Magor- Topic 9: CTL Evasion Flashcards
_________ presents peptides from intracellular proteins
MHC class I
_________ are linear parts of the intracellular protein that fits right in the cleft of MHC class I
Peptides
Viral escape by down-modulating surface expression of MHC: Poliovirus interferes with protein transport in the cell to make vacuoles
- Vesicles budding from ER never make it to the membrane. No new surface proteins get to the cell surface.
- Old MHC, with self peptides bound remain on surface, even though the cell is infected.
The ____________ keeps HIV under control for many years
CTL response
When ______ declines, opportunistic infections and disease start.
CTL
HIV probably initially infects ___________ & ___________ that are in the mucosal tissues where it enters.
Those cells can take up those viruses either by ______________, ____________, or ______________
dendritic cells & macrophages
phagocytosis, presented by MHC class II, or they can also become infected by HIV
CTL made in HIV infected individuals are defective.
Even though the cytotoxic T cell response is keeping that virus under control for 2-10 years, we still know that when you actually look at those cytotoxic T cells from an HIV person, about 80% of them are immature. They’re not actually able to kill. They have no ribozymes & perforin that are needed for killing.
humans co-dominantly express three _____________ genes
MHC class I (HLA)
one of our genes in our body that we express two alleles
An epitope bound by MHC class I is a linear ___ amino acid sequence from within the protein. Viral peptides can be presented if they fit. Each peptide varies except at _______ residues
9
anchor
HIV is evolving to eliminate ____________ (especially for common HLA alleles)
CTL epitopes
Epitope that you really hope to have is the epitope that
the virus can change
Epitopes that are easy to change
Immunodominant epitopes
- CTL immune response tends to focus on a few epitopes originally seen.
- Sometimes called ‘original antigenic sin’
- Focusing first on a really strong epitope & then as that epitope changes it will move to different epitopes.
You can take cytotoxic T cells out of a person & just give them ______ in petri culture dish and they will expand & proliferate
IL-2
HLA-B27 allele
They noticed that many individuals who are HLA-B27 were fine even though they’ve been infected for years.
HLA-B57 allele
- not a common allele
- 11/13 long-term HIV nonprogressors have this allele
Nef
- virulence factor
- targets HLA-A and HLA-B for degradation
- HIV makes this
- targets the HLA that’s on the surface
- binds to the cytotoxic tail of HLA & sends it to the endosome for recycling
- binds to the sequences of the proteins for HLA-A & HLA-B, but not HLA-C
What happens by having Nef internalizing (remove HLA-A & HLA-B from the surface of the cell but leave HLA-C)?
The cell is no longer a target for cytotoxic T cells & it’s aso not a target for NK cells.
Most of the things that the cytotoxic T cell responds are presented by ______ & _______
HLA-A & HLA-B
There are many targets of antiretroviral drugs: (3)
- There are inhibitors of the chemokines that prevent entry
- There are protease inhibitors
- There are reverse transcriptase inhibitors
HAART- Highly Active Antiretroviral Therapy
By giving these drugs in combination, it suppresses the viral load to the extent that person is no longer considered infectious & works really well.
- AZT
- 3-TC
- Darunavir (binds and blocks active site of the HIV protease
Reason why the HIV virus is so challenging
Because of the step where it integrates into the genome of the cells it infects. It makes it basically impossible to get rid of.
It just hangs out there in those infected cells
People are trying strategies to get that virus out of the reservoir.
- we don’t really know what the reservoir is, but presumably it’s those CD4 T cells that remain infected.
- could also be some dendritic cells, but most likely CD4 T cell
- some of the strategies attempted are to basically turn on transcription, get that virus making copies of itself & then use antiretroviral therapy to prevent that virus from infecting the next round of cells.
Vorinostat
- is a histone deacetylase inhibitor that opens chromatin
- they used this to shock the cells & prevent the virus from thriving
ZR59
- pandemic strain
Does vaccines prevent HIV infection?
They don’t prevent infection. They prevent disease from that infection
what is the best type of HIV vaccine
live attenuated vaccine
- go through a round of replication & presentation to MHC class I
These three types of vaccines induce both major histocompatibility complex (MHC) class I and MHC class II antigen presentation and activate pattern recognition receptors (PRRs) expressed by dendritic cells through several pathogen-associated molecular patterns (PAMPs)
Live attenuated, viral vectors and nucleic acid vaccines
Killed whole-organism vaccines
activate dendritic cells through the same PAMPs and induce good CD4 and B-cell responses
These three vaccines may need an adjuvant for optimal dendritic cell activation and CD4 T-cell priming.
Protein vaccines, viral-like particles, and glycoconjugate vaccines
Polysaccharide vaccines
induce a T-cell-independent antibody response
