Rabson - HIV And AIDS Flashcards
What is AIDS
Profound immunodeficiency leading to development of opportunistic infections such as bacterial, fungal, protozoan, and viral
Also increased number of malignancies
What is the cause of AIDS
Infection with HIV
What is the rate of disease progression influenced by?
Host genetic makeup
Viral genome
Co-factors such as other infections
Host immune response
How is HIV spread
Contact with bodily fluids
- sex
- blood products
- sharing of needles
- perinatal infection during delivery
How do you diagnose HIV
ELISA or PCR with confirmation then by western blot.
- the issue is that there is a window of insensitivity post-infection for about 30 days but could be longer.
How does the western blot work?
They lyse the patients cells that are suspected to be infected with HIV and then incubate it with antibodies from a patient who had HIV and made the proper antibodies. If the patient has HIV, they will have those HIV proteins (Env, Gag, Pol, etc.) and then the antibodies will bind to them.
when would you test someone for HIV
- clinical suspicion
- everyone should be tested at least once at some point
What is the shape of the HIV virion?
Conical shaped
Why is HIV so difficult to completely cure?
The provirus can remain latent in the cell for a very long time so even if you could kill the viruses, you can’t really get the virus DNA that is in the various cells.
NF-kB
Master regulator of immunity and inflammation but it is also a regulator of the HIV provirus.
- so, every time the immune system gets revved up, the HIV provirus gets transcribed more often as well.
Tat
Strong activator of HIV transcription.
- it binds to “TAR” RNA at the 5’ end of the HIV RNAs
- this then activates transcription through recruitment of various cell proteins that cause increased phosphorylation of the tail of RNA pol-II and increases the transcription of the RNA.
Rev
promotes nuclear export of large unsliced or singly spliced RNAs
- it is essentially the “go to jail” card in immediately. You stop what you are doing and leave the nucleus.
- without Rev, the transcript will get spliced into a million small pieces.
Regulation of RNA export through Rev
Basically in the beginning there is not that much Rev made, so almost all of the proteins made are small and are required for RNA transcription (Rev, Tat, and Nef). Once Rev is made now, it can go back and ensure that longer RNA strands are made.
Rev mechanism
Basically Rev exports the long RNA directly to the nuclear pore.
Nef
2 main roles:
- increased infectivity of the virus particles
- inhibiting anti-HIV immune response
It is required for the disease development. People who hate Nef mutants are non-progressors.
How does Nef inhibit anti-HIV immune response
- Down regulates cell surface proteins such as MHC1
- down-regulates surface CD4 levels (less important)
Vif
Viral infectivity factor
- strongly enhances replication of virus in primary cells by inhibiting a cellular antiviral protein called “APOBEC3G”.
- Vif binding to APOBEC3G causes proteosomal degradation to occur leading to virion incorporation.
APOBEC3G
Innate cellular defense that is inhibited by Vif.
- it is a cytosine deaminase against ssDNA, and leads to massive mutations of the viral DNA and thus degradation.
- when Vif binds it is degraded proteosomally.
VPU
Counteracts the action of tetherin.
- usually when a virus particle is going to bud off of the cell, a protein called tetherin holds onto the virus particle with dear life and then sequesters it back into the cytosol. VPU counteracts the action of Tetherin.
What cells does HIV target?
CD4+ T cells
Monocytes and macrophages
What type of cells does HIV have a preference for?
Activated T cells because then there are more targets.
- increased nucleotide pool
How exactly does HIV cause death of CD4+ T cells?
- direct killing by cytopathic infection - virus just kills the cell
- immune “exhaustion” - in chronic immune response, the normal T cells can become exhausted from fighting the HIV infection and just die
- immune destruction of infected cells - immune restriction of infected cells that haven’t yet produced virus but did put virus proteins on their surface. CTLs will kill them
- death of bystander cells - HIV toxic gene products such as envelope or Tad can cause killing of cell
How does one get HIV Encephalopathy
infection of monocytes and/or microglia - causes pro-inflammatory cytokines release in CNS, which causes Pathogenesis.
HIV infection of dendritic cells
Dendritic cells can be infected or they can carry HIV to CD4 T cells on the surface or to the lymphoid tissue.
HIV Pathogenesis timeline
1) primary infection (first few days) leads to initial rise in HIV RNA copies and initial drop in CD4+ T cells (Very infectious at this time)
2) Over the course of the next few weeks the NK cells, CTLs, and then neutralizing antibodies kick in and the viral load begins to decrease dramatically.
3) eventually their is a clinical latency period where the CD4+ numbers stabilize and the HIV RNA numbers stabilize to almost undetectable levels.
4) Then, things start to happen and the CD4 cell count decreases rapidly and viral production goes way up so numbers are high in the blood. CD4+ cells go way down too. This can cause opportunistic disease and possibly death.
Acute HIV infection
Mononucleosis-like symptoms
Associated with high levels of HIV particles in the blood.
Early HIV infection
Breaches the mucosal barrier with infection of a small founder population, which then explodes in the lymphoid tissue. This causes a massive depletion of memory CD4+CCR5+ T cells mostly in the gut.
Initial immune response to HIV
Initial NK cell activity
Antibody production doesn’t start till 3-7 weeks though and by that time it has already taken up home in the lymph nodes and there is already viremia.
CTL is initially effective.
A symptomatic period of HIV infection
Clearance of virus from the blood to low set point of HIV levels.
- but remember, the HIV is still replicating in the lymphoid tissue
- although at t his point they may be clinically latent they may not be virologically latent because the provirus is still integrated into the cells and is just chilling there.
What’s the area of the HIV virus that the neutralizing antibodies act on? What is important about this region?
V3 region of the envelope
- this region is very variable though so we can’t really give antibodies against it because the region is so variable each time.
Factors in HIV progression
Levels of viral replication
- levels of CD4 tells you where you are in the infection - whether you are early, latent, or asymptomatic
- HIV RNA blood levels predict where you are going.
Immune response to HIV
Development of viral variants
Role of co-factors that may increase viral replication
with regards to co-receptors what is the early one and what is the late one?
- In early infections, the co-receptor is CCR5 and usually affects monocytes and memory T cells.
- eventually there is emergence of CXCR4-binding viruses late in the disease. These kill T cells
HAART therapy
Antiretroviral therapy
- biphasic decay curve where initially three is rapid decay and then there is slower decay.
- once you stop the drugs the virus comes back because it doesn’t affect the reservoirs.
Issues with making A HIV vaccine
- correlated of protective immunity is slowly being defined
- genetic diversity especially within envelope variability
- latent reservoir means you need to block the initial infection
- what is an acceptable animal model? Acceptable protection rate? Can’t use live attenuated vaccines.
