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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