Flashcards in Retroviruses-AuCoin Deck (107)
What type of RNA viruses are retroviruses, like HIV?
+ strand RNA viruses with a DNA intermediate
Human T lymphotropic virus (HTLV) is what type of virus? What is this virus associated with? Which cells do they target?
oncovirus & retrovirus
adult T cell leukemia
spread via CD4+ T cells
How is the HTLV virus spread?
What is the incubation period for HTLV?
What does the patient experience when they are infected with HTLV?
increased skin lesions
higher levels of parathyroid hormone related peptide
How do you diagnose HTLV infection?
ELISA looking for antibody int he serum of the pt
T/F Effective vaccines exist for HTLV.
False. No vaccine or specific therapy is present.
Why might a pt experience hypercalcemia when they have a malignant lymphoma?
increased bone resorption
impairment of renal mechanisms that clear increased calcium load
Thus, High Ca++ in blood.
Why might a pt with HTLV esp experience hypercalcemia?
infected T cells overproduce PTHRP
this causes hypercalcemia in pts who have adult T cell leukemia
How is HIV transmitted?
IV drug use
b/w mom & child
Which glycoprotein on HIV binds the CD4 receptor on T cells? Which other cells does it bind?
monocytes & dendritic cells
Which types of infections are common in patients with HIV?
opportunistic microbial infections are common
What does a patient with HIV experience during the acute phase?
flu like symptoms
What does a patient with HIV experience during the clinical latency phase?
How long does it typically take for HIV to progress to AIDS?
In AIDS, what is the CD4+ T cell count? What is the normal level of T helper cells?
less than 200 cells/microliter of blood
What techniques are used to diagnose HIV infection & perhaps AIDS?
RT PCR (quantitates the viral load in the blood)
What is the name of the therapy for HIV? Is there a vaccine?
No vaccine available
HAART: high active anti-retroviral therapy
Describe the structure of retroviruses.
enveloped! have viral glycoproteins, acquired from plasma membrane
**envelope surrounds the capsid with RNA
+ strand RNA viruses (2 identical copies)
What important thing do retroviruses encode? How do they replicate?
Encode RNA-dependent -DNA polymerase aka reverse transcriptase
**replicate w/ RT thru a DNA intermediate
Once the reverse transcriptase makes a DNA copy of the RNA genome of a retrovirus...what happens to the DNA copy?
it is integrated into the host chromosome & becomes cellular genes aka provirus
What was the first retrovirus to be isolated? What did it produce?
Rous Sarcoma Virus
produced solid tumors in chickens
What are cancer causing retroviruses called?
RNA tumor viruses
How do retroviruses alter cellular growth?
by expressing analogues of cellular growth controlling genes (oncogenes).
Normal Growth Gene: c-src
Viral Growth Gene: v-src
Retroviruses take up what % of the genome, potentially?
up to 8%!
What is the key different b/w the c-src gene & v-src gene?
c-src is the growth control gene that forms a tyrosine kinase deal that must be phosphorylated to be activated.
v-src has no phosphorylation site so it is always on! Out of control growth!
T/F HIV, like HTLV, has tumor causing genes.
How does reverse transcriptase work?
+ strand RNA (like mRNA) in the retrovirus.
RT forms a complementary DNA strand for it (cDNA)
It destroys the + RNA strand
It forms a complementary DNA strand for the cDNA.
Now, you have a double stranded DNA that can be incorporated into the host genome.
What was the first retrovirus found to be associated with human disease?
it was isolated from a pt with T cell leukemia by Gallo
What are the 4 H subpopulations that were dying of opportunistic infections in the 1980s?
How many people worldwide suffer from AIDS?
34 million worldwide
Who were the first people to isolate the HIV virus?
**of the Pasteur Institute
Who was the first to demonstrate that HIV was the causative virus of AIDS?
Where is the strain HIV-2 common?
How are retroviruses classified?
1. the disease they cause
2. tissue tropism & host range
3. virion morphology
4. genetic complexity
What must a retrovirus be able to do to be considered an oncovirus?
immortalize or transform target tissue
T/F HIV is considered an oncovirus.
FALSE. It is considered a lentivirus.
What does it take to be considered a lentivirus like HIV?
associated with neurologic & immunosuppressive diseases
Note: lentiviruses can be used as vectors for research.
Overall, what are the 3 subfamilies of retroviruses?
1. oncoviruses: HTLV1,2,3
2. lentiviruses: HIV1, 2
3. Spumavirinae: first retrovirus discovered, no disease. Called foamy virus.
How large is the RNA genome found in retroviruses?
about 9 kilobases
What are some important friends that retroviruses take with them for the ride in the virion?
10-50 copies of RT
integrase enzymes (allow them to get into the nuclear pores & become a part of the host genome)
2 cellular tRNAs (used as a primer for the RT)
**primer helps attach nucleotides to the 3' OH.
Describe the structure of HIV, D-type particle.
so you have this ribonucleocapsid in the middle with everything like RT etc & 2 RNA genomes.
then there is this layer of matrix proteins right before the phospholipid envelope.
On the envelope is glycoproteins, including VAPs. gp41 is the stem to the flower of gp120. This binds CD4+ T cells
Describe the structure of HTLV, C-type particle.
central symmetrical nucleocapsid
Does HIV have a tegument layer?
Herpes does, though.
All retroviruses have 3 major genes that encode polyproteins. These are cleaved to form active & important viral proteins. What are the 3 polyproteins?
What is gag? What is it cleaved to make?
group specific antigen
matrix & nucleic acid binding proteins
**these are structural proteins
What is pol? WHat is it cleaved to form?
What is env? WHat is it cleaved to form?
glycoproteins-gp120 & gp41
What is found on each end of the retroviral genome?
LTR: long terminal repeat sequences
**these contain certain promoters & enhancers to bind cellular transcription factors
help to integrate into the host genome
What is a little something' extra that complex retroviruses, like HTLV & HIV have?
require more complex processing-like splicing
What is the role of gp160 in HIV?
this is the glycoprotein that is cleaved into gp41 & gp120
they form a trimer originally. usu happens in the RER on their way out via secretory pathway
Once again, what are the special functions of gp41 & gp120?
gp41: fusion protein, stem of the lollipop
gp120: super glycosylated, mutates frequently-esp b/c of lack of proofreading of RT
binds cell surface receptors
bound by neutralizing antibodies
Describe how HIV gets into a cell.
gp120 binds CD4 receptor
CCR5 chemokine coreceptor is also bound
gp41 helps the cells fuse.
the capsid & matrix of the HIV are free in the cytoplasm
the capsid disintegrates
Once the RNA genome is free in the host cell, how does HIV replicate?
**+ RNA gives template for cDNA formation by RT; uses tRNA from virion as primer
**+RNA is degraded by RT
**dsDNA is made by RT
**Integrase brings circularized dsDNA into nuclear pore & integrates it into host chromosome.
**DNA Pol II transcribes various proteins.
**eventually the virions bud off of the host cell to infect another.
How is it that 2 RNA genomes can fit into the HIV capsid?
RNA can form stem loops.
Called kissing complex of HIV (2 genomes that are stuck together thru homologous binding).
Get 2 copies of each virion.
The co-receptor CCR5 is expressed on which cell types?
During chronic infection, the ___ gene mutates and gp120 can bind _____(chemokine receptor which is expressed primarily on T cells).
We know that the mutation rate of reverse transcriptase is part of what helps HIV & other retroviruses adapt & survive...what is the mutation rate? How does this compare to the mutation rate of DNA pol in humans?
RT 1 error/2K bases
Human DNA pol: 1 error/1 billion bases
How many bases does HIV have? How many genes? How many errors roughly for each replication?
5 errors per replication
only 8 genes
What is integrated viral DNA called?
the long term sequences at the end of a retroviral genome allow for what?
better integration of the viral genome into the host chromosome.
LTRs also contain enhancer & promoter sequences for the regulation of transcription.
Host RNA pol II transcribes the provirus into full length RNA which is processed into ___, ______ or ___.
gag: matrix, capsid, nucleocapsid
gag-pol: protease, RT, integrase
The rev gene of HIV regulates what?
Regulation of RNA splicing and promotion of export to the cytoplasm
The tat gene of HIV regulates what?
transactivation of viral and cellular genes
**Tat is a regulatory protein that drastically enhances the efficiency of viral transcription. Tat binds to cellular factors and mediates their phosphorylation, resulting in increased transcription of all HIV genes
The nef gene of HIV regulates what?
decreases cell surface CD4 & MHCI; T cell activation; progression to AIDS
The vpr gene of HIV regulates what?
Transport of complementary DNA to nucleus, arresting of cell growth
The vif gene of HIV regulates what?
virus infectivity, promotion of assembly, blocks a cellular antiviral protein
The vpu gene of HIV regulates what?
– facilitates virion assemble and release
What is the pathway of the viral glycoproteins that are made in a host cell?
translated on RER
glycosylated in ER
delivered to Golgi Apparatus
**called the secretory pathway
When does the HIV virion mature fully?
After it has already budded. This is when the viral protease cleaves all of the polyproteins
HIV targets CD4 T cells, but what else does it target?
brain microglial cells
HIV causes syncytia formation. What is involved in this?
cells expressing large amounts of CD4 (T helper cells) coalesce & form a giant multinucleated cell
eventually get lysis of the cell
What does HIV do to CD4 T cell & CD8 & macrophage function & number?
How do nucleoside analogs work in treatment of HIV?
they put in a terminal nucleotide to the reverse transcriptase
**don't affect host polymerases, though.
used in combo with protease inhibitors & RT inhibitors
Lentiviruses cause neurological disorders. How does this relate to HIV?
HIV is a lentivirus.
Its targeting of microglial cells in the brain is what causes the neurological symptoms.
Where do you see these giant cells from synctia w/ HIV?
pretty common in lymphoid organs
When HIV gets into a person which cell type does it usu affect first?
**causes cytokine release & dysfunction of immune fcns
Once HIV gets in the blood what do you start to see?
CD4 T cell dysfunction & reduction in #s
Loss of B cell control
Hypergammaglobulinemia (B cells that are producing antibody b/c they are out of control)
Loss of Delayed Type Hypersensitivity reactions
DTH responses with CD8 cells are super important for what especiallY?
eliminating viral, fungal, & mycobacterial infections
Once again, what are the important functions of microglial cells?
supply nutrients to neurons
Those lacking which coreceptor are resistant to HIV infection? & black plague!!
Once again, which protein promotes the progression of HIV into AIDS?
**if you have mutants of Nef don't progress into AIDS
What happens during the acute phase of HIV infection?
large burst of virus production
T cell proliferation in response
get mononucleosis like syndrome
experience fever, weight loss, decreased appetite, chills, lymphadenopathy, pharyngitis, rash, myalgia, malaise, mouth and esophageal sores
happens 2-4 weeks after infection
When the viral levels in the blood decrease you enter the latent period...but viral production continues where? WHat are the hallmarks of this period?
viral production continues in the lymph nodes
fewer acute symptoms
CD4 levels will start to decrease
Late in the disease, what happens to levels of HIV, CD4 & CD8 in the blood?
CD4 & CD8 decreases
w/o meds takes 10 yrs to get there
What does the CD4/CD8 ratio tell you?
this is a diagnostic marker of AIDS
when your ratio is super low & CD8 greatly outnumber CD4-abnormal. We are immunosuppressed.
Normal CD4 T cells initiate immune response by releasing cytokines that activate which cell types?
CD4 cells release Th2 substances to cause what to mature?
naive B cells to mature into plasma cells that secrete antibodies
CD4 cells release TH1 substances to cause what to mature?
CD8 T cells to mature into cytotoxic T lymphocytes
What are some protozoal opportunistic infections that you see in patients with AIDS?
toxoplasmosis of the brain
crytposporidiosis with diarrhea
isosporiasis with diarrhea
What are some fungal opportunistic infections that you see in patients with AIDS?
candida of the esophagus, trachea, lungs
**pneumocytis carinii pneumonia
What are some viral opportunistic infections that you see in AIDS patients?
Herpes simplex virus infection
Progressive multifocal leukoencephalopathy
hairy leukoplakia w/ EBV
What are some bacterial opportunistic infections that you see in patients with AIDS?
pyogenic bacterial infections
What are some opportunistic neoplasias that you see in patients with AIDS?
Kaposi Sarcoma (skin spots)
Primary lymphoma of the brain
HIV wasting syndrome
lymphoid interstitial pneumonia
What is HIV wasting syndrome?
weight loss & diarrhea for more than 1 month
seen in AIDS
What do you see in AIDS dementia? What causes it?
a slow deterioration of intellectual abilities
due to infection of macrophages & microglial cells of the brain
T/F HIV has a long prodromal period and the virus can be shed before development of identifiable symptoms.
Means that someone can seem fine but be infectious.
When were screening programs implemented for HIV in transplants?
before that people who had blood & organ transplants sometimes received HIV
T/F HIV is easily inactivated b/c of its sensitive envelope.
T/F Serologic tests can help identify recently infected people.
These people can be identified by large amounts of viral RNA in the blood, p24 viral antigen, & RT
Describe the process of lab diagnosis of HIV/AIDS.
If +, do HIV1/2 antibody differenitation immunoassay to figure out which type of HIV you have.
If -, may be a recent infection. So, do the RT PCR looking for viral antigen.
If +, you have an acute HIV infection.
What is the main treatment for AIDS now?
Anti-HIV therapy is currently given as a cocktail of several antiviral drugs termed highly active antiretroviral treatment (HAART)
The use of a mixture of drugs with different mechanisms of action has less potential to select for resistance
Multidrug therapy can reduce blood levels of virus to nearly zero and reduce morbidity and mortality in many patients with advanced AIDS
When do you start ART in HIV+ patients?
Initiation of HAART: CD4 count 100,000/ml), even if CD4 numbers are >350/µl
Therapy is also suggested for post-exposure prophylaxis (e.g., needle stick) if HIV is detected in the individual
CDC recommends now that if you are HIV+ or just a high risk group-take the meds!
What's the deal with the promising HIV vaccines these days?
The most recent HIV vaccines prime T-cell responses with a vaccinia, canarypox, herpesvirus, or a defective adenovirus vector. They are cleared of their stuff & inserted with HIV viral proteins..
Get a strong T cell & IgA response.
Once again, what are some of the drugs involved in ART?
fusion inhibitors-target gp41
A 40-year-old male was seen by his internist with chief complaints of fever, night sweats, increased episodes of diarrhea during the past month, and a 30 pound weight loss over the previous 4 months. On physical exam, he had oral thrush, and cervical lymphadenopathy. Laboratory findings were significant for a CD4+ cell count of 30 cells /uL.
What might this patient have?
This patient might be HIV+