HIV Flashcards
HIV virology
Enzymes within capsid:
Major capsid protein (and significance)
envelope glycoproteins
Main Genes: structural, regulatory (replicative)
enveloped, 2x + sense ssRNA (a dimer)
Within capsid = protease, reverse transcriptase, integrase
Major capsid protein: p24, isolated in serum for early HIV infection
glycoproteins: gp120, gp 41
MAIN GENES
structural 3 -> (gag, pol, env)
replication/regulatory 6-> Important
–(tat, rev) are the required for replication (promoters)
MORE
- -nef Downregulates MHC-I and CD4 receptors (remember CD4 helps TCR with signal cascade)
- -Vif breaks down APOBEC (breaks down viral DNA)
- Vpr nuclear import
- vpu dowregulate CD4/MHC I receptors
**HIV makes it’s different mRNA/proteins by alternate splicing
HIV gag gene encodes?
nucleocapsid proteins p24 and p7
AND some matrix proteins
These are all somewhat antigenic
HIV pol gene encodes?
reverse transcriptase, integrase, and a protease that cleaves some viral proteins.
**reverse transcriptase gene has one of highest error rates described
HIV env gene encodes?
What is the V3 loop?
gp160 which is cleaved -> gp120 (head) and gp41 (stalk) -> bind CD4 receptor on T-cells
**env has hypervariable regions with common point mutations = V3 loop
Some phosphotyrosine linked receptors
Insulin, EGF, PDGF
Where do viral oncogenes come from in acute transforming viruses vs non-acute transforming viruses
ACUTE TRANSFORMING: Over time some viruses have mis-spliced an oncogene out of DNA from host such that they contain an oncogene within their RNA. Rous virus is the only one that still has its replication machinery. The rest require hosts and othere viruses to replicate them.
NON-ACUTE TRANSFORMING: retroviridae that integrate into DNA in key regulatory areas. They have room for replication instructions
HTLV-1?
Human T-cell leukemia virus 1
Retrovirus that Causes leukemia, especially caribbean and Japan
In HIV genome, what is LTR?
LTR = long terminal repeat (sequences), used as “sticky part that integrase recognizes to put into DNA. Also contains promotor/enhancer functions essential post incorporation into host DNA
HIV epidemiology
40million dead since 1981
#34million living with HIV/AIDS 2010 #2.7 infected/yr, 90% in dvlping world, 2/3 Africa 1.1 in USA
HIV transmission
Parenteral #Sexual activity: Virus present in vaginal/cervical/seminal fluid #Blood product transfusion #IV drug use #Rate of infection 30% incidence (transplacentally, DURING DELIVERY, nursing) #Health care exposure #NO EVIDENCE OF TRANSMISSION IN mosquitos/kissing, sharing food, saliva, urine, tears, sweat
HIV cell infection mechanism and brief cycle
gp120 + gp41 -> bind CD4 +CCR5 or CCR4 -> envelope fusion -> capsid entry
**Some ppl are resistant bc low lvls CCR5. Some drugs target/inhibit CCR5
viral RNA reverse transcribed cytoplasm -> dsDNA transported to nucleus/integrated ->->-> viral capsid and RNA bud through host cell membrane
**Also T-cell -> t-cell fusion with gp120 proteins to form syncytium
With no tx, what is median survival of patients after they dvlp AIDS?
2yrs after AIDS dvlps
AIDS definition
CD4 T-lymphocyte count <200, serologic evidence of HIV, and/or AIDS defining opportunistic infections
Usual HIV progression
1) Acute viral illness (mono-like)
- fever, malaise, lymphadenopathy, pharyngitis
2) Clinical (not viral) Latency… median 8yrs but can be widely variable. You have an HIV immune response but cannot get into all the T cells… steady destruction of CD4 T-lymphs.
3) AIDS
What cells do HIV infect?
MOST CD4 T-cells
but also
Monocytes, macrophages, CNS dendritic cells
because they have low lvls of CD4 receptors. But these cells do not die as the T cells do. BUT they do allow transport and dissemination (like to CNS)
Prognostic value of viral load (plasma HIV RNA) vs CD4 count
Opportunistic infections/symptoms at different CD4 counts
1000cells/microliter
400-200
<50
Viral load = speed of train heading for cliff
CD4 count = where the train is
1000cells/microliter
-normal; declines about 60/yr
400-200
-around 7yrs
Constitutional symptoms (fever, weight loss, night sweats, lymphadenopathy)
athletes foot
Candida (oral thrush)
herpes zoster
Tb, and other bacteria (staph/ H.flu/ PNEUMOCOCCUS)
meningitis
- Toxoplasma gondii -> brain mass
- pnuemocystis carinii -> pneumonia
<50
- Mycobacterium avium-intracellulare
- CMV (retinitis, esophagitis, disseminated)
**also B cell dysfunction with shitty hypergammaglobulinemia
AZT therapy
MOA
Use
SE
rapid resistance if used alone
azidothymidine
1st HIV medication. Used throughout illness and in babies for 6 weeks
MOA: nucleoside reverse transcriptase inhibitor NRTI. Integrated into DNA and terminates transcription. Thymidine analog
SE anemia, neutropenia,
+ headache, insomnia, myalgia, nausea, CNS issues
Lamivudine
MOA
USE
SE
NRTI, backbone of most HIV therapy. Also suppresses Hep B DNA replication
SE are notably mostly absent.
NRTI class
MOA
SE’s
MOA: enters as prodrug -> phosphorylated -> competes for RT binding site.
SE: peripheral neuropathy, lactic acidosis, fat redistribution
NNRTI MOA
Resistance
Rapid resistance alone; CROSS-RESISTANCE occurs heavily in this class
Non-nucleoside reverse transcriptase inhibitor, binds hydrophobic p66 pocket of RT
MOA: Binds noncompetitively to reverse transcriptase #No need to be phosphorylated to become active, are not incorporated into DNA like NRTI's
What HIV drug class ends in -navir?
MOA
USE and considerations
SE
Protease inhibitors (10 in market) MOA: binds directly to active site, is selective for viral enzyme vs human.
USE: in combination. P450 CYP3A4 metabolism, ritonavir is administered with a CYP3A4 inhibitor to increase lvls
SE: dyslipidemia, insulin resistance, central obesity (like cushingoid), hepatotoxicity
Enfuvirtide
MOA
USE
SE
ONLY Fusion inhibitor binds gp41
Used in “salvage” regimen, requires injection bid
SE: neutropenia
IL-2 infusion in HIV
Shown to increase/sustain CD4 count but without clinical benefit
Maraviroc
MOA
USE
SE and considerations
ONLY CCR5 inhibitor
MOA: binds ccr5 to prevent fusion
SE generally not much. But don’t work if primary receptor is CCR4 (which is often the dominant coreceptor in advanced HIV). So you have to check if CCR5 or CCR4 is dominant.
“Viroc” thrown at CD4 to keep it away from temptress HIV
Raltegravir and Elvitegravir
MOA
USE
SE
MOA Integrase inhibitor
USE: Often 1st line HAART
SE: diarrhea, nausea, fatigue, muscle ache
HIV post exposure prophylaxis
Risk of seroconversion
Tx
0.3% risk from needle stick
Tx; 4wk triple therapy
Antiretroviral therapy viral load goal
Durable suppression of HIV viral load (< 50 copies/ml)
HAART therapy
Initial therapy
Considerations
Mainstay is 2NRTI + 1 of either protease/NNRTI/integrase inhibitor
Consider: Always test for resistances
