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233 Cards in this Set
- Front
- Back
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RNA tumor viruses belong to what families?
|
retroviruses
or flaviviruses |
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DNA tumor viruses belong to many families, including:
|
Papovavirus Family (HPV)
Herpesvirus Family (Epstein Barr virus, Karposi's sarcoma herpesvirus) Hepadnavirus Family (Hepatitis B virus) |
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Cutaneous T-cell lmyphoma
is strongly associated with what virus and what virus family? |
Human T-cell leukemia virus-1,2
(member of RETROVIRUS Family of RNA viruses) |
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Adult T-cell leukemia
is strongly associated with what virus and what virus family? |
Human T-cell leukemia virus-1,2
(member of RETROVIRUS Family of RNA viruses) |
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Hepatocellular Carcinoma
is strongly associated with what viruses, members of what virus families?)? |
Hepatitis C virus
(member of the FLAVIVIRUS Family of RNA viruses) Hepatitis B virus (member of HEPADNAVIRUS family of DNA viruses) |
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Cervical carcinoma
is strongly associated with what virus (a member of what virus family?)? |
Human Papilloma virus
(member of the PAPOVAVIRUS family of DNA viruses) |
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Burkitt's lymphoma
is strongly associated with what virus (a member of what virus family?)? |
Epstein Barr virus
(member of the HERPESVIRUS family of DNA viruses) |
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Nasopharyngeal carcinoma
is strongly associated with what virus (a member of what virus family?)? |
Epstein Barr virus
(member of the HERPESVIRUS family of DNA viruses) |
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Kaposi's Sarcoma
is strongly associated with what virus (a member of what virus family?)? |
Kaposi's sarcoma herpes virus
(member of the HERPESVIRUS family of DNA viruses) |
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What do tumor viruses do?
|
cause cancer in laboratory animals
cause cells grown in tissue culture to undergo transformation |
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In most cases, what element is responsible for cell transformation by tumor viruses?
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usually a viral gene (ONCOGENE) is responsible for transformation
frequently, viral oncogene is integreated into the host cell chromosomal DNA |
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result of expression of viral oncogene product
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disruption of regulation of cellular growth control
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Detection of oncogenic viruses in tumors:
4 techniques |
1. detect INFECTIOUS VIRUS by preparing a cell free extract of tumor and
a) testing for its ability to cause tumors when injected into animals b) determining its ability to transform tissue culture cells 2. Viral proteins may be detected by immunological methods, Fluorescent Abs, W. Blotting, ELISA 3. Viral nucleic acid may be detected by N. Blotting, S. Blotting or PCR 4. Detection of viral nucleic acids and/or proteins (from tumors that retain small portion of viral genome) |
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Morphological differences between normal cells and cancer cells
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NORMAL CELLS:
grow in orderly way flat in culture CANCER CELLS: grow in disordered way rounded |
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Biochemical differences between normal cells and cancer cells
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CANCER CELLS: have an increased rate of glycolysis and glucose transport
often have loss of actin filaments, secrete high levels of proteinases and have reduced surface fibronectin |
|
|
RNA tumor viruses belong to what families?
|
retroviruses
or flaviviruses |
|
|
DNA tumor viruses belong to many families, including:
|
Papovavirus Family (HPV)
Herpesvirus Family (Epstein Barr virus, Karposi's sarcoma herpesvirus) Hepadnavirus Family (Hepatitis B virus) |
|
|
Cutaneous T-cell lmyphoma
is strongly associated with what virus and what virus family? |
Human T-cell leukemia virus-1,2
(member of RETROVIRUS Family of RNA viruses) |
|
|
Adult T-cell leukemia
is strongly associated with what virus and what virus family? |
Human T-cell leukemia virus-1,2
(member of RETROVIRUS Family of RNA viruses) |
|
|
Hepatocellular Carcinoma
is strongly associated with what viruses, members of what virus families?)? |
Hepatitis C virus
(member of the FLAVIVIRUS Family of RNA viruses) Hepatitis B virus (member of HEPADNAVIRUS family of DNA viruses) |
|
|
Cervical carcinoma
is strongly associated with what virus (a member of what virus family?)? |
Human Papilloma virus
(member of the PAPOVAVIRUS family of DNA viruses) |
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|
Burkitt's lymphoma
is strongly associated with what virus (a member of what virus family?)? |
Epstein Barr virus
(member of the HERPESVIRUS family of DNA viruses) |
|
|
Nasopharyngeal carcinoma
is strongly associated with what virus (a member of what virus family?)? |
Epstein Barr virus
(member of the HERPESVIRUS family of DNA viruses) |
|
|
Kaposi's Sarcoma
is strongly associated with what virus (a member of what virus family?)? |
Kaposi's sarcoma herpes virus
(member of the HERPESVIRUS family of DNA viruses) |
|
|
What do tumor viruses do?
|
cause cancer in laboratory animals
cause cells grown in tissue culture to undergo transformation |
|
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In most cases, what element is responsible for cell transformation by tumor viruses?
|
usually a viral gene (ONCOGENE) is responsible for transformation
frequently, viral oncogene is integreated into the host cell chromosomal DNA |
|
|
result of expression of viral oncogene product
|
disruption of regulation of cellular growth control
|
|
|
Detection of oncogenic viruses in tumors:
4 techniques |
1. detect INFECTIOUS VIRUS by preparing a cell free extract of tumor and
a) testing for its ability to cause tumors when injected into animals b) determining its ability to transform tissue culture cells 2. Viral proteins may be detected by immunological methods, Fluorescent Abs, W. Blotting, ELISA 3. Viral nucleic acid may be detected by N. Blotting, S. Blotting or PCR 4. Detection of viral nucleic acids and/or proteins (from tumors that retain small portion of viral genome) |
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|
Morphological differences between normal cells and cancer cells
|
NORMAL CELLS:
grow in orderly way flat in culture CANCER CELLS: grow in disordered way rounded |
|
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Biochemical differences between normal cells and cancer cells
|
CANCER CELLS: have an increased rate of glycolysis and glucose transport
often have loss of actin filaments, secrete high levels of proteinases and have reduced surface fibronectin |
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Differences in Growth of Cancer cells and normal cells:
|
Cancer cells do not exhibit contact inhibition and continue to divide after they touch eachother
cancer cells also have a reduced requirement for EC growth factors or serum |
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many viruses grow better is cells that are doing what?
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actively synthesizing DNA
however most cells in the body are quiescent and not dividing |
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what do several DNA viruses do to facilitate their growth in host cells
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'push' the host cell into the cell cycle by modifying host proteins or gene expression
normally this results in cell death and production of more virus however, rarely this can result in transformation of host cells |
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Papovaviruses (family members include)
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Papilloma virus (human and other mammalian hosts)
Polyoma virus (rodent hosts) SV40 (monkey hosts) |
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Papovavirus (nucleocapsid)
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small
NAKED circular dsDNA genome (<10kb, encoding <10 genes) relies greatly on host proteins (DNA pol and RNA pol) for replication and gene expression |
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SV40
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a papovavirus
non-cytopathic virus of rhesus monkeys could produce lytic infection in green monkey cells and cause tumors in hamsters does not cause tumors in humans |
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what is essential for papovavirus growth?
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all the papovavirus genes
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Temporal Regulation of Viral gene expression and DNA replication
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1. Early host RNA pol transcribes the early TAg
2. TAg binds to the ori and then host DNA pol binds to TAg 3. Semiconservative, bidirectional DNA replication results in many copies of Gene for TAg 4. After replication the capsid genes are transcribed from the late promoter |
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classes of Papovavirus genes
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Early genes
Late genes |
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With SV40 when is the large T-antigen gene is expressed?
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EARLY
T-antigen recognizes the start site for SV40 DNA replication (ori) and binds to it |
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How are SV40 viral particles released?
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via cell lysis following self-assembly of SV40 nucleocapsids following late transcription of the capsid genes
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Large T-antigen
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multifunctional protein
also binds to an inactivates tumor suppressor genes Rb and p54. This overcomes cell growth inhibition leading to tumor development. essential for virus replication and tumor development |
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Tumor suppressors
|
act as gatekeepers to prevent entry into the cell cycle. In health cells these are inactivated by cyclin/CDK complexes to promote entry into the cell cycle
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HPV (virus family)
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most important member of Papovavirus family
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HPV (reponsible for what patholgies)
|
-responsible for benign tumors (papillomas, including plantar and genital warts (chondylomata acuminata)
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# of types of HPV
# associated with anogenital lesions |
>60 different HPV types
~1/3 associated with anogenital lesions |
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% of college aged women who harbor HPV in their cervix
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1/3
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epidemiological studies suggest direct causal realtionships between cervical neoplasia and
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sexual activity (multiple partners or early onset of sexual relations)
or exposure to a promiscuous male |
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molecular analysis has indicated that 80-90% of cervical carcinomas....
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harbor HPV viral sequences integrated into the cellular DNA
HPV is considered an eitiologic agent of invasive cervical carvinoma |
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most common manifestations of urogenital HPV infection
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condylomas
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most condylomas (the most common manifestation of urogenital HPV infection) are caused by
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nononcogenic type of HPV (6b and 11)
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greater than 75% of cervical carcinomas are caused by two high risk papillomaviruses
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HPV16 and HPV18
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identified HPV oncogenes
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early genes E6 and E7 (also essential for viral growth)
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in HPV caused warts; the viral genome is...
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extrachromosomal (not integrated) and the virus replicates
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in HPV related cervical tumor cells the E6 and E7 oncogenes are found...
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integrated into the cellular chromosome and are highly expressed
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Early gene E6 binds...
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p53,
thus inactivating this tumor suppressor and allowing entry to the cell cycle, leading to transformation |
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Early gene E7 binds...
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Rb,
thus inactivating this tumor suppressor and allowing entry to the cell cycle, leading to transformation |
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other cofactors are involved in the generation of cervical carcinoma, evidenced by the fact that
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women infected with HPV 16 or 18 do not always develop cervical cancer
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current clinical strategy for prevention of cervical cancer is based on:
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encouraging "safe sex"
and early detection of abnormal cells by early cytologic examination of cervical spears (Papanicolaou stain) |
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HPV vaccine
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recombinant vaccine, has been developed and is now licensed for pediatric use (based on viral capid proteins expressed in yeast)
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adenovirus as tumor virus
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not associated with tumors in humans
some can cause tumors in hamsters and transform rat cells in vitro |
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adenovirus proteins associated with transformation
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E1A (can partially transform cells on its own)
E1B (that does not transform, but increases levels of E1A) |
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E1 binds to
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tumor suppressor proteins (Rb, p300, and CBP)
cellular transcription factors to stimulate transcription associated with S phase where DNA replication occurs |
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Herpesvirus (genome)
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large, linear, dsDNA genome
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Herpesvirus (nucleocapsid)
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icosahedral nucleocapsid,
surrounded by a protein tegument, enclosed in a glycoprotein bearing envelope (large, linear dsDNA genome) |
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two herpesviruses are known to cause cancer:
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epstein barr virus causes burkitt's lymphoma
kaposi's sarcoma herpes virus (HHV8) is a virus isolated from AIDS patients that causes Kaposi's sarcoma |
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Burkitt's lymphoma
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(caused by Epstein Barr virus)
is the most frequent childhood tumor in africa, boys are at greater risk |
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tumors of Burkitt's lymphoma
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multifocal, malignang B-cell lymphomas, which often present as large masses in the jaw or lower abdomen
histologically: "starry cell" appearance in untreated, patients generally die within 6 months of diagnosis, chemotherapy works |
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Burkitt's lymphoma (where is it prevalent?)
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in certain regions of Africa (hot/wet regions... originally thought virus with mosquito vector) virus part correct, mosquito part WRONG
very rare in the US and Europe |
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Where are EB viral particles found?
|
in cell lines from Burkitt's lymphoma tissue
and in B-cells from patients with infectious mononucleosis |
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biological hallmark of EB virus infection
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presence of transformed, latently infected B-cells
transformed B-cells always contain extrachromosomal EB virus genomes, however no virus is produced INTEGRATION of viral genes is NOT required for cell transformation |
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genetic mutation in Burkitt's lymphoma tumors
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chromosomal translocation between chromosome 8 and chromosome 14 or 22 (t(8;14) and t(8;22)
either translocation places the c-myc proto-oncogene on chromosome 8 under transcriptional control of an immunoglobulin gene this causes the proto-oncogene to be overexpressed and causes immortalization |
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ordinarily immune system contains transformed cells by:
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an aggressive T cell response
only when the immune response is compromised do these cells grow as tumors |
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restricted geographic distribution of Burkitt's lymphoma is attributed to
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role of infection with malarial parasites in disease development
malaria is a cofactor because it inhibits cell-mediated immunity in children |
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EB virus also infects what type of cells?
also associated with what type of cancer in addition to Burkitt's lymphoma? |
epithelial cells
nasopharyngeal carcinoma (98/100,0000= high incidence in older males in s. china and se asia) |
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what virus causes lyphoproliferative disease in immunesuppressed graft recipients
|
Epstein Barr virus
has also been associated with other malignancies such as gastric carcinoma, Hodgkin's disease, and tumors seen in AIDS patients (CNS lymphomas, non-Hodgkin's lymphoma) |
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most frequent neoplasm occuring in AIDS patients
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AIDS-associated Kaposi's sarcoma (KS) 15-20% of AIDS patients develop KS
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KSHV (Kaposi's sarcoma-associated herpesvirus)
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aka HHV8
has been found in virtually all biopsies of AIDS associated Kaposi's sarcomas |
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Prior to the 1980s KS was typically found
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rare
observed mostly in elderly males of Mediterranean or eastern european descent |
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KS tumors usually present as:
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multiple, pigmented highly vascularized nodules of skin (contain replicating spindle cells)
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vascular endothelial growth factor
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powerful angiogenic factor expressed in KS tumors cells
this is a cellular protein, not from a virus |
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Kaposi's sarcoma-associated herpesvirus (KSHV) oncogenes
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a GPCR induces VEGF expression and angiogenesis
virally encoded cyclin homolog and the LANA antigen has been shown to activate cellular genes promoting cell growth |
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Retroviruses (virion)
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ENVELOPED
nucleocapsid contains 2 identical copies of +ssRNA (~10kb long) |
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all nondefective retroviruses encode:
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three essential genes:
gag pol env |
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essental retrovirus gene
gag, encodes: |
encodes nucleocapsid and capsid proteins
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essental retrovirus gene
pol, encodes: |
reverse transcriptase and integrase
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essental retrovirus gene
env, encodes: |
envelop glycoproteins
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retrovirus (replication and viral protein translation)
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mRNA copies of retroviral genes are translated into large precursor proteins that are posttranslationally cleaved into the individual viral proteins
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2 subfamilies of medically important retroviruses
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1. ONCOVIRUSES (associated with tumor formation)
2. LENTIVIRUSES (not directly associated with tumor formation) |
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examples of retroviral ONCOVIRUSES
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RSV (Rous sarcoma virus)
FeLV (feline luekemia virus) ALV (avian leukosis virus) MuLV (murine leukemia virus) HTLV-1,-2 (human T-cell luekemia virus-1 and 2) |
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examples of retroviral LENTIVIRUSES
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HIV-1 and HIV-2
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two stages of retrovirus lifecycle
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extracellular phase as a viral particle
intracellular phase as a provirus |
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what blocks retroviral replication?
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inhibitors that specifically block DNA synthesis
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what first led to the proposal that retroviruses replicate from a DNA intermediate?
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the fact that retroviral replication is blocked by inhibitors that specifically block DNA synthesis
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retroviral (replication)
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virion RNA is copied into dsDNA by reverse transcriptase (a viral protein, an RNA-directed DNA polymerase)
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reverse transcriptase
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an RNA-directed DNA polymerase
a retroviral protein that copies retroviral RNA into dsDNA |
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the sequence of the DNA provirus is the same as what?
except for?? |
the RNA genome in viral particles
except for the very long 5' and 3' ends which become duplicated during reverse transcirption and are called LTRs (long terminal repeats) |
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LTRs contain regulatory elements for what?
|
viral transcription
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what is the template for genome replication and mRNA transcription of a retrovirus?
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the DNA provrius (synthesized by reverse transcriptase from retroviral ssRNA)
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where does reverse transcriptase involved in retroviral replication come from?
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it is inside the retroviral virion bound to the nucleocapsid
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where does reverse transcription begin?
what is the initial product of reverse trasncription? |
begins at a promer of cellular tRNA
initial product is a DNA-RNA hybrid |
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why degrades viral RNA of DNA-RNA hybrid
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RNase H (a ribonuclease specific for DNA-RNA hybrids)
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what synthesizes the 2nd DNA strand of dsDNA copied from retroviral RNA?
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reverse trasncriptase (it does it all!)
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what is longer retroviral dsDNA or RNA?
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dsDNA genome is slightly longer than the initial viral RNA because during reverse tnrascription Long Terminal Repeats (LTRs) sequences are added to each end.
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provirus
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newly synthesized dsDNA (released from nucleocapsid, has entered nucleus and has) integrated at a random site in the cellular DNA
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LTRs are important to what part of retroviral lifecycle?
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the integration of dsDNA genome into the host cellular DNA (to create a provirus)
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how does replication/transcription of the retroviral PROVIRUS begin?
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begins from the viral PROMOTER in the LTR by the host RNA polymerase (to produce gag,pol mRNA)
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what happens to the viral mRNA produced from provirus?
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either:
translated into viral proteins or packaged into viral nucleocapsids with reverse transcriptase |
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how are new retroviral particles released from host cell?
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nucleocapsids bud through the cytoplasmic membrane for final assembly into mature enveloped viral particles
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retroviruses rarely cause cancer in humans, what species do they effect?
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most oncogenic retroviruses infect rodent or avian species
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acute transforming retroviruses
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(category of oncogenic retroviruses)
cause cancer rapidly in lab animals and quickly transform tissue culture cells these viruses have an oncogene (in most cases the oncogene replaces on of the normal viral genes (gag,pol and env) and so they are DEFECTIVE |
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nonacute transforming retroviruses
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take many years to cause cancer in laboratory animals. these viruses do not have oncogene
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categories of oncogenic retroviruses
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a. acute transforming viruses (quick, oncogene replaces normal viral gene)
b. nonacute transforming retroviruses (slow, no oncogene) also classified into types (A,B,C,D) based on appearance under electron microscope |
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Rous sarcoma virus (RSV)
type of virus (and specific category) |
retrovirus (acute transforming virus)
induces sarcoma rapidly in chickens (wks-months) and transforms tissue culture cells w/in 24 hours of infection carries viral oncogene, called src (was id'd using transformation defective mutants of RSV that contained a deletion in the viral genome) |
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oncogene is RSV
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src
expression of src is required for both the induction and maintenance of the transformed phenotype |
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proto-oncogene
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cellular gene from which oncogenes are derived
positive growth control switches "GO SIGNALS" in normal cells proto-oncogenes do not cause cancer, rather they regulate growth and cellular differentiation |
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what did radioactive src gene (RSV oncogene) probe hybridize with?
|
DNA of normal chicken cells
indicating that normal cells have a gene homologous to the viral gene |
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src gene encodes
|
a tyrosine specific protein kinase
viral src gene is mutated relative to the cellular proto-oncogene, and the oncoprotein has a 50-100 fold higher kinase activity than the normal Src protein |
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what src protein is more active?
the protein of the cellular proto-oncogene or the viral oncoprotein |
the oncoprotein has a 50-100x higher kinase activity than the normal Src protein
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proto-oncogenes can be divided into 5 groups:
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1. growth factors
2. growth factor receptors 3. protein kinases 4. signal transducing G proteins 5. nuclear proteins that regulate transcription and DNA replication |
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how do protooncogenes become oncogenes?
|
if they are mutated or expressed at abnormally high levels
the tightly regulated networks that control cellular growth are short-circuited |
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all of the known acute transforming retroviruses (except 1) are...
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DEFECTIVE RETROVIRUSES: have one or more of the viral gene(s) required for growth (gag, pol, or env) replaced by an oncogene
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acute transforming virus MC29 causes
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myelocytomas
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in acute transforming virus MC29, the pol and env genes have been replaced by what?
|
the myc oncogene
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what is required for DEFECTIVE (acute transforming) RETROVIRUSES to produce infectious virions?
|
a "helper virus":
the cell must also be infected with a related nondefective retrovirus, which supplies the missing viral proteins |
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isolates of a defective virus will be mixtures of what?
|
defective and helper virus
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why do viral oncogenes cause cancer when they reside in retroviral genomes?
|
1. viral oncogene is expessed at very high levels
2. viral oncogenes frequently have mutations that cause them to have increased activity |
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NONACUTE TRANSFORMING RETROVIRUSES (in this class)
|
a) do NOT have a viral oncogene
b) are nondefective and replicate by themselves (w/o a helper virus) c) take a long time to induce cancer (many months or years) 2. in tumors caused by nonacute transforming retroviruses the provirus is often found integrated adjacent to a proto-oncogene 3. this places the proto-oncogene under the control of the highly active retroviral promoter (transcriptional control region in the LTR) and causes increased proto-oncogene expression. |
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oncogenic human retroviruses
|
T-cell luekemia virus-1 and 2 (HTLV-1,2)
|
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what is the etiologic agent of adult T-cell leukemia (ATL)?
|
HTLV-1
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HTLV (where is it endemic?)
|
southern Japan, central Africa and the Caribbean
incidence of infection in the US is 0.025% |
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HTLV (transmission)
|
horizontal transmission via sexual contact in blood
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HTLV (symptoms of infected individuals)
|
usually asymptomatic
~0.1% develop adult T-cell luekemia following a long latency of 10-30 years |
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Viral tax protein
|
transcription factor
induces IL-2 and its receptor and may set up an autocrine loop, predisposing to transformation |
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HTLV (transmission)
|
horizontal
via sexual contact or in blood |
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HTLV (symptoms of infection)
|
usually asymptomatic
|
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HTLV (incidence/incubation of ATL)
|
~0.1% of infected individuals develope adult T-cell luekemia following a long latency of 10-30 years
|
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Viral Tax protein
|
transcription factor
induces IL-2 and its receptor may set up an autocrine loop, predisposing to transformation |
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leading cause of cancer deaths worldwide
|
hepatocellular carcinoma
|
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Hepatitis B (causes what type of cancer)
|
hepatocellular carcinoma (leading cause of cancer deaths world wide)
responsible for 500,000 cancer deaths annually |
|
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Hepatitis B (incidence of chronic disease and hepatocellular carcinomas)
|
~5% of infected individuals become chronic carriers and express the virus for life
2-4% of carriers go on to develop primary hepatocellular carcinoma |
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what characterizes hepatocellular tumors caused by hepatitis B
|
tumors have integration of HepB virus DNA
mechanism of tumor induction is unclear (no identified viral oncogene) suspected that integration near a cellular proto-oncogene leads to overexpression and induces transformation |
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potential mechanism of tumorgenesis in HepB patients
|
constant destruction of liver tissue by the immune response, followed by regeneration, which may predispose to mutations leading to cell transformation
|
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Immunization against Hep B may help prevent:
|
primarily hepatocellular carcinoma (particularly in the case of maternal transmission to neonates)
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How is hepadnavirus replication similar to retroviral replication
|
Hep B is a hepadnavirus, replication is similar to retroviral replication in that it utilizes hepadnavirus reverse transcriptase
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Hep B (replication)
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1. genome of HepB is circular dsDNA (w/ 2 gapped, ss regions)
2. Hep B virus encodes reverse transcriptase (sometimes called DNA polymerase) 3. Following adsorption, viral nucleocapsid travels to the nucleus (where gaps are filled in by reverse transcriptase) 4. Cellular RNA polymerase transcribes viral genes into short mRNAs and viral proteins are translated 5. Late in infection, RNA pol makes long RNA copies of the entire genome called pregenomes 6. nucleocapsid forms around pregenome, which is copies into DNA by hepB reverse transcriptase INSIDE capsid 7. nucleocapsid, containing newly replicated dsDNA genome buds through plasma membrane to form an enveloped virus |
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pregenomes
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long RNA copies of the entire genome
(made by RNA polymerase late in HepB infection, nucleocapsid forms around pregenomes which are copied into DNA by hep B virus reverse transcriptase INSIDE the nucelocapsid) |
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where is dsDNA of HepB viral progeny copied?
|
in the nucleocapsid of new viral particle
(copied by hep B virus reverse transcriptase from pregenome) |
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both retrovirus and hepB virus depend on what for replication?
|
reverse transcriptase that is found in the virion
-in RETROVIRUSES: reverse transcription is early in the infection of a cell -in HEP B VIRUS- the reverse transcription takes place very alte in production of virions |
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lamuvidine
|
inhibits both:
the reverese transcriptase of Hep B and retroviral reverse transcriptase |
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Hepatitis C (virus type)
|
RNA virus- Flavivirus
|
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Hep C (prevalence of persistent infection, cirrosis and hepatocellular carcinoma)
|
the majority of patients infected with HCV become persistently infected
20% will develope life-threatening cirrosis and some will develop life-threatening hepatocellular carcinoma |
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Hep C (potential mechanism for tumorgenesis)
|
does NOT contain any known oncogenes
does NOT integrate into genome (RNA virus) Infection by itself does not kill liver cells, but immune response to infection likely promotes tumor development as for HBV, alcoholism enhances rate of hepatocellular carcinoma, suggesting costnat liver damage and regeneration may predispose to mutations and cancer dvpt |
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AIDS (caused by what virus?)
|
aquired immune deficiency syndrome
(caused by the HUMAN T CELL LYMPHOTROPHIC RETROVIRUS HIV-1, also HIV-2 |
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lentivirus is a subfamily of what virus type?
|
retroviruses
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HIV-2
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endemic in regions of West Africa, along with HIV-1 a cause of AIDS
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What does it mean, that the HIV retrovirus is "NONDEFECTIVE"
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that it is replication competent
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what happens to an HIV-infeceted cell once it begins to produce viral protein and HIV virus
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it will eventually be killed
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Does HIV have a viral oncogene?
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NO
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characterize the life-cycle of HIV
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similar to the typical retrovirus lifecycle
a complex virus HIV has regulatory genes that are not present in most other retroviruses |
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HIV (adsorption by host cell)
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by specific interaction between envelope glycoproteins and proteins in the plasma membrane of the cell
viral envelope glycoprotein (gp120) binds to host cell surface CD4 antigen |
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an important host cell of HIV-1:
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the CD4+ helper T-lymphocyte (CD4+CD8-)
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The CD4 antigen is primarily found on:
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CD4+ helper T-lymphocytes (CD4+CD8-)
monocytes macrophages microglial cells dendritic cells and on other cells that HIV infects |
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What is required to permit entry of HIV into host cell?
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CD4 antigen
AND interaction w/ a host cell co-receptor [CXCR4; CCR5] of the chemokine receptor superfamily] |
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what mediates fusion of HIV viral envelope with the cell membrane resulting in nucelocapsid entry?
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viral envelop glycoprotein (gp41)
gp120 binds to host cell surface CD4 antigen |
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What happens once HIV virus enters host cell
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1) Virus sheds protein coat
2) HIV-associated reverse transcirptase makes a DNA copy of HIV RNA 3) HIV integrase protein acts to physically integrate the HIV DNA into the DNA of the host cell (now = PROVIRUS) |
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at what point in HIV infection is the HIV virus a Provirus?
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once HIV integrase has physically integrated the copies HIV DNA into the DNA of the host cell
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what can integrated HIV viral DNA do?
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one of 3 things:
a) latency b) controlled HIV growth c) extensive viral growth resulting in lysis of the host cell |
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what transcribes mRNA encoding HIV proteins
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HOST RNA polymerase
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HIV (modes of transmission)
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primarily sexual contact and by transfer of infected blood
HIV-1 has been detected in various body fluids including semin, blood, tears, vaginal secretions, breast milk, etc. Infection occurs by transfer of HIV virus or HIV-infected cells higher concentrations of HIV virus are associated with increased transmission risks saliva and tears are probably insignificant in natural transmission |
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HIV (relative risks)
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a) Homosexual and heterosexual intercourse: receptive anal> receptive vaginal > penetrative (STDs and penile lesions increase risk of all)
b) Perinatal (25-30% risk if not treatment provided) > Transplacentral d) breast feeding (can be eliminated, but at cost) e) blood transfusion (rare bc of testing) f) administration of products derived from blood g) inadvertant blood transfer: major problem among intravenous drug addicts (concern for med personnel) |
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HIV (cost of life)
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current world-wide HIV pandemic has caused millions of deaths
still growing at alarming rate recent data has shown substantial declines in AIDS incidence and deaths in the US, but that rate of decline is now slowing |
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HIV (symptoms of primary infection)
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mono- or flu-like syndrome, fever, enlarged lymphnodes, tiredness, headache
viremia is high during this early symptomatic phase following this acute symptomatic episode the patient often has a period of normal health and immunity |
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HIV (characterize the viremia in the clinically latent period)
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Decrease in viremia, correlating with seroconversion
(generally low levels of virus in plasma and PMNs) however... EXTENSIVE HIV REPLICATION in LYMPHOID TISSUE (and viral growth in CD4+ T-cells) |
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In HIV:
extensive viral growth in CD4+ T-cells appears to require what? |
activation of the cells by the antigen for which they are specific
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HIV (what is happening during the clinically altent stage, how long does it usually last)
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CD4+ cells are lost at a steadly slow rate (that accelerates with time)
cinically latent stage usually lasts 3-10 years |
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consequences of depletion of CD4+ T-cells
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loss of cell-mediated immunity
increase in the incidence of a variety of infectious diseases (the usual final cause of death) and some tumors |
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CDC definition of AIDS:
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<200 CD4+ T-cells/mm^3
(Normal = 600-1,200) or a CD4+ T cell percentage < 14% of total lymphocytes + one of the AIDS-defining infections or cancers |
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Immune response to HIV
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humoral and cellular immune responses detected w/in weeks/months of primary infection
includes specific Ab response to HIV glycoproteins and other HIV proteins CTL response directed against HIV-infected cells these immune responses ultimately fail to protect against HIV-induced disease |
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Immune defects seen in HIV infection
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primarily defined as loss of CD4+ helper T-cells,
also-chronic activation of the immune system impaired fnx of monocytes-macrophages |
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susceptibility fo infectious diseases in HIV/AIDS
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AIDS patients have a specific spectrum of susceptibility to certain infectious diseases? LIKE??????
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Malignancy in HIV/AIDS
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AIDS patients have increase susceptibility to malignancy
Kaposi's sarcoma and B cell lymphoma |
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Kaposi's sarcoma in HIV/AIDS patients is associated with what other co-viral infection
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Herpesvirus
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additional clinical aspects of HIV/AIDS
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a. Chronic lymphadenopathy
b. autoimmune thrombocytopenia c. dementia/diffuse brain disease is well recognized in later stages of HIV infection |
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AIDS (rate of progression)
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highly variable (rapid progression, slow progression, or less frequently, non-progression)
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some common pathogenic mechanisms in HIV/AIDS
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cytopathic effect of a protective HIV infection on CD4+ cells
CTL destruction of HIV-infected cells altered function of HIV-infected cells (aberrant cytokine production/signalling/lymphocyte trafficking, chronic immune system activation, etc) and apoptosis of HIV-infected CD4+ cells |
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Factors contributing to varied pathogenesis of AIDS (J-21 ??? WHAT IS IMPORTANT HERE?)
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a. inoculating dose/route, virulance of HIV train at primay infection
b. effectiveness of immune response c. gender (women have same progression w/ 1/2 viral load of men) d. HIV replication is occuring throughout e. mechanisms of CD4+ helper T-cell depletion in HIV/AIDS |
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TESTS for HIV
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1) ELISA for Ab against mixed virion antigens
2) Western blot of Ab against HIV antigens of molecular weight 25,000 or 41,000 3) New generation tests for HIV detect HIV Ag and Ab against HIV antigen simultaneously 4) PCR for HIV RNA |
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tests for HIV:
ELISA for Ab against mixed virion antigens |
a) virion antigens (gp41 or p24) fixed to a plastic bead
b) react the bead with patient's serum (Ab to HIV-1 will attach to the bead) c) wash away unattached Ab, then detect the attached Abs with an enzyme-linked anti-human IgG Ab SENSITIVITY: 99% (prob. of positive test when serum +) SPECIFICITY: >99% of a negative test when serum negative |
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tests for HIV:
WESTERN BLOT for Ab against HIV antigens of MW 25,000 or 41,000 |
a) resolve the HIV Antigens by MW using acrylimide gel electrophoreses
b) transfer (blot) the resolved proteins to membrane c) react membrane with patient's serum and wash away unbound Ab d) detect the attached human Ab with labeled second Ab against human IgG e) Sensitivity: less than ELISA f) Specificity: greater than ELISA |
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tests for HIV:
better SENSITIVITY |
ELISA is more sensitive than Western blot for anti-HIV Ag Antibodies
more likely to be positive when serum is positive |
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tests for HIV:
better SPECIFICITY |
Western blot for anti-HIV ag Antibodies is more specific than ELISA
(more likley to be negative when serum is negative) |
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Use of Tests for infection with HIV-1
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1) Exclusion of Blood Donors: single + ELISA, presence of HIV Ag, or presence of HIV RNA
2) Serological detection of HIV infection: 2 consecutive + ELISAs followed by a + Western blot 3) HIV-1 can be isolated by infection of certain lines of CD4+ T-lymphocytes known to be susceptible 4) HIV-1 genomes can be detected by reverse transcription into DNA followed by PCR. The DNA copy of the retrovirus genome that is integrated into the host genome can be directly detected by PCR |
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zoster (shingles) (early)
caused by what pathogen? |
varicella-zoster virus
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what pathogen causes...
oral hariy leukoplakia (middle) |
EB virus
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what pathogen causes...
herpes infection of esophagus, skin, and mucous membranes (middle) |
Herpes Simplex Virus
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what pathogen causes...
cytomegalovirus disease of: (late) retina, esophagus, and colon |
cytomegalovirus
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what pathogen causes...
risk of genital epithelial cancer in HIV+ women; risk of anal cancer in HIV+ men who have sex with men |
HPV
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what pathogen causes...
Kaposi's sarcoma |
Herpes virus
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HAART
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HIGHLY ACTIVE ANTIRETROVIRAL THERAPY (current HIV treatment strategy)
typically deploys more than one potent inhibitor of HIV to reduce the HIV viral load more potent than any monotherapy, both at reducing viral load and reducing selection of HIV mutants that are resistant to drugs used in HAART has improved health of those with AIDS by reducing amt of circulating virus to nearly undetectable levels and by increasing levels of CD4+ T lymphocytes |
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Immune reconstituion syndrome may occur in some patients after HAART therapy due to:
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exacerbation of inflammatory response to certain co-infections
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where is HIV likely to remain present, even while burden reduced by HAART
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lymph nodes, brain, testes, retina
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neuroAIDS
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describes memory loss and cognitivie loss seen in about 20% of patients surviving AIDS through HAART therapy
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Nucleoside analog reverse transcriptase (RT) inhibitors (mechanism)
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dideoxynucleoside analogues)
"chain-terminators" AZT is phosphorylated by host cell kinases to make the triphosphate HIV RT recognizes and uses these triphosphates more readily than the host DNA polymerases when incorporated these analogues block further synthesis, preventing conversion of HIV RNA to DNA (blocks reverse transcription of viral RNA still in original nucleocapsid into DNA) |
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nuceloside analogues used alone will reduce HIV levels by how much?
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~10-fold over the first 2-4 months of therapy (modest mean rise of CD4+ T-cells occurs transiently)
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Clinical efficacy of AZT
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measureable and proven clinical efficacy on the basis of randomized control trials
degree of efficacy varies with the severity of HIV/AIDS disease AZT is most effective when it is used together with other HIV inhibitors |
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what can be used to reduce perinatal transmission of HIV?
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AZT has a significant clinical benefit in reducing the perinatal transmission of HIV.
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Non-nucleoside (HIV-specific) reverse transcriptase inhibitors (mechanism)
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act by binding to a site of HIV RT which is separate from where the nucleoside inhibitors bind, inhibiting RT activity. thus preventing the conversion of HIV RNA to DNA
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Non-nucleoside (HIV-specific) reverse transcriptase inhibitors (biological activity)
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similar activity as the nucleoside analog inhibitors
however, HIV resistant mutations seem to arise more quickly than with the nucleoside inhibitors |
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Non-nucleoside (HIV-specific) reverse transcriptase inhibitors (clinical efficacy):
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monotherapy is inadequence due to high level of resistance mutations
appears to be most effective when used in combination with anti-HIV therapy |
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Protease inhibitors (mechanism of action)
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protease inhibitors are competitive inhibitors of HIV protease.
they bind to the active (catalytic) siteof HIV protease and prevent enzyme from cleaving the gag-pol polypeptide into individual viral proteins (see diagram of HIV genome) thus they prevent HIV from being successfully assembled and released from the infected cells the HIV virions made in the presence of protease inhibitors are immature and non-infectious they cannot adsorb to host cells, nor can they penetrate (infect) host cells |
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protease inhibitors (biological activity)
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inhibit HIV in vitro at nM concentrations
can reduce plasma viral load by 100fold work synergistically w/ dideoxynucleoside RT inhibs and other HIV inhibitors |
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protease inhibitors (clinical effiacy)
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protease inhibitors have their best clinical effectiveness when used in combo with other anti-HIV therapies
triple-therapy with a protease inhibitor and two anti-RT inhibitors can reduce HIV viremia to "undetectable" levels in some patients as well as partially restoring CD4+ T-cells |
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HIV Antiviral Therapies:
Entry inhibitor(s) (mechanism of axn) |
Fuzeon (only licensed entry inhibitor) binds to gp41 on the surface of the HIV virion
once bound, the HIV virion cannot successfully bind and fuse with the plasma membrane of CD4+ T-cells, thus preventing it from infecting healthy cells |
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HIV Antiviral Therapies:
Entry inhibitor(s) (biological activity) |
Fuzeon is a peptide drug (fragile, cannot be taken orally)
currently injectable 2x/day can reduce viral loads by up to one log (10-fold) |
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HIV Antiviral Therapies:
Entry inhibitor(s) (clinical efficacy) |
Fuzeon must be used in combination with other anti-HIV drugs (to avoid HIV resistance to Fuzeon)
licensed only for HIV/ADS patients who have tried anti-HIV drugs and are unable to keep viral loads undetectable using currently available drugs (2nd line treatment) |
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Arenavirus (nucleocapsid structre)
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enveloped
(-)ssRNA virion contains a few ribosomes (of host cell origin and unknown fxn) |
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lymphocytic choriomeningitis virus (virus type)
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arenavirus
zoonosis |
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Lassa fever virus (virus type)
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arenavirus zoonosis
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zoonosis
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an infectious disease of humans in which the usually infected host (the reservoir) is an animal
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viral zoonoses
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arenaviruses (lymphocytic choriomeningitis virus and Lassa fever virus)
and eastern and western equine encephalitis |
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Lymphocytic choriomeningitis in humans (symptoms in humans)
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mild influenza-like disease
many inapparent infections, but also a few deaths (these have lymphocytic infiltration of CNS) Most clinical cases present as aseptic meningitis. |
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Lymphocytic choriomeningitis in humans (transmission)
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ingestion or inhalation of mouse excreta
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Lymphocytic choriomeningitis in humans (endemic in what species?)
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mice
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Lymphocytic choriomeningitis in humans (immune response)
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appears to be the cause of disease pathology
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Lassa Fever (animal reservoir)
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African rat
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Lassa Fever (characteristics of human disease)
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diverse symptoms of systemic viral infection: headache, comiting, fever, marked pharyngitis, etc..
ab 1/3 of hospitalized cases are fatal |
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Lassa Fever (transmission)
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common in hospitals with fatal infections of medical personnel
Passive immunization with serum from patients who survived infection appears to be useful treatment |
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filoviruses
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African Hemorrhagic Fever viruses:
Marburg Virus and Ebola virus |
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filovirus (virion)
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enveloped
long cylinder (much like a rhabdovirus, but LONGER) (-)ssRNA |
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african hemorrhagic fever virus (transmission)
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only where open skin lesions or mucous membranes come in contact with blood or tissue or bodily secretions of infected patients
many cases in medical personnel barrier protection (gloves, masks) markedly reduces transmission |
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filovirus (pathogenesis)
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not well understood
disruption of the vascular system and widespread hemorrhages common feature death of ~50% for hospitalized patients may overestimate severity of the infection |
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filovirus (animal resevoir host)
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most likely a rodent, but not known for sure.
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