viral interference with human class i major...
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Viral interference with Human Class I Major Histocompatibility Complex Presentation.
Adam Huys
Department of Microbiology and Immunology University of Saskatchewan
Saskatchewan, Saskatoon, SK. Canada
For: Advance Virology, VTMC 833 © Adam Huys
Abstract Introduction Proper folding, loading, transportation and presentation of a functional MHC-I molecule
Early Folding Peptide generation Peptide transport
The Peptide Loading Complex Export to the Golgi and surface expression Viral interference
Targeting MHC for degradation within the ER Preventing virus-derived peptides Interfering with peptide transport Disrupting the Peptide Loading Complex Inhibiting MHC-I transport from the ER to the cell surface Removal of MHC-I molecules from the cell surface Other
Conclusion
Abstract
While most viruses capable of infecting humans fail to maintain their infection for a long
period of time, others can maintain a life-long infection. Viruses capable of maintaining a long
infection period have evolved a wide variety of mechanisms to avoid the human immune system.
One of the ways these select viruses do this is by limiting the effectiveness of the class I major
histocompatibility complex (MHC-I) presentation. This limitation is a result of viral interference
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in the MHC-I pathway at various points, such as MHC-I folding, peptide generation and
translocation, and MHC-I transport to and presentation on the cell surface. This review will
examine the viruses that have been identified to interfere with MHC-I presentation and where the
interference occurs along the pathway.
Introduction
Viruses and their human hosts have evolved together for millions of years. As a result the
host has evolved mechanisms for controlling virus spread and infection. Likewise, the viruses
have adapted mechanisms to avoid the host defenses. One of the important defenses employed
by humans against virus infection is the CD8+ cytotoxic T-lymphocyte (CTL), which is capable
of identifying and killing virally infected cells. Identification of infected cells by CTLs is
mediated by presentation of endogenously expressed peptides on the surface of infected cells.
These peptides are exported and presented on the cell surface via the class I major
histocompatibility complex (MHC-I) molecule.
MHC-I molecules and the peptides they present function as a communication device
between cells and the immune system. The peptides being carried on the MHC-I molecules
represent a mechanism by which the cell reports what is transpiring internally. In normal healthy
cells, the peptides being expressed are those which are considered “self” and under normal
conditions do not stimulate CTLs. When conditions within the cell change such as during a viral
infection, the viral proteins being translated become candidates for MHC-I presentation. These
proteins are viewed as foreign by the CTLs and therefore the MHC-I has delivered a message
that internal processes are not normal. Due to this mechanism, any virus having its protein
presented in the form of peptides on the MHC-I molecule is a great threat to the survival of the
virus, as CTL detection of foreign peptides leads to CTL-mediated cell killing to eliminate any
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threat. However, as viruses and humans have evolved together, viruses have developed
mechanisms to inhibit MHC-I molecules from delivering warnings to the immune system. These
mechanisms can affect almost every aspect of the MHC-I presentation pathway (pathway is
shown in Figure 1) from proper loading and folding, to transport to the cell surface. These
mechanisms of viral interference are shown in Figure 2 and summarized in Table 1.
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Proper folding, loading, transportation and presentation of a functional MHC-I molecule
Early Folding
A functional MHC-I molecule found on the surface of a cell is composed of a heavy
chain (HC), a β2-microglubulin (β2m) and a peptide. The HC and β2m are independently
translated directly into the endoplasmic reticulum (ER) via the Sec61 translocon, an ER
membrane transport protein (6, 61). Upon entry into the ER the HC is immediately glycosylated.
This added sugar allows the recruitment of resident ER chaperones, of which the most strongly
implicated is calnexin (CNX). If a cell is deficient of CNX it is still able to make functional
MHC-I molecules, this is believed to be the consequence of immunoglobulin-binding protein
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(BiP) performing a similar task to that of CNX. The binding of the chaperone alters the HC
conformation to allow it to associate with β2m. This association releases the chaperone leaving
an “empty” MHC-I molecule ready for peptide loading (15, 56).
Peptide generation
Peptides are small proteins that are either translated on their own or are derivatives of
protein degradation. The peptides that are most often associated with MHC-I molecules are
defective ribosomal translation products (DRIPs) (59), which are degraded into peptides in the
cytosol by the 26S proteasome (18). Because of the MHC-I preference to present DRIPs, it
ensures that the peptides being presented are a representative of what is currently being
transcribed within the cell as opposed to displaying old, used degraded proteins. This preference
leads to a reduction in the amount of time required for the cell to alert the immune system as they
represent proteins that are actively undergoing translation with no lag time for the protein to be
fully synthesized, used, and degraded.
Peptide transport
The “empty” MHC-I molecules are localized in the ER, while the peptides they require
are generated in the cytosol. In order for the MHC-I to be loaded, the peptides must be
transported into the ER. This transportation is facilitated by heterodimers composed of TAP1
and TAP2. Transporter associated with antigen presentation (TAP), is a member of the ATP-
binding cassette (ABC) transporter family. Peptide translocation to the ER is a form of active
transport as it requires energy supplied by ATP to function. TAP preferentially binds peptides
that are 8-16 amino acids (aa) long but is capable of binding both smaller and longer peptides.
The binding of a peptide to TAP produces a conformational change within the transporter to
allow the binding of ATP. The hydrolysis of ATP results in the transposition of the peptide in
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the cytosol to the lumen of the ER. TAP is most efficient at transporting peptides 8-12 aa long
(2, 3, 65). Once the peptide has been successfully transported across the ER membrane it is
trimmed by the aminopeptidases ERAAP (ER aminopeptidase associated with antigen
presentation) to make it more suitable for MHC-I loading (56, 70).
The Peptide Loading Complex
The peptide loading complex (PLC) is constructed for the loading of the peptide onto the
empty MHC-I molecule. The exact mechanism of PLC assembly is not yet fully understood, but
there are some aspects that are already known. Calreticulin (CRT), which is virtually a soluble
homologue of the CNX chaperone, described previously, binds to the empty MHC-I molecule.
The molecule then associates with tapasin and ERp57. Whether ERp57 associates with CRT or
tapasin first is unknown. Tapasin is bound to TAP, and its association with MHC-I molecules
therefore brings MHC-I molecules to the site of peptide translocation. Tapasin is also believed
to be involved in ensuring the binding of high affinity peptides with MHC-I by keeping the
MHC-I in an open form, this ensure that only high affinity peptides will be able to induce MHC-I
closure. Lower affinity peptides will come into the opening but will disassociate because they do
not interact strongly enough to close the binding pocket. When a high affinity peptide enters the
MHC-I opening, it is strong enough to close the MHC-I molecule, which results in the
disassociation of MHC-I from the PLC (15, 56, 70).
Tapasin knockout cell lines exhibit decreased peptide presentation and decreased CTL
response. This phenotype is attributed to a decrease in quality peptide binding (23, 58). Humans
encode four different MHC-I alleles also known as human leukocyte antigens (HLA) -A, -B, -C,
and –E. Interestingly it has been demonstrated that variation within the HLA alleles can lead to
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phenotypes which do not associate with tapasin, therefore negating its ability to associate with
the PLC (47, 57).
Export to the Golgi and surface expression
After dissociation from the PLC, the peptide-loaded MHC-I molecules interact with
cargo protein BAP31, which escorts the MHC-I molecule within the ER to exit sites. Once at an
exit site, the BAP31-MHC-I complex is secreted in a COP II decorated vesicle and is destined
for the Golgi apparatus (1, 45, 67). If a low-affinity peptide is loaded, tapasin is less likely to
detach from the MHC-I molecule when it exits the PLC. This allows tapasin to be transported
along with the MHC-I molecule to the Golgi apparatus. However, tapasin contains an ER
retrieval signal, so when it reaches the Golgi apparatus, this signal will promote the return of the
MHC-I molecule to the ER, where the MHC-I will be given another chance to associate with a
peptide with higher binding affinity (55). Successfully loaded MHC-I molecules will travel
through the Golgi and be expressed on the cell surface, where it can present its peptide to the
immune system.
Viral interference
Targeting MHC for degradation within the ER
Human cytomegalovirus (HCMV) encodes two glycoproteins, US2 and US11, which are
capable of removing MHC-I molecules from the ER and promoting their proteasome degradation
in the cytosol (40, 71). The ER has a maintenance system called ER associated degradation
(ERAD) for ensuring that improperly folded proteins are discarded. Proteins destined for
degradation by ERAD are polyubiquinated and digested by proteasomes in the cytosol (51).
US2 and US11 promote ERAD of MHC-I molecules in two unique fashions (21). US11 is able
to recruit Derlin-1, a known initiator of ERAD, to MHC-I molecules. This results in MHC-I
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entering the ERAD process to be ubiquinated and undergo proteolysis. US2 promotes
translocation to the cytosol and ubiquination of MHC-I in a yet to be determined mechanism that
does not involve Derlin-1 (48, 66). Although US2 and US11 perform a similar function, they
interact with MHC-I in different regions of the MHC-I molecule. This makes the likeliness of
the host avoiding both degradation systems much lower. Because they recognize MHC-I in
different locations of the protein, US2 and US11 have different binding domains and will vary in
the specificity to which they recognize the different human alleles (11, 12, 24, 25, 49).
The p12 protein of Human T-cell leukemia virus (HTLV-I) has been shown to promote
the ER exit and degradation of MHC-I HC before it interacts with β2m (39). Unfortunately, at
this point in time there is no suggested mechanism of how p12 interacts with MHC-I and
promotes its early exit from the ER.
Preventing formation of virus-derived peptides
One of the mechanisms viruses can use to prevent being displayed on MHC-I molecules
is preventing the formation of peptides derived from their proteins. Two human viruses which
have displayed this ability come from the family Herpesviridae. Epstein-Barr virus (EBV) and
Karposi sarcoma-associated herpesvirus (KSHV) both infect and establish latency in human B
cells. During a latent infection of EBV, Epstein-Barr nuclear antigen 1 (EBNA-1) is expressed
to maintain the viral episome (72). As this is the only viral protein present during latency, it is
the only viral protein that could potentially trigger an immune response through CTL antigen
recognition during latent infection. EBNA-1 prevents itself from being displayed on the MHC-I
molecule in two fashions. The first mechanism encoded by EBNA-1 is limiting its translation
speed (73). By limiting its own translation speed, it is much more likely to be synthesized
correctly, decreasing the likelihood that it will become a DRIP. The second method EBNA-1
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employs to avoid being presented on MHC-I is its stability and ability to avoid being degraded
by the proteasome (46). Both of these mechanisms are attributed to the glycine-alanine repeat
region (GAr) found within the EBNA-1. Latency-associated nuclear antigen 1 (LANA-1) is
synthesized by KSHV during latency, and carries out the same functions as EBNA-1, by
preventing the formation of LANA-1 derived peptides in an identical manner. The sole
exception to the similarities between LANA-1 and EBNA-1 is that LANA-1 contains a GZ
(glycine, glutamic acid/aspartic acid) repeat region as opposed to a GAr (42, 74). Overall
EBNA-1 and LANA-1 both decrease the amount of their specific peptides being synthesized,
therefore decreasing the probability of being displayed on the MHC-I molecule and having its’
host cell destroyed.
Interfering with peptide transport
As discussed earlier, peptides must be transported across the ER to be loaded onto MHC-
I molecules. Thus viruses have evolved to target this step to prevent MHC-I presentation.
Herpes simplex virus type 1 (HSV-1) translates a protein, ICP47 which has high binding affinity
for TAP. This results in ICP47 competing with cellular-derived peptides for TAP binding (5, 31,
68). ICP47 binding to TAP also interferes with the stabilization of the heterodimer TAP1/TAP2
(44). When ICP47 binds TAP it prevents other peptides from binding to the transporter, therefore
preventing the transportation of any peptides from the cytosol into the ER.
HCMV encodes the US6 protein, which when translated is located in the lumen of the
ER, but is embedded in the ER membrane through its trans-membrane domain (28). US6
interferes with TAP on the ER side. The interference leads to a conformational change in TAP
that prevents it from binding ATP. TAP is still able to bind peptides, but is unable to receive the
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energy from ATP to transport the peptide into the ER (30, 43). The inability of TAP to access its
energy source leads to inhibition of peptides being transported into the ER for MHC-I loading.
BNLF2α is a protein expressed during the lytic phase of EBV infection and has recently
been shown to decrease MHC-I surface expression. It has been demonstrated that BNLF2α
interacts with TAP and inhibits the ability of TAP to bind both ATP and peptides (33, 60). It is
predicted to be able to accomplish this by inserting itself into the ER membrane, and then
interacting with TAP1, which stabilizes BNLF2α. This interaction directly interferes with ATP
and peptide binding on the cytosol side of the ER membrane. Although BNLF2α structure has
not been determined, it is hypothesized that this protein contains a trans-membrane domain in its
C-terminal end, because the C-terminal domain is hydrophobic. BNLF2α localization assays
also visualize the protein at the ER membrane (34), providing further support to the possibility
that BNLF2α inhibits MHC-I surface expression by interacting with TAP resulting in the
inhibition of peptide transport into the ER.
The E7 protein encoded by Human papillomavirus-11 has been demonstrated to interact
with TAP1. This interaction inhibits the ability of TAP to transport peptides across the ER. The
lack of available peptides for MHC-I loading decreases the surface expression of MHC-I
molecules (69).
Disrupting the Peptide Loading Complex
Disabling the formation of the PLC results in a decrease in MHC-I surface expression,
and this represents targets which viruses have evolved to disrupt. The adenoviruses translate the
early protein E19, which has been demonstrated to reduce the surface expression of MHC-I (7,
13). E19 has the ability to bind to empty MHC-I molecules and to TAP (14). This ability is a
mimic of the role tapasin plays in the PLC. Another mechanism employed by E19 to diminish
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MHC-I surface expression is encoded in its cytosolic tail, which contains a dilysine motif
(KKXX). This motif functions as an ER retrieval signal. If the MHC-I molecule is bound by
E19 when it is transported to the Golgi, the coatamer protein complex (COPI) will recognize the
motif and return it to the ER (22, 38).
The US3 protein of HCMV has also been demonstrated to interfere with the PLC. US3
functions similarly to E19 in that it too has the ability to bind TAP and MHC-I molecules
reducing the amount of MHC-I being successfully loaded with peptides (54). However unlike
E19, US3 does not contain an ER retrieval motif, therefore the protein does not force MHC-I
molecules to return to the ER after transportation to the Golgi.
Inhibiting MHC-I transport from the ER to the cell surface
All MHC-I molecules must make the journey from the ER to the Golgi apparatus. This
step in the MHC-I presentation pathway is the limiting factor for how much MHC-I is expressed
on the cell surface (67). As it is a limiting step viruses have evolved mechanisms to reduce its
speed. As discussed above, adenoviruses have a mechanism to inhibit MHC-I molecules by
perturbing the transportation of the MHC-I from the ER to the Golgi. Another human
pathogenic virus which inhibits this process is HCMV, which encodes US10. US10 is capable of
interacting with MHC-I and retaining the molecule in the ER (20). This alone does not decrease
MHC-I presentation, but allows the MHC-I molecules to be exposed to other HCMV proteins,
such as US2 and US11, for a greater period of time (52). If US2 and US11 have more time to
interact with MHC-I it will further decrease MHC-I surface expression. This additive affect is
seen with US3 also (53).
Human herpesvirus 7 (HHV-7) and human herpesvirus 6 (HHV-6) encode the protein
U21. Although this protein demonstrates only 30% similarity between the two viruses, it has
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been shown to downregulate MHC-I presentation (32, 36). U21 has the ability to bind properly
folded MHC-I molecules in the ER and accompany it to the Golgi apparatus. Once the MHC-
I/U21 complex arrives at the Golgi, the U21 dictates their transport to lysosomal compartments
where the two proteins are degraded (26, 35).
The Nef protein encoded by HIV-1 has been shown to downregulate several surface-
expressed receptors, one of these being the MHC-I molecule (8). Nef associates with MHC-I
and accompanies it to the Golgi (41). The Nef/MHC-I complex travels through the trans Golgi
network (TGN) until it comes into contact with adaptor protein 1 (AP-1). AP-1 is capable of
retaining proteins in TGN and initiating its re-direction to lysosomes (63). Nef, when associated
with MHC-I, is capable of recruiting AP-1 to MHC-I cytosolic tail. Whether AP-1 interacts with
Nef/MHC-I on its way to the cell surface or whether it interacts with the complex upon being
internalized from the cell surface, which would also be induced by Nef, is still not understood,
but there is evidence supporting both models (50, 62).
Human papillomavirus-16 encodes the protein E5. This protein has been demonstrated to
interfere with MHC-I presentation pathway. E5 has been shown to interact with both the heavy
chain of the MHC-I and the ER chaperone CNX. This interaction is hypothesized to form a
ternary protein complex consisting of MHC-I molecule, CNX and E5 resulting in the MHC-I
molecule being accumulated in the ER and Golgi apparatus preventing its expression on the cell
surface (9, 10, 27).
Removal of MHC-I molecules from the cell surface
The proteins K3 and K5, also called modulator of immune recognition 1 and 2 (MIR-1,-
2), are expressed by KSHV and promote internalization of surface-expressed MHC-I molecules
(37), thus inhibiting the final stages of MHC-I presentation: the ability to interact with CTLs. K3
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and K5 are able to recruit enzymes capable of initiating ubiquination of surface-expressed MHC-
I. The KSHV proteins are able to promote this recruitment through their variant really
interesting new gene (RING-CH) motif located in the N-terminal domain (17). The ubiquination
results in the MHC-I being internalized from the cell surface and shipped to a lysosome for
degradation (16). K3 and K5 association with MHC-I is predicted to occur in the medial-Golgi
compartment (29). K3 and K5 have identical functions, but their effectiveness for each HLA
allele differs: K3 is capable of down regulating all of the HLA alleles, while K5 is only able to
decrease the expression of HLA-A, and –B (64).
During the lytic stage of an EBV infection, EBV produces BILF1. This protein has
recently been demonstrated to reduce the amount of MHC-I surface expression. BILF1 has the
ability to directly interact with MHC-I molecules. This interaction results in an increase of
MHC-I surface turnover and presumably their degradation in lysosomal compartments. This
interaction between MHC-I and BILF1 is hypothesized to occur early in the MHC-I expression
pathway as immunoprecipitation indicate that there is association between the two proteins
within 15 minutes of MHC-I expression(76).
Other
Varicella-zoster virus (VZV) encodes the protein ORF66 which has been shown to
decrease surface expression of MHC-I molecule, however the mechanism by which ORF66
function is still unknown (4, 19).
Core protein of hepatitis C has also been demonstrated to down regulate surface
expression of MHC-I molecules. However at this time there has been no published suggestion of
mechanism of how core protein achieves this feat (75).
Conclusion
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By examining all the viruses that interfere with MHC-I presentation, it is possible to
identify a common theme amongst them. These viruses are all capable of becoming latent or
establishing long term chronic infections in humans. This is an interesting common theme
because if a virus wishes to become latent or cause a chronic infection, it must remain unnoticed
by the adaptive immune response. MHC-I presentation of peptides and the recognition of the
peptides by CTLs is a form of adaptive immunity. Viruses which infect their host and rapidly
replicate and spread to a new host do not appear to inhibit MHC-I presentation because they do
not benefit, or are not capable of becoming latent. The theme also demonstrates how important
the MHC-I presentation is to immune protection. Viruses that can successfully establish a long
infection period interfere with it, while those that do not interfere fail to establish an infection for
a long period of time.
Viral interference with MHC-I presentation also demonstrates how humans and viruses
have evolved together. The viruses that are most effective at evading the human immune system
are also those that are believed to have infected humans the longest. Some viruses affecting
MHC-I presentation encode multiple proteins which affect MHC-I, while other viruses encode
only one protein. Perhaps the redundancy and multiple modes of MHC-I inhibition can act as
markers for how long humans have been evolving with infection to these viruses. For example
HCMV has multiple proteins which are involved in preventing MHC-I presentation. Perhaps this
apparent redundancy has occurred as a result of an arms race between the human immune system
and HCMV, which has been occurring since the dawn of humans. Humans evolved MHC-I
presentation, so under selective pressure HCMV evolved a protein to inhibit MHC-I formation.
Humans then evolved different alleles, so in turn HCMV evolved a second protein that would
better recognize that allele. As discussed above, HSV only encodes one protein which inhibits
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MHC-I presentation. This protein, ICP47, inhibits all MHC-I alleles by affecting peptide supply
in the ER. This illustrates that perhaps HCMV evolved with us, maybe even before we were
humans, where as HSV may have become a pathogen to us more recently in our and its
evolution.
Acknowledgements
I would like to extend my gratitude to Jennifer Zaba and Patricia McGee for their help and time
with proof reading and editing, without it this paper would have suffered grammatically.
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