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233 Cards in this Set

  • Front
  • Back
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)
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
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)
Morphological differences between normal cells and cancer cells
NORMAL CELLS:
grow in orderly way
flat in culture

CANCER CELLS:
grow in disordered way
rounded
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
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)
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
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)
Morphological differences between normal cells and cancer cells
NORMAL CELLS:
grow in orderly way
flat in culture

CANCER CELLS:
grow in disordered way
rounded
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
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
many viruses grow better is cells that are doing what?
actively synthesizing DNA

however most cells in the body are quiescent and not dividing
what do several DNA viruses do to facilitate their growth in host cells
'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
Papovaviruses (family members include)
Papilloma virus (human and other mammalian hosts)

Polyoma virus (rodent hosts)

SV40 (monkey hosts)
Papovavirus (nucleocapsid)
small
NAKED

circular dsDNA genome (<10kb, encoding <10 genes)

relies greatly on host proteins (DNA pol and RNA pol) for replication and gene expression
SV40
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
what is essential for papovavirus growth?
all the papovavirus genes
Temporal Regulation of Viral gene expression and DNA replication
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
classes of Papovavirus genes
Early genes
Late genes
With SV40 when is the large T-antigen gene is expressed?
EARLY

T-antigen recognizes the start site for SV40 DNA replication (ori) and binds to it
How are SV40 viral particles released?
via cell lysis following self-assembly of SV40 nucleocapsids following late transcription of the capsid genes
Large T-antigen
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
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
HPV (virus family)
most important member of Papovavirus family
HPV (reponsible for what patholgies)
-responsible for benign tumors (papillomas, including plantar and genital warts (chondylomata acuminata)
# of types of HPV
# associated with anogenital lesions
>60 different HPV types
~1/3 associated with anogenital lesions
% of college aged women who harbor HPV in their cervix
1/3
epidemiological studies suggest direct causal realtionships between cervical neoplasia and
sexual activity (multiple partners or early onset of sexual relations)

or exposure to a promiscuous male
molecular analysis has indicated that 80-90% of cervical carcinomas....
harbor HPV viral sequences integrated into the cellular DNA

HPV is considered an eitiologic agent of invasive cervical carvinoma
most common manifestations of urogenital HPV infection
condylomas
most condylomas (the most common manifestation of urogenital HPV infection) are caused by
nononcogenic type of HPV (6b and 11)
greater than 75% of cervical carcinomas are caused by two high risk papillomaviruses
HPV16 and HPV18
identified HPV oncogenes
early genes E6 and E7 (also essential for viral growth)
in HPV caused warts; the viral genome is...
extrachromosomal (not integrated) and the virus replicates
in HPV related cervical tumor cells the E6 and E7 oncogenes are found...
integrated into the cellular chromosome and are highly expressed
Early gene E6 binds...
p53,
thus inactivating this tumor suppressor and allowing entry to the cell cycle, leading to transformation
Early gene E7 binds...
Rb,
thus inactivating this tumor suppressor and allowing entry to the cell cycle, leading to transformation
other cofactors are involved in the generation of cervical carcinoma, evidenced by the fact that
women infected with HPV 16 or 18 do not always develop cervical cancer
current clinical strategy for prevention of cervical cancer is based on:
encouraging "safe sex"
and
early detection of abnormal cells by early cytologic examination of cervical spears (Papanicolaou stain)
HPV vaccine
recombinant vaccine, has been developed and is now licensed for pediatric use (based on viral capid proteins expressed in yeast)
adenovirus as tumor virus
not associated with tumors in humans

some can cause tumors in hamsters and transform rat cells in vitro
adenovirus proteins associated with transformation
E1A (can partially transform cells on its own)
E1B (that does not transform, but increases levels of E1A)
E1 binds to
tumor suppressor proteins (Rb, p300, and CBP)
cellular transcription factors to stimulate transcription associated with S phase where DNA replication occurs
Herpesvirus (genome)
large, linear, dsDNA genome
Herpesvirus (nucleocapsid)
icosahedral nucleocapsid,
surrounded by a protein tegument, enclosed in a glycoprotein bearing envelope

(large, linear dsDNA genome)
two herpesviruses are known to cause cancer:
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
Burkitt's lymphoma
(caused by Epstein Barr virus)
is the most frequent childhood tumor in africa, boys are at greater risk
tumors of Burkitt's lymphoma
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
Burkitt's lymphoma (where is it prevalent?)
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
Where are EB viral particles found?
in cell lines from Burkitt's lymphoma tissue

and in B-cells from patients with infectious mononucleosis
biological hallmark of EB virus infection
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
genetic mutation in Burkitt's lymphoma tumors
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
ordinarily immune system contains transformed cells by:
an aggressive T cell response

only when the immune response is compromised do these cells grow as tumors
restricted geographic distribution of Burkitt's lymphoma is attributed to
role of infection with malarial parasites in disease development

malaria is a cofactor because it inhibits cell-mediated immunity in children
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)
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)
most frequent neoplasm occuring in AIDS patients
AIDS-associated Kaposi's sarcoma (KS) 15-20% of AIDS patients develop KS
KSHV (Kaposi's sarcoma-associated herpesvirus)
aka HHV8

has been found in virtually all biopsies of AIDS associated Kaposi's sarcomas
Prior to the 1980s KS was typically found
rare

observed mostly in elderly males of Mediterranean or eastern european descent
KS tumors usually present as:
multiple, pigmented highly vascularized nodules of skin (contain replicating spindle cells)
vascular endothelial growth factor
powerful angiogenic factor expressed in KS tumors cells

this is a cellular protein, not from a virus
Kaposi's sarcoma-associated herpesvirus (KSHV) oncogenes
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
Retroviruses (virion)
ENVELOPED
nucleocapsid contains 2 identical copies of +ssRNA (~10kb long)
all nondefective retroviruses encode:
three essential genes:
gag
pol
env
essental retrovirus gene

gag, encodes:
encodes nucleocapsid and capsid proteins
essental retrovirus gene

pol, encodes:
reverse transcriptase and integrase
essental retrovirus gene

env, encodes:
envelop glycoproteins
retrovirus (replication and viral protein translation)
mRNA copies of retroviral genes are translated into large precursor proteins that are posttranslationally cleaved into the individual viral proteins
2 subfamilies of medically important retroviruses
1. ONCOVIRUSES (associated with tumor formation)

2. LENTIVIRUSES (not directly associated with tumor formation)
examples of retroviral ONCOVIRUSES
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)
examples of retroviral LENTIVIRUSES
HIV-1 and HIV-2
two stages of retrovirus lifecycle
extracellular phase as a viral particle

intracellular phase as a provirus
what blocks retroviral replication?
inhibitors that specifically block DNA synthesis
what first led to the proposal that retroviruses replicate from a DNA intermediate?
the fact that retroviral replication is blocked by inhibitors that specifically block DNA synthesis
retroviral (replication)
virion RNA is copied into dsDNA by reverse transcriptase (a viral protein, an RNA-directed DNA polymerase)
reverse transcriptase
an RNA-directed DNA polymerase

a retroviral protein that copies retroviral RNA into dsDNA
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)
LTRs contain regulatory elements for what?
viral transcription
what is the template for genome replication and mRNA transcription of a retrovirus?
the DNA provrius (synthesized by reverse transcriptase from retroviral ssRNA)
where does reverse transcriptase involved in retroviral replication come from?
it is inside the retroviral virion bound to the nucleocapsid
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
why degrades viral RNA of DNA-RNA hybrid
RNase H (a ribonuclease specific for DNA-RNA hybrids)
what synthesizes the 2nd DNA strand of dsDNA copied from retroviral RNA?
reverse trasncriptase (it does it all!)
what is longer retroviral dsDNA or RNA?
dsDNA genome is slightly longer than the initial viral RNA because during reverse tnrascription Long Terminal Repeats (LTRs) sequences are added to each end.
provirus
newly synthesized dsDNA (released from nucleocapsid, has entered nucleus and has) integrated at a random site in the cellular DNA
LTRs are important to what part of retroviral lifecycle?
the integration of dsDNA genome into the host cellular DNA (to create a provirus)
how does replication/transcription of the retroviral PROVIRUS begin?
begins from the viral PROMOTER in the LTR by the host RNA polymerase (to produce gag,pol mRNA)
what happens to the viral mRNA produced from provirus?
either:

translated into viral proteins
or
packaged into viral nucleocapsids with reverse transcriptase
how are new retroviral particles released from host cell?
nucleocapsids bud through the cytoplasmic membrane for final assembly into mature enveloped viral particles
retroviruses rarely cause cancer in humans, what species do they effect?
most oncogenic retroviruses infect rodent or avian species
acute transforming retroviruses
(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
nonacute transforming retroviruses
take many years to cause cancer in laboratory animals. these viruses do not have oncogene
categories of oncogenic retroviruses
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
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)
oncogene is RSV
src

expression of src is required for both the induction and maintenance of the transformed phenotype
proto-oncogene
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
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
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
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
proto-oncogenes can be divided into 5 groups:
1. growth factors
2. growth factor receptors
3. protein kinases
4. signal transducing G proteins
5. nuclear proteins that regulate transcription and DNA replication
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
all of the known acute transforming retroviruses (except 1) are...
DEFECTIVE RETROVIRUSES: have one or more of the viral gene(s) required for growth (gag, pol, or env) replaced by an oncogene
acute transforming virus MC29 causes
myelocytomas
in acute transforming virus MC29, the pol and env genes have been replaced by what?
the myc oncogene
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
isolates of a defective virus will be mixtures of what?
defective and helper virus
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
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.
oncogenic human retroviruses
T-cell luekemia virus-1 and 2 (HTLV-1,2)
what is the etiologic agent of adult T-cell leukemia (ATL)?
HTLV-1
HTLV (where is it endemic?)
southern Japan, central Africa and the Caribbean

incidence of infection in the US is 0.025%
HTLV (transmission)
horizontal transmission via sexual contact in blood
HTLV (symptoms of infected individuals)
usually asymptomatic

~0.1% develop adult T-cell luekemia following a long latency of 10-30 years
Viral tax protein
transcription factor

induces IL-2 and its receptor and may set up an autocrine loop, predisposing to transformation
HTLV (transmission)
horizontal

via sexual contact or in blood
HTLV (symptoms of infection)
usually asymptomatic
HTLV (incidence/incubation of ATL)
~0.1% of infected individuals develope adult T-cell luekemia following a long latency of 10-30 years
Viral Tax protein
transcription factor

induces IL-2 and its receptor

may set up an autocrine loop, predisposing to transformation
leading cause of cancer deaths worldwide
hepatocellular carcinoma
Hepatitis B (causes what type of cancer)
hepatocellular carcinoma (leading cause of cancer deaths world wide)

responsible for 500,000 cancer deaths annually
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
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
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
Immunization against Hep B may help prevent:
primarily hepatocellular carcinoma (particularly in the case of maternal transmission to neonates)
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
Hep B (replication)
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
pregenomes
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)
where is dsDNA of HepB viral progeny copied?
in the nucleocapsid of new viral particle
(copied by hep B virus reverse transcriptase from pregenome)
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
lamuvidine
inhibits both:
the reverese transcriptase of Hep B
and
retroviral reverse transcriptase
Hepatitis C (virus type)
RNA virus- Flavivirus
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
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
AIDS (caused by what virus?)
aquired immune deficiency syndrome

(caused by the HUMAN T CELL LYMPHOTROPHIC RETROVIRUS HIV-1, also HIV-2
lentivirus is a subfamily of what virus type?
retroviruses
HIV-2
endemic in regions of West Africa, along with HIV-1 a cause of AIDS
What does it mean, that the HIV retrovirus is "NONDEFECTIVE"
that it is replication competent
what happens to an HIV-infeceted cell once it begins to produce viral protein and HIV virus
it will eventually be killed
Does HIV have a viral oncogene?
NO
characterize the life-cycle of HIV
similar to the typical retrovirus lifecycle

a complex virus

HIV has regulatory genes that are not present in most other retroviruses
HIV (adsorption by host cell)
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
an important host cell of HIV-1:
the CD4+ helper T-lymphocyte (CD4+CD8-)
The CD4 antigen is primarily found on:
CD4+ helper T-lymphocytes (CD4+CD8-)
monocytes
macrophages
microglial cells
dendritic cells
and on other cells that HIV infects
What is required to permit entry of HIV into host cell?
CD4 antigen
AND
interaction w/ a host cell co-receptor [CXCR4; CCR5] of the chemokine receptor superfamily]
what mediates fusion of HIV viral envelope with the cell membrane resulting in nucelocapsid entry?
viral envelop glycoprotein (gp41)

gp120 binds to host cell surface CD4 antigen
What happens once HIV virus enters host cell
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)
at what point in HIV infection is the HIV virus a Provirus?
once HIV integrase has physically integrated the copies HIV DNA into the DNA of the host cell
what can integrated HIV viral DNA do?
one of 3 things:
a) latency
b) controlled HIV growth
c) extensive viral growth resulting in lysis of the host cell
what transcribes mRNA encoding HIV proteins
HOST RNA polymerase
HIV (modes of transmission)
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
HIV (relative risks)
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)
HIV (cost of life)
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
HIV (symptoms of primary infection)
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
HIV (characterize the viremia in the clinically latent period)
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)
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
HIV (what is happening during the clinically altent stage, how long does it usually last)
CD4+ cells are lost at a steadly slow rate (that accelerates with time)

cinically latent stage usually lasts 3-10 years
consequences of depletion of CD4+ T-cells
loss of cell-mediated immunity

increase in the incidence of a variety of infectious diseases (the usual final cause of death) and some tumors
CDC definition of AIDS:
<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
Immune response to HIV
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
Immune defects seen in HIV infection
primarily defined as loss of CD4+ helper T-cells,

also-chronic activation of the immune system
impaired fnx of monocytes-macrophages
susceptibility fo infectious diseases in HIV/AIDS
AIDS patients have a specific spectrum of susceptibility to certain infectious diseases? LIKE??????
Malignancy in HIV/AIDS
AIDS patients have increase susceptibility to malignancy

Kaposi's sarcoma and B cell lymphoma
Kaposi's sarcoma in HIV/AIDS patients is associated with what other co-viral infection
Herpesvirus
additional clinical aspects of HIV/AIDS
a. Chronic lymphadenopathy
b. autoimmune thrombocytopenia
c. dementia/diffuse brain disease is well recognized in later stages of HIV infection
AIDS (rate of progression)
highly variable (rapid progression, slow progression, or less frequently, non-progression)
some common pathogenic mechanisms in HIV/AIDS
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
Factors contributing to varied pathogenesis of AIDS (J-21 ??? WHAT IS IMPORTANT HERE?)
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
TESTS for HIV
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
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
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
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
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)
Use of Tests for infection with HIV-1
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
zoster (shingles) (early)

caused by what pathogen?
varicella-zoster virus
what pathogen causes...

oral hariy leukoplakia (middle)
EB virus
what pathogen causes...

herpes infection of esophagus, skin, and mucous membranes (middle)
Herpes Simplex Virus
what pathogen causes...

cytomegalovirus disease of:
(late) retina, esophagus, and colon
cytomegalovirus
what pathogen causes...

risk of genital epithelial cancer in HIV+ women;
risk of anal cancer in HIV+ men who have sex with men
HPV
what pathogen causes...

Kaposi's sarcoma
Herpes virus
HAART
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
Immune reconstituion syndrome may occur in some patients after HAART therapy due to:
exacerbation of inflammatory response to certain co-infections
where is HIV likely to remain present, even while burden reduced by HAART
lymph nodes, brain, testes, retina
neuroAIDS
describes memory loss and cognitivie loss seen in about 20% of patients surviving AIDS through HAART therapy
Nucleoside analog reverse transcriptase (RT) inhibitors (mechanism)
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)
nuceloside analogues used alone will reduce HIV levels by how much?
~10-fold over the first 2-4 months of therapy (modest mean rise of CD4+ T-cells occurs transiently)
Clinical efficacy of AZT
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
what can be used to reduce perinatal transmission of HIV?
AZT has a significant clinical benefit in reducing the perinatal transmission of HIV.
Non-nucleoside (HIV-specific) reverse transcriptase inhibitors (mechanism)
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
Non-nucleoside (HIV-specific) reverse transcriptase inhibitors (biological activity)
similar activity as the nucleoside analog inhibitors

however, HIV resistant mutations seem to arise more quickly than with the nucleoside inhibitors
Non-nucleoside (HIV-specific) reverse transcriptase inhibitors (clinical efficacy):
monotherapy is inadequence due to high level of resistance mutations

appears to be most effective when used in combination with anti-HIV therapy
Protease inhibitors (mechanism of action)
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
protease inhibitors (biological activity)
inhibit HIV in vitro at nM concentrations
can reduce plasma viral load by 100fold
work synergistically w/ dideoxynucleoside RT inhibs and other HIV inhibitors
protease inhibitors (clinical effiacy)
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
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
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)
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)
Arenavirus (nucleocapsid structre)
enveloped
(-)ssRNA
virion contains a few ribosomes (of host cell origin and unknown fxn)
lymphocytic choriomeningitis virus (virus type)
arenavirus

zoonosis
Lassa fever virus (virus type)
arenavirus zoonosis
zoonosis
an infectious disease of humans in which the usually infected host (the reservoir) is an animal
viral zoonoses
arenaviruses (lymphocytic choriomeningitis virus and Lassa fever virus)

and eastern and western equine encephalitis
Lymphocytic choriomeningitis in humans (symptoms in humans)
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.
Lymphocytic choriomeningitis in humans (transmission)
ingestion or inhalation of mouse excreta
Lymphocytic choriomeningitis in humans (endemic in what species?)
mice
Lymphocytic choriomeningitis in humans (immune response)
appears to be the cause of disease pathology
Lassa Fever (animal reservoir)
African rat
Lassa Fever (characteristics of human disease)
diverse symptoms of systemic viral infection: headache, comiting, fever, marked pharyngitis, etc..

ab 1/3 of hospitalized cases are fatal
Lassa Fever (transmission)
common in hospitals with fatal infections of medical personnel

Passive immunization with serum from patients who survived infection appears to be useful treatment
filoviruses
African Hemorrhagic Fever viruses:
Marburg Virus and Ebola virus
filovirus (virion)
enveloped
long cylinder (much like a rhabdovirus, but LONGER)
(-)ssRNA
african hemorrhagic fever virus (transmission)
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
filovirus (pathogenesis)
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
filovirus (animal resevoir host)
most likely a rodent, but not known for sure.