HIV pathogenesis Flashcards
1
Q
what are the 3 most important structural gene groups of HIV
A
env
gag
pol
2
Q
what are the genes encoded by the env genes and what are their functions
A
gp120 = cell attachment (surface) gp40 = fusion domain (transmembrane)
3
Q
what are the genes encoded by the gag genes and what are their functions
A
structural proteins of the capsid - encase the 2 copies of RNA
4
Q
what are the 3 important proteins encoded by the pol genes
A
reverse transcriptase
integrase
protease
5
Q
explain the 3 steps of HIV fusion with T cells
A
- attachment of the gp120 protein to CD4 molecule –> causes structural change in gp120 –> recruits CCR5/CXCR4
- binding to CCR5/CXCR4 –> promotes fusion of gp41 peptide
- structural rearrangement of gp41 trimer to drive membrane fusion
6
Q
when are CCR5 or CXCR4 used
A
CCR5 - early
CXCR4 - late
7
Q
functions of HIV reverse transcriptase
A
- converts the viral genomic RNA to proviral cDNA
- duplicates the sequences at the end of the viral DNA –> LTRs
8
Q
function of HIV integrase
A
catalyses the random integration of HIV cDNA into cell DNA
9
Q
what part of the cDNA made by RT acts as the promoter
A
the 5’ LTR
10
Q
explain the regulation of the 5’ LTR promotor of the HIV cDNA
A
- increases expression in response to HIV Tat protein
- silences HIV expression soon after initial replication
- responds to cellular proteins made during T cell immune activation to dramatically increase HIV expression
11
Q
which HIV enzyme has the greatest error rate and therefore the cause of viral diversity
A
reverse transcriptase
12
Q
what is the protein that is made by HIV that is like a protein made by T cells
A
NF-KB
13
Q
what are the cis and trans factors that can regulate HIV basal transcription
A
- cis = chromatin and associated factors (switch off transcription)
- trans = TFs made by T cells can activate transcription (eg NF-KB)
14
Q
what are the 2 major regulatory proteins of HIV
A
Tat
Rev
15
Q
functions of Tat protein
A
- promotes HIV transcriptional elongation
- inhibits MHC-1 gene transcription
16
Q
functions of Rev protein
A
stabilises and transports unspliced and partially spliced HIV RAN to the cytoplasm
17
Q
what are the 4 main accessory proteins of HIV
A
Vif
Vpr
Vpu
Nef
18
Q
what is the overall function of the accessory proteins of HIV
A
prevent MHC-1 presenting HIV peptides to APCs
19
Q
functions of Vif
A
- promotes infectivity of cell free virus
- blocks cell defences targeting ss cDNA
- degrades APOBEC3
20
Q
functions of Vpr
A
- protein for nuclear import
- cell growth arrest
21
Q
functions of Vpu
A
- promotes MHC-1 and CD4 degradation through direction MHC-1 to proteasome and lysosomal degradation
- antagonises tetherin
facilitates the release of fully infectious virions
22
Q
functions of Nef
A
down modulates cell MHC-1 and CD4 through lysosomal degradation of MHC-1
23
Q
how does the HIV virus mature
A
- ribosome shift causes the icosahedral core of HIV to form a complex rod shape after budding and the GAG polyprotein gets jointed onto Pol
- the protease activity of the Gag-Pol precursor protein causes cleavage of polyproteins into individual proteins –> assemble into fully infectious virus particles
24
Q
in which T cells is HIV latent
A
central (mostly) and transitional memory T cells
25
how is latent HIV reactivated
Tat protein activates RAN expression
- causes recruitment of histone acetyl-transferases --> leads to acetylation of histones in chromatin --> opening the DNA promotor for access by RNA polymerase II
26
what are the reasons for HIV persistence
- integrates into the cells that would be in charge of their removal
- highly mutagenic
- mechanisms that direct active evasion
- integration into host DNA
27
what are the 3 phases of untreated HIV
primary infection
asymptomatic infection
symptomatic infection and AIDS
28
what is primary infection characterised by
- a rapid and massive loss of the body's CD4+ T cells
- initial decline in HIV due to CD4 substrate exhaustion
- loss of memory T lymphocytes in GALT
29
what is the incubation period of primary HIV infection
2-4 weeks
30
in what percentage of people seroconvert if not treated
50-95%
31
what are the best tests to test for early HIV infection
those that measure viral RNA
32
what is HIV viral load
amount of HIV RNA in plasma
33
what are the initial immune responses that contain HIV replication
- high titres of HIV specific Ab
| - 5% of total IgG specific for HIV envelope
34
why are Ab against the HIV env protein essentially useless
- does not neutralise it
- high level of Env glycosylation
- low immunogenicity of virus bound gp120 oligomers compared to circulating free monomers
- greatest sequence variability
35
what are the mechanisms by which HIV escapes from the immune system
- sequence variation
- altered antigen presentation
- loss of effector cells
- latency
- privileged sites of viral replication
36
when is the viral load said to be undectectable
when viral load <50copies/ml
37
what predicts survival if you have untreated HIV
viral load
38
how does HIV cause indirect destruction of uninfected CD4+ T cells
- cytolysis by HIV specific CT or NK cells
- incorporation into syncitia
- immune ACTIVATION of CD4 and CD8 T cells
39
what causes the chronic immune activation leading to T cell depletion in HIV
integrity of gut mucosal barrier lost --> microbial products leak into systemic circulation --> immune cells stimulated through TLR --> elevation of pro-inflammatory cytokines --> CD4 T cells enter cell cycle and die, CD8 T cells beome trapped in lymph nodes, B cells make auto-Ab
40
what are the results of depleted T cells on the rest of the immune system
- reduced T cell help for B cells and macrophages
- reduced killing of bacteria by neutrophils
- increased autoantibodies by B cells, and reduced killing of encapsulated bacteria
- reduced phagocytosis, chemotaxis and killing by macrophages
- reduced NK function
41
at what CD 4 Tcell level do you start to get opportunistic infections
less than 200cells/ml
42
mean survival after untreated AIDS
1.3 years
43
what factors determine disease progression
- strain of HIV virus
- coinfection with hepatitis G
- HLA type
- immunology
- age
44
what are the main general types of antiviral therapy for HIV
- RT inhibitors
- fusion/entry inhibitors
- protease inhibitors
- integrase inhibitors
45
what is the reason for combinational anti-HIV therapy
improbability of multiple different viral changes to combat all 3 drugs
46
how do the fusion/entry inhibitors anti-HIV drugs act
binds to CCR5 or CXCR4 on human cells to block it interacting with envelope proteins on HIV
47
difference between nucleoside and nucleotides
```
nucleoside = no phosphate groups
nucleotide = phosphate group
```
48
how does acyclovir work
it is a nucleoside analogue that lacks the 3' hydroxyl group required to form DNA polymer
49
how is acyclovir encorporated into the cell
herpes virus thymidine kinase has to perform the first phosphorylation of the acyclovir. Cellular kinases do the further 2 phosphorylations
50
what is the difference between acyclovir and valacyclovir
valacyclovir has an additional valine side chain that increases the passage of the drug through the digestive tract and into the circulation (improved oral bioavailability)
51
what is ribavirin
a guanosine analogue that inhibits replication of many DNA and RNA viruses in vitro
52
what are the uses for ribavirin
- RSV bronchiolitis and pneumonia
- influenza
- haemorrhagic fevers
- hep c
53
what are the nucleoside reverse transcriptase inhibitors for HIV-1
thymidine, cytidine and guanosine analogues that are used by viral RT in preference to cellular nucleosides causing transcription termination
54
what is zidovidine
thymidine analogue
55
how do non-nucleoside reverse transcriptase inhibitors for HIV-1
directly inhibit the RT enzyme by other mechanisms
56
what is raltegravir
integrase inhibitor
57
how do integrase inhibitors work
blocks strand transfer of viral DNA into host DNA
58
how do protease inhibitors of HIV work
they bind tightly to the enzyme active site preventing their action
59
what are two drugs that are protease inhibitors
indinavir
| nelfinavir
60
what were the long term complications of HAART in the 1st decade
lipoatrophy
lipodystrophy
neuropathy
multi-drug resistance
61
why does HAART fail to cure HIV
a small proportion of HIV remains latent in:
- resting memory T cells
- reservoirs (brain, gut, testis)
62
even though patients are not dying of OI anymore with HIV, what are the long term consequences now
```
ongoing immune activation, which leads to:
- decreased endothelial activation
- increased monocyte activation
- dyslipidaemia
- hypercoagulation
- endothelial dysfunction
leading to "diseases of old age"
```
