher, or keep monkeys as pets in South Cameroon
    HTLV-3, -4
  19. Origin of HIV
    monkey -> ppl who hunted them -> ppl in cities -> haitian peacekeepers -> caribean -> US
  20. Virus present in what body fluids?
    • Blood
    • Semen
    • Vaginal Secretions
    • Saliva
    • Tears
    • Breast milk
    • CSF
    • amniotic fluid
    • urine
  21. 3 Ways HIV is transmitted
    • 1) Parenterally: blood, blood products, needles
    • 2)  Sexually:  vaginal, oral, and anal routes
    • 3) Perinatally: in utero, during delivery, or post-partum via breast milk
  22. Probability of transmission depends on
    Virus load

    *Transmission is uncommon when virus load is <1500 copies/ml
  23. Chance on contracting HIV from heterosexual encounter
    1:200- 1:3000
  24. Chance of contracting HIV from homosexual encounter
    1:20 - 1:300
  25. HIV Transmission:
    Genital lesions increase probability of infxn
    Male to female transmission rate is higher than female to male.
  26. Risk of HIV infxn:
    Needle stick=
    Blood Products=
    • Needle stick= 0.33%
    • Mother-Child= 20-30%
    • Blood products= 95%
  27. Primary HIV-1 Infection
    • Mono- or Flu-like illness with a macular-papular rash
    • 50-90% of pts show clinically apparent symptoms within 15 days
    • Primary illness lasts 2 wks
    • (*15 days until symptoms, 15 days of symptoms)
    • 15% require hospitalization
  28. Pts. seroconvert within
    30-60 days
  29. HAART increases the length of
    Clinical Latency (prior to HAART it was 8-10 years)
  30. Full blown AIDS (CD4 count below 200) leads to death within
    1-2 years
  31. "Set point" is the point where
    Plasma viral RNA stabilizes

    • High set point= worse prognosis
    • Low set point= better prognosis
  32. Virus replicates in
    lymph nodes (regardless of present symptoms)
  33. 80% of mucosally transmitted HIV-1 infxns are initiated by
    a single virus particle
  34. Initial targets of HIV at mucosal surfaces
    Lymphoid cells

    *But within 5-10 days the virus enters draining lymph nodes where it encounters and replicates within CD4+/CCR5+ T cells
  35. 80% of CD4+ T cells within GALT are lost within
    3 weeks of infxn and numbers remain low thereafter
  36. Up to ____ of germinal centers within GALT are lost within 80 days of infxn.  Leads to defects with
    • 50%
    • Defects with the ability to rapidly generate high-affinity HIV-1 Abs and lead to delays in the induction of virus-neutralizing Abs
  37. Cytokine storm takes place 10-30 days post infection and is characterized by appearance of
    • IFN-a, IFN-y
    • IL-10, 15, 18, 22
    • CXCL10
    • TNF

    Intense cytokine response may promote viral replication and mediate immunopathology
  38. The window of opportunity for preventing the establishment of viral reservoirs may be as short as
    5-10 days
  39. Innate and anti-viral T cell responses reduce the virus load but do NOT
    • Eliminate the infxn OR
    • Prevent the establishment of viral reservoirs
  40. Early anti-HIV Ab is ineffective in controlling infxn.  Potentially protective Abs do NOT appear until after the initial control of viremia ~12 wks after transmission and are focused on only a few epitopes
    Overall, natural antiviral responses are "too little, too late"
  41. Clinical signs of HIV
    • Wt. loss
    • Night sweats
    • Fever
    • Lymphadenopathy
    • Diarrhea
    • Fatigue
  42. Tests for HIV Diagnosis
    • ELISA:  Requires two positive tests for anti-viral Abs (note: lupus, syphilis, etc. can give false positive results)
    • Western Blot Test:  A positive test for anti-viral antibodies or a positive indirect immunofluorescence assay (IFA) test
  43. HIV Stages:
    HIV+; CD4 >500 cells/ul or >29%
    Stage 1
  44. HIV Stages:
    HIV+; CD4 200-499 cell/ul or CD4/CD8 T cell percentage of 14-28%
    Stage 2
  45. HIV Stages:
    HIV +; CD4 >200 cells/ul or <14% or AIDS defining condition
    Stage 3
  46. AIDs-defining conditions:
    Fungal Infections
    • PCP
    • Candidiasis (esophagus, trachea, and lungs)
    • Disseminated histoplasmosis or coccidiodomycosis
    • Extrapulmonary cryptococcus
  47. AIDs-defining conditions:
    • Disseminated MAC
    • Atypical or extrapulmonary mycobacterial disease (M. avium-intracellularae (4%) and M. tuberculosis (2%))
    • Recurrent salmonella septicemia
    • Recurrent pyogenic bacterial infxns
  48. AIDS-defining conditions:
    • CMV
    • HSV
    • EBV
    • Polyomavirus JC (PML, Progressive Multifocal Leukoencephalopathy)
  49. AIDs-defining conditions:
    • Kaposi's Sarcoma
    • Primary lymphoma of the brain
    • other Non-Hodgkin's lymphomas
  50. AIDs-defining conditions:
    • Cryptosporidiosis
    • Isosporiasis
    • Toxoplasmosis of the brain
  51. AIDs-defining conditions:
    HIV encephalopathy
  52. 2 important factors in predicting HIV progression to AIDS
    • CD4 counts
    • RNA levels as determined by qRT-PCR
  53. HIV Target Cells:
    Positive for?
    • CD4+, CCR+
    • Cells of the macrophage/monocyte lineage (Langerhans cells, Follicular dendritic cells, microglial cells)
    • Other cells in the brain (endothelial cells, astrocytes, and fibroblasts)...these are all positive for galactosyl ceramide
  54. HIV infects cells in the brain that are positive for
    Galactosyl ceramide (Endothelial cells, astrocytes, fibroblasts)
  55. Infects monocytes macrophages, primary T cells, granulocyte precursors and microglial cells.
    It requires CD4 AND CCR5 (or CCR3) and is blocked by RANTES, MIP-1 alpha, -1beta
    May be required to establish an initial infxn
    M-tropic virus
  56. Cells that may act as mechanical vectors and carry HIV-1 to lymph nodes where infxn of T cells can take place.
    Dendritic cells
  57. May be required to establish initial HIV infxn
    M-tropic virus
  58. Infects a broader range of CD4+ cells
    T-tropic virus
  59. Co-receptors:
    M-tropic viruses?
    T-tropic viruses?
    • M-tropic:  CD4 and CCR5 (or CCR3)
    • T-tropic:  CDr and CXCR4
  60. Direct cause of immunodeficency in AIDS
    Loss of CD4 T cells
  61. Mechanism of CD4 cell loss
    • Direct cytopathic effect
    •          Loss of luxury functions (e.g. IL-2 synthesis)
    • ENV or TAT is cytotoxic
    • CTL-mediated lysis (autoreactive CTLs target uninfected CD4+ cells for destruction)
  62. Specific immunity is generated in the
    Lymph nodes (where 98% of HIV-1 replication takes place)

    Ultimately virus destroys the architecture of the lymph node
  63. HIV-1 and GI Infection:
    Replicates preferentially in mucosal tissues (such as gut) that are rich in
    a4B7+/CD4+/CCR5+ T helper cells

    *Loss of gut immunity, couple with damage to intestinal epithelium, allows the translocation of microorganisms from the intestinal lumen leading to systemic immune activation
  64. Prevention of Opportunistic Infections in HIV Patients:  PCP
    TMP/SMX (Bactrim)
  65. Prevention of Opportunistic Infections in HIV Patients:  MTB
  66. Prevention of Opportunistic Infections in HIV Patients:  T. gondii
  67. Prevention of Opportunistic Infections in HIV Patients:  MAC
  68. Prevention of Opportunistic Infections in HIV Patients:  VZV
    VZV Ig/ vaccination
  69. Prevention of Opportunistic Infections in HIV Patients:  S. pneumoniae
    23-valent polysaccharide vaccine
  70. Prevention of Opportunistic Infections in HIV Patients:  HBV, HAV, influenza
  71. Viruses and Cancer: 
    Kaposi Sarcoma
  72. Viruses and Cancer: 
    B cell lymphomas
  73. Viruses and Cancer:
    Anal/genital carcinomas
    HPV infxns
  74. Viruses and Cancer:
    HIV is not a
    causative agent.  It only causes immunosuppression and allows these viruses to initiate and progress.
  75. Patient Profile:  >40 years, Eastern European, Italian Jewish
    Kaposi's Sarcoma
  76. Localized, nodular tumors first on soles of feet then hands
    Kaposi's Sarcoma

    KS precedes full-blown AIDs