HIV immune evasion and implication for vaccine design Flashcards
What form is the gp160 protein in?
In trimers of gp41 (TM) and gp120 (globular) proteins.
Polypeptides encoded by GAG and POL?
GAG: matrix, capsid and nucleocapsid
POL: Integrase, reverse trascriptase and protease
Two tropisms of HIV?
CCR5 and CXCR4 (more pathogenic)
What happens in acute phase of HIV infection?
Large viral replication which causes drop in CD4 T cells.
Large immune response against infection which dramatically reduces viral replication to a persistent level.
CD4 T cells levels recover.
What happens in asymptomatic phase of HIV infection?
virus still replicates at persistent level.
CD4 T cells will be made by thmus, but will gradually drop with impairment of thymus function with age.
GALT damage thought to cause chronic grade immune activation and inflammation.
What happens in end stage of infectoin?
Viral replication increases rapdily.
Rapid decrease in CD4 T cells.
Impairment of immune system and susceptibility to opportunistic infections.
AIDS.
Why is fever seen in acute infection?
Becuase of high levels of inflammation and ctyokines.
How do persistent viral load compare between individuals?
Varies with individuals, and can predict the speed of AIDS progression.
Where does HIV infect and damage initially?
Mucosal barrier, infection of founder cells in lamina propria and GALT damaged.
Infection establishment timeline 5 stages
Founder cell infection in lamina propria.
Small foci of infection.
local spread.
Dissemination into local lymphoid tissues.
Dissemination into all lymph nodes.
When is it too late to eliminate HIV in acute infection?
After dissemination to lymph nodes and establishment of the reservoir of latent cells.
3 broad factors that can affect the persisting viral load of HIV?
- Properties f infecting virus
- Host genetics
3 Efficiency of initial immune response.
What factors involve in properties of infecting virus that influence persistent load?
- CCR5/ CXCR4 virus.
2. Virus genetics e..g deletions in Nev reduces pathogenicity.
What factors involved host genetics that influences persistent load?
Homozygous/ heterozygous for CCR5 deletion.
HLA B57:01 MHC allele is protective, very low persistent viral load.
What cytokines are upregulated locally and systemically in response to HIV, and what are their sources?
type 1 IFNs (particularly by pDCs) and IL-15. Then TNF-a ad IL-18 slightly later.
Why might inital innate cyotkine production be beneficial?
Stimulate type 1 IFN reponses (interfereon stimulated genes ISG).
Has an adjuvant effect, activates innate and adaptive immune cells.
Why might initial innate cytokine production be bad?
Can recruit ACTIVATED CD4+ immune cells to infecction site to fuel infection.
Unlike HBV and HCV, HIV hasn’t evolved to block this cytokine response.
Pro apoptotic effects of IFNa and TNFa could contribute to CD4 cell loss.
What does a reduced antiviral gene expression upon infection show?
Increased reservoir size, and faster CD4 T cell depletion and progression to AIDS.
Does HIV avoid the IFN response?
Yes, HIV-founder viruses found to be resistant to IFN.
HIV accessory proteins vif and vpu..
How does HIV affect DCs?
Doesn’t in primary infection, but DC numbers and cytokine production later on are decreased.
How does vif and vpu accessory proteins coutneract ISGs?
Vif will degrade APOBEC3G.
Vpu will sequester tetherin.
Whihc population of NK cells exapnds in HIV infection that correlates with better response with which HLA?
Exapnsion of (activating) KIR3DS1+ NK cells with HLA-Bw4 Ile-80 allele.
Through what process may co-expression of highly inhibitory KIR3Dl and HLA-Bw4 II2-80 be beneficial in infection?
Perhaps through NK cell licensing? But probably unknown.
How could NK cells have detrimental effects?
They could lyse HIV-specific CD4 T cells.
How do HIV infected cells evade NK response?
Reduces the number of NK cells in chronic infection.
Changes balance to more inhibitory receptors.
may block Ca2+ and cytotoxic degranulation.
Downregulates HLA-A,B,C but not HLA-E.
Why might antibody responses not be effective despite early seroconversion?
Because Ab produced are non-neutralising. ay have some Fc-dependent mechanisms though.
Neutralising Ab may only come later.
Why might effective neutralising antibody responses be delayed?
Many sites are ‘self like’, so a limited number of pre-existing appropriate BCRs.
Lack of CD4 T cell help
Need lots of somatic hypermutation to overcome peripheral tolerance to self.
Antigenic variance and avoidance of neutralisation.
One way antigenic variants can escape the neutralising antibodies?
Addition of glycans to epitopes.
How does HIV hide neutralising epitopes?
With a dense glycan shield,.
Variable protein loops near CD4 binding site.
Chemokine binding site only transiently exposed upon CD4 binding. At this time, this site becomes hard to access via Ab.
6 broadly neutralising Ab sites?
CD4 binding site V1/V2-glycan V3-glycan Fusion peptide gp120, gp41 interface, Membrane proximal external region (includes a lipid portion).
Why is it difficult to generate Ab against broadly neutralising sites?
Ab footprints contain glycan and lipid binding sites, which are similar to self.
Lots of somatic hypermutation required to overcome peripheral tolerance.
Need to bind sites on envelope trimer very precisely.
What is the primary reason for weak HIV-specific CD4+ T cells responses in HIV?
Because of CD4+ T cell infection and depletion.
How can DCs indirectly contribute to HIV-specific CD4+ T cell depletion?
DCs can be infected with HIV, or internalise it via DC-SIGN then come into contact with HIV-sepcific CD4+ T cels in LN.
How does bystander apoptosis of CD4+ T cells occur?
exposure to gp120 can mediate Fas and FasL apoptosis.
What other immune cells may destroy HIV-specific CD4+ T cells?
NK cells
What (selection associated) evidence is there that CD8+ T cells are important for controlling HIV replication?
Selection for variatns observed that can avoid CD8+ T cell responses.
What allelic evidence is there that CD8+ T cells are important for controlling HIV replication?
The HLA class I alleles HLAB35-02/3 and B8 are associated with rapid disease progression. HLAB27 and HLAB57 are associated with slow progression.
How does HIV avoid CD8 T cell responses? 5 ways?
Latency. Replication in immune privelaged sites. Down regulation of MHC I (tat, Nef, Vpu.) antigenic variation. T cell exhaustion
How does tat, Nef and Vpu downregualte class I expression?
tat- via decreasing activity of the MHC class I promoter.
Nef by inducing endocytosis and degradation of HLA A/B.
Vpu does similar for HLA-C
What 3 ways can amino acid changes around CD8 epitpope give rise to escape?
By changing:
epitope presentation
peptide binding to MHC
TCR recognition.
What kind of mutations will and won’t revert of selection pressures lifted?
More ‘costly’ mutations will revert.
Costless won’t revert and will preseits.
what factors of the CD8 T cell response can affect viral escape?
1) breadth of the response.
number of T cell epitopes targeted
Or a number of different clones recognising each epitope.
2) Responses directed against conserved epitopes (HLA-B27 and 57 associated with control of HIV and are associated with dominant Gag-specific responses.
Characteristics of exhausted CD8 T cells in chronic infection?
low perforin/ granzyme levels, and an increase in checkpoint inhibitors.
How else does NEf contribute to ihibition of apoptosis?
Nef inhibits Fas and TNF-R killing. Does this by binding ASK-1.
3 issues with triggering prophylactic HIV vaccines ttargeig T cells?
1) limiited window of opportunity to mount effective T cell response that prevents dissemination.
2) HIV mechanisms for evasion of these responses.
3) vectors stimulating CD4+ T cells as well, activates CD4+ T cells which are more susceptible to infection.
What was interesting about the CMV vaccine that provided protection against SIV in 50-60%?
It stimulated an MHC-E and MHCII restricted CD8+ T cell response.
