HIV Pathogenesis Flashcards
What family does HIV belong to?
Retroviridae
What does retroviridae family do to replicate?
RNA viruses which use RNA-dependent DNA polymerase (reverse transcriptase) to make a cDNA replication intermediate
What was HIV originally named?
HTLV-3
When was ‘HIV’ first reported?
1981
Does HIV-1 or 2 have more virulence and infectivity?
HIV-1
Is the most prevalent, highest virulence and high infectivity
Where does HIV-1 come from?
Common chipanzee
Where does HIV-2 come from?
Sooty mangabey
What are the 4 groups of HIV-1?
M, N, O, P
What is the most common HIV group?
Group M
Where is HIV-2 largely restricted to?
West Africa
What is the predominant subtype of HIV-1 group M?
Subtype C (makes up 52% of HIV cases)
What is the significance of HIV subtypes?
Impacts viral load testing, vaccine design and drug resistance as tests have to test all subtypes otherwise it wont work
What can you do with SIV sampling?
Sample a gorilla SIVs in different sites across Congo etc. and map onto phylogenetic trees, starts to map where these different HIV variants might have come from in the SIV ancestors based on their phylogenetic relationships
What does HIV rapidly evolve to form
A quasispecies due to its error rate of RT
How do you estimate the rate of HIV-1 evolution?
Dol = distance ‘outgroup’ vs ‘late’
Doe = distance ‘outgroup’ vs ‘early’
d = Dol-doe
t = time difference
Rate = d/t
(See diagram on lecture to make sense)
What is there at each end of the genome?
Long terminal repeats
What is the main structural protein?
Gag
What is the gag polyprotein made up of?
Capsid, matrix and nucleoprotein
What function does pol have?
Has enzymes virus needs in order to infect a cell e.g. protease, reverse transcriptase etc.
What are the two subunits of env?
Gp120, gp41
What are the two regulatory genes?
Tat and rev
What are the accessory genes?
Nef
Vif
Vpr
Vpu
What do accessory genes do?
Control teh host in some way e.g. inhibiting resitrction factors
What does vpr do?
Keeps cell in G2 cell cycle phase
What does vpu do?
An accessory protein invovled in antagonism of resitrction factors most famously for tetherin antagonism
What does APOBEC3 protein do and what does HIV do to it?
It induces random mutations
VIF targets ABOBEC3 and takes it away so it can no longer be incorporated into budding virion
What is the relationship between HIV resitrction and tetherin?
Tetherin tethers budding virions to cell surface of productively infected T cells, vpu pritein comes along and snips it off cell surface and takes it away from the cell
What is the receptor for HIV viruses?
CD4
What do most basic lentiviruses not need that HIV does?
Accessory proteins
What are the two co receptors for HIV?
CCR5 and CXCR4
Where is CXCR4 mainly found?
On T cells, happens later in infection
Where is CCR5 mainly found?
In dendritic cells and other mucosal cells where the virus initially infects
What happen with HIV viral entry?
Virus binds to receptor and undergoes conformational changes, interacts with co-receptor, this change exposes fusion peptide inside the strutcure and comes thorugh and embeds itself into the membrane
Which steps are reversible vs irreversible?
First two entry steps, binding to CD4 and binding to co receptor are reversible
But once fusion peptide is released then it can no longer be reversed
What is important about the HIV genome?
LTRs are identical to each other
What is the reverse transcription process?
TRNA acts as a primer for synthesis
RT sits on end of the tRNA and synthesise DNA from RNA genome of the virus until it reaches 5’ end of the genome
At this point RNAse and chews up RNA that is in complex with the DNA
End up with a sticky end
Have piece of ssDNA hanging off end of genome with tNRA holding it in place
As 3’ end and 5’ end are identical, 3’ end of this sticky end can bind to 3’ end of RNA genome then DNa polymerase can carry on running along, copy the DNA and keep making DNA along the circle
What are the effects of variability?
Immune escape by changing/masking antigenic determinants
Resistance to anti-retro viral drugs
Altered cytopathogencitiy
What is the integration process?
Once dsDNA arrives at nucleus, can be extrachromosomal circular or linear or can integrate into host DNA
During integration , two bases are removed from the ends by integrase, this creates a sticky end
The integrase will also Knick two bases and create a stick end inside the host genome, get ligation reaction
Ligases the genome into the host
DNA repair processes repair broken ends and it will be fully integrated into the cell
Where is there a ribosomal frameshift between gag and pol?
Between gag and pol
What are the transmission methods of HIV?
Transcutaneous e.g. needle-stick injury
Sexual
Vertical (mother-infant)
What are disease stages classified as?
A, B, C
With 1, 2, 3 subtypes
Based on CD4 counts, can classify what clinical progression they are in through it
What is category A?
Asymptomatic or acute
What is category B?
Symptomatic
What is category C?
AIDS-indicator conditions
What are subtypes 1, 2, 3 based on?
Number of CD4 counts
What happens in acute phase infection with antibodies and antigen levels?
HIV-1 antibody negative
HIV-1 RNA/ antigen positive
What happens in seroconversion stage of HIV-1 acute phase?
HIV-1 anitbody positive
Decreased viraemia (RNA decrease, antigen decrease)
What receptor is primarily used in asymptomatic phase?
CCR5
What receptor is primarily used in symptomatic phase?
CXCR4 receptor
What is the CD4 count usually above for asymptomatic phase?
CD4 >200
What is the defect that causes people to be resistant to infection?
Delta32 - CCR5
What is the difference between homozygous delta 32-CCR5 and heterozygous?
Homozygote - very resistant to HIV-1 infection
Heterozygous - delayed onset of AIDS, some resistance to infection
What stem cell transplant can cure HIV?
Stem cell transplant from delta 32 knockout human
Why were some sex-workers HIV-1 negative following exposure?
Had HLA subtypes that make them particularly resistant to HIV infection
Means people never seroconvert to HIV
Why are some HLAs protective and others not?
Virus escape
Some mutaitons neutral
Some induce fitness cost
