Part of the normal functioning of cells involves the
breakdown of disused protein products, which become the equivalent of cellular
garbage. A diverse group of molecules called class I MHC receptors have the job
of transporting fragments of these trashed proteins (epitopes) to the cell
surface where they are displayed to passing CD8 T cells. As long as the
epitopes being displayed belong to “self” proteins, the cell is usually allowed
to go about its business. But if a CD8 T cell recognizes an epitope from an
infectious agent, this acts as an immunological alarm bell, triggering a
cascade of events resulting in the CD8 T cell destroying the infected
cell. Not too surprisingly, some
viruses have evolved mechanisms that try and circumvent this process by
downregulating class I MHC receptors from the surface of infected cells.
Cytomegalovirus (CMV) possesses several genes that can inhibit class I MHC
expression, and the nef genes from both HIV and SIV also have this capacity.
Two recent papers shed additional light on the importance of
this immune evasion mechanism. In this week’s issue of Science, Louis Picker’s
research group show that class I MHC downregulation explains the susceptibility
of CMV-infected macaques to re-infection. The finding was made while evaluating
CMV as a potential vaccine vector; the researchers had noted that their CMV
vector could induce immune responses to an insert (encoding SIV proteins) in
both CMV-infected and uninfected macaques. To try and understand why
CMV-infected macaques were not immune to the CMV vector, a new version was
created that lacked the genes that modulate class I MHC expression. This
modified vector was unable to infect CMV-infected macaques and therefore could
not induce immune responses to the SIV inserts. The researchers conclude that
class I MHC downregulation by CMV is essential for circumventing immunity and
allowing re-infection, and may explain the difficulty of developing a vaccine
against the virus.
A separate paper in J. Virology reports that extensive downregulation
of class I MHC by SIV appears to play a role in rapid progression to simian
AIDS. The researchers developed a novel assay to measure class I MHC expression
on SIV-infected cells, using uninfected cells from the same samples as
controls. Comparing rapid progressors to normal progressors, class I MHC
downregulation was found to be significantly greater in the former group. The
researchers note that their reagent for detecting class I MHC expression
recognizes some “non-classical” proteins (known as E and I) in addition to the
“classical” A and B proteins that are involved in CD8 T cell recognition of
SIV-infected cells, and thus more specific reagents are needed to explore the
issue further. But they go on to say: “Nonetheless our observations have
afforded the first measurement of MHC-I expression levels on
AIDS-virus-infected cells directly ex vivo. They revealed that high levels of
MHC-I downregulation on SIV-infected cells are associated with uncontrolled
virus replication and a lack of strong SIV-specific immune responses. Our results therefore raise the
possibility that expression of MHC-I molecules that are particularly sensitive
to MHC-I downregulation may play a role in rapidly progressive AIDS virus
infection.”
An excellent resource for more information on the ins and
outs of antigen processing is Ian A. York’s virology & immunology blog, Mystery Rays from Outer Space. It includes a beginners guide to class I MHC and an antigen processing category containing many posts on the topic.
Science 2 April 2010: Vol. 328. no. 5974, pp. 102 – 106
DOI: 10.1126/science.1185350
REPORTS
Evasion of CD8+ T Cells Is Critical for Superinfection by
Cytomegalovirus
Scott G. Hansen,1, Colin J. Powers,1,*, Rebecca Richards,1
Abigail B. Ventura,1 Julia C. Ford,1 Don Siess,2 Michael K. Axthelm,1,2 Jay A.
Nelson,1,2 Michael A. Jarvis,1 Louis J. Picker,1,2,Klaus Früh1,2
1. Vaccine and Gene Therapy Institute, Oregon Health and
Science University, 505 Northwest 185th Avenue, Beaverton, OR 97006, USA. 2.
Oregon National Primate Research Center, Oregon Health and Science University,
505 Northwest 185th Avenue, Beaverton, OR 97006, USA.
Cytomegalovirus (CMV) can superinfect persistently infected
hosts despite CMV-specific humoral and cellular immunity; however, how it does
so remains undefined. We have demonstrated that superinfection of rhesus
CMV–infected rhesus macaques (RM) requires evasion of CD8+ T cell immunity by
virally encoded inhibitors of major histocompatibility complex class I (MHC-I)
antigen presentation, particularly the homologs of human CMV US2, 3, 6, and 11.
In contrast, MHC-I interference was dispensable for primary infection of RM, or
for the establishment of a persistent secondary infection in CMV-infected RM
transiently depleted of CD8+ lymphocytes. These findings demonstrate that
US2-11 glycoproteins promote evasion of CD8+ T cells in vivo, thus supporting
viral replication and dissemination during superinfection, a process that
complicates the development of preventive CMV vaccines but that can be
exploited for CMV-based vector development.
JVI Accepts, published online ahead of print on 10 March
2010
J. Virol. doi:10.1128/JVI.02452-09
Thomas C. Friedrich, Shari M. Piaskowski, Enrique J. Léon,
Jessica R. Furlott, Nicholas J. Maness, Kimberly L. Weisgrau, Caitlin E. Mac
Nair, Andrea M. Weiler, John T. Loffredo, Matthew R. Reynolds, K Y. Williams,
Yann C. Klimentidis, Nancy A. Wilson, David B. Allison, and Eva G. Rakasz*
Department of Pathobiological Sciences, School of Veterinary
Medicine, University of Wisconsin -Madison, WI 53706, USA; AIDS Vaccine
Research Laboratory, University of Wisconsin-Madison, Madison, WI 53711, USA;
Immunology and Virology Core Laboratory, Wisconsin National Primate Research
Center, University of Wisconsin -Madison, WI 53715, USA; Section on Statistical
Genetics, Department of Biostatistics, University of Alabama at Birmingham,
Birmingham, AL 35294, USA
Human and simian immunodeficiency viruses downregulate major
histocompatibility complex I (MHC-I) molecules from the surface of infected
cells. Although this activity is conserved across viral isolates, its
importance in AIDS pathogenesis is not clear. We therefore developed an assay
to detect the level of MHC-I expression of SIV-infected cells directly ex vivo.
Here we show that the extent of MHC-I downregulation is greatest in
SIVmac239-infected macaques that never effectively control virus replication.
Our results suggest that a high level of MHC-I downregulation is a hallmark of
fast disease progression in SIV infection.
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