HIV Flashcards
What family of viruses does HIV belong to?
retroviridae
What is the capsid symmetry of HIV?
icosahedral
Does HIV have an envelope?
yes
What is the genome of HIV?
+ sense ssRNA
Where does the genome of HIV replicate?
in the nucleus
Where is virus assembly of HIV?
in the cytoplasm
What are the 3 major genes of the HIV genome?
gag, pol and env
What is encoded by the gag gene?
the matrix, capsid and nucleocapsid
What is encoded by the env gene?
the surface glycoprotein (SU or gp120) which binds to the CD4 receptor and the transmembrane protein (TM or gp41) which enables the virus to attach to target cells
What is encoded by the pol gene?
reverse transcriptase, protease and integrase
How does HIV enter cells?
the surface glycoprotein binds to the CD4 receptor which induces structural changes in the protein - this leads to exposure of coreceptor binding sites which bind to CCR5 or CXCR4 which leads to structural rearrangement and membrane fusion
What is the difference between CCR5 and CXCR4 binding HIV?
CCR5 binding happens early in the infection and has less pathogenicity
Why is there a high level of mutation in HIV?
because the reverse transcriptase is highly error prone
What is the role of integrase?
catalyses the random integration of HIV DNA into cell DNA which is required for the production of new virus
What is the LTR and what is its role?
the LTR is a long terminal repeat on both ends of the viral DNA which binds to integrase so the DNA can be integrated into the host DNA - it is important because the 5’ LTR acts as a promoter and is activated by NFkappaB when T cells are activated - therefore T cell activation results in transcription of viral proteins
What is the function of the tat protein?
binds to TAR (transactivating response element) which is essential for efficient transcription and also has a role in phosphrylating RNA polymerase II to make it an efficient enzyme
What is the function of the rev protein?
allows fragments of HIV mRNA that contain a HIV Rev response element (RRE) to be exported from the nucleus to the cytoplasm
Are tat and rev essential for HIV replication?
yes
Are vif, vpr, vpu and nef essential for HIV replication?
no - but they are essential for pathogenesis
What is the role of vif?
blocks APOBEC (an enzyme which mutates viral DNA)
What is the role of vpr?
nuclear import of DNA
What is the role of nef?
down regulates MHC class I
What is the role of vpu?
down regulates MHC class I and counteracts tetherin (a protein which prevents the release of viral particles)
How does tat down regulate MHC class I?
by blocking transcription
What is involved in the maturation of HIV particles?
the gag-pol precursor acts as a protease which cleaves the polyproteins into individual proteins
What is viral latency?
the HIV lies dormant and hidden in T cells so that when patients come of HAART the virus can come back - latency is the barrier to curing HIV
What are the 3 phases of untreated HIV?
primary infection where there is a big increase in the amount of virus and a plunge in the number of CD4 cells, asymptomatic infection where there is a stabilisation of the amount of virus and the number of CD4 cells and then the symptomatic infection and AIDS where there is a decline in the number of CD4 cells and increase in the number of virus
What are the clinical features of primary HIV?
- Fever
- Myalgia/arthralgia
- Nausea/vomiting/diarrhoea
- Weight loss
- Malaise/lethargy
- Rash
- Lymphadenopathy
- Pharyngitis
- Oral thrush
- Headache/retro-orbital pain
- Meningitis
- Transient CD4 depletion
What happens in the gut in primary HIV?
there is loss of peyer’s patches and a breakdown of gap junctions in gut epithelial cells
What is the incubation period of HIV?
2-4 weeks
How long does the clinical illness of primary HIV last?
1-4 weeks
How long after infection can an HIV p24 antigen be detected?
from 20-60 days
How long after infection can HIV RNA be detected?
between day 1 and day 18
How long after infection can HIV antibodies be detected?
40-50 days
Do HIV antibodies neutralise the virus?
no because of high levels of envelope glycosylation
Why does HIV escape the immune system?
because there are high levels of sequence variation, because of down regulation of MHC class I, because of loss of effector cells (CD4 cells), because of viral latency and because of priveleged sites of viral replication (the brain)
Why is it so difficult to make a vaccine for HIV?
because the envelope gp120 protein has so much variability and there are glycans masking the envelope
What is a predictor of survival in untreated HIV?
the viral load during the quasi steady state where viral production is equal to viral clearance
What are the 3 causes of T cell depletion?
CD4 T cell destruction, chronic immune activation and impaired T cell production
What is the attenuated strain of HIV?
where the nef gene has been deleted so its less pathogenic
What is the viral R5 phenotype?
where the virus is able to alter is envelope so its more pathogenic
What is the result of a CCR5 mutation in the host?
resistance to HIV
What is HAART?
highly active anti retro-viral therapy
How is development of drug resistance minimised?
by using 3 different anti virals in combination
What are the different anti retro viral therapies for HIV?
nucleoside reverse transcription inhibitors, nucleotide reverse transcription inhibitors, non nucleoside reverse transcription inhibitors, entry inhibitors, protease inhibitors and integrase inhibitors
What different entry inhibitors are there?
coreceptor antagonists and enfuviritide which prevents the molecular gymnastics to stop fusion
What is the mechanism of action of nucleoside reverse transcription inhibitors?
the drugs are analogues of nucleosides but lack the 3’ hydroxyl group - they are prefentially used by the virus in replication but because of the lack of the 3’ hydroxyl group they prevent chain elongation
What is the mechanism of action of non nucleoside reverse transcriptase inhibitors?
directly inhibit the reverse transcriptase enzyme
What is the mechanism of action of raltegravir?
it is an integrase inhibitor - it blocks the strand transfer step of integration
What is the mechanism of action of protease inhibitors?
inhibits maturation of the HIV particle by binding and inhibiting the protease enzyme
Why does HAART fail to cure HIV?
because a small proportion of HIV remains latent
What causes the non AIDS co morbidities of HIV?
chronic inflammation
What are the non AIDS co morbidities of HIV?
cardiovascular disease, cancer, osteoporosis, liver failure, kidney failure, cognitive decline, frailty
