Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection

Manley, Thomas; Luy, Lisa; Jones, Thomas R.; Boeckh, Michael; Mutimer, Helen; Riddell, Stanley R.

doi:10.1182/blood-2003-06-1937

Cited by 100 publications

(112 citation statements)

References 54 publications

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“…The same may be true for other structural proteins that are prominent targets of CD8 + T-cell memory responses (Boppana & Britt, 1996;Elkington et al, 2003;Sylwester et al, 2005). Another Achilles heel of HCMV is the requirement for high-level expression of IE proteins that are also highly immunogenic (Borysiewicz et al, 1988;Kern et al, 1999;Manley et al, 2004;Sylwester et al, 2005). Peptides from IE1, for example, are already presented to CD8 + T-cells at 6 h p.i.…”

Section: Discussionmentioning

confidence: 99%

“…This is a critical phase in the lytic cycle of the virus, as both exogenously introduced structural proteins and regulatory IE proteins are present in abundance at this time postinfection (p.i.). Both classes of proteins, in particular pp65 and IE1, serve as dominant sources of antigenic peptides presented by MHC I (Borysiewicz et al, 1988;Jackson et al, 2011;Kern et al, 1999;Manley et al, 2004;Wills et al, 1996). It has been shown that MHC class I molecules are retained in the ER under infection conditions that allow expression of only IE proteins of HCMV (Ahn et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

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Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection

Hesse

Ameres

Besold

et al. 2013

Journal of General Virology

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Human cytomegalovirus (HCMV) interferes with MHC class I-restricted antigen presentation and thereby reduces recognition by CD8 + T-cells. This interference is mediated primarily by endoplasmic reticulum-resident glycoproteins that are encoded in the US2-11 region of the viral genome. Such a suppression of recognition would be of particular importance immediately after infection, because several immunodominant viral antigens are already present in the cell in this phase. However, which of the evasion proteins gpUS2-11 interfere(s) with antigen presentation to CD8 + T-cells at this time of infection is not known. Here we address this question, using recombinant viruses (RV) that express only one of the immunoevasins gpUS2, gpUS3 or gpUS11. Infection with RV-US3 had only a limited impact on the presentation of peptides from the CD8 + T-cell antigens IE1 and pp65 under immediate-early (IE) conditions imposed by cycloheximide/ actinomycin D blocking. Unexpectedly, both RV-US2 and RV-US11 considerably impaired the recognition of IE1 and pp65 by CD8 + T-cells, and both US2 and, to a lesser extent, US11 were transcribed under IE conditions. Thus, gpUS2 and gpUS11 are key effectors of MHC class I immunoevasion immediately after HCMV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection

Hesse

Ameres

Besold

et al. 2013

Journal of General Virology

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“…To examine the frequency and speciWcity of CD8+ CTL, a recent study using Wbroblasts as antigens presenting cells infected with a mutant strain deleted of the US immunoevasins, showed that most eVector T cells were directed against IE and E antigens [17]. These data suggest that after primary infection in vivo, naïve T cells could be activated by DCs which acquired IE and E proteins available before the time point at which US immunoevasins are expressed in amounts suYcient to exert their blocking activities.…”

Section: T Cell Repertoire Against Hcmv Exhibits a Broad Pattern Of Smentioning

confidence: 97%

Interplay between human cytomegalovirus and dendritic cells in T cell activation

Martin

Mandron

Davrinche

2008

Med Microbiol Immunol

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Control of human cytomegalovirus (HCMV) infection and prevention of associated diseases in immunocompetent hosts are ensured mainly by CD8+ T cells, in spite of numerous viral tricks to impair antigen presentation and activation of T cells. At sites of primary infection, dendritic cells (DCs) are in the forefront to ensure capture of viral antigens and their capacity to bypass the eVects of viral immunoevasins is crucial in moulding CD8+ T cell repertoire. In HCMV-seropositive donors, the spectrum of CD8+ T cells speciWcities was shown to include immediate-early (IE), early (E) and late (L) gene products, a surprising Wnding if we consider that expression of immunoevasins could paralyse infected DCs from the IE phase of infection. In the present report, we suggest that uninfected dendritic cells could acquire HCMV-antigens derived from input virus or neosynthesis, either in soluble forms or in association with infected dead cells resulting from death-ligand-mediated apoptosis and necrosis. Activation of naïve CD8+ T cells could then occur in lymph nodes through cross-presentation by antigen-loaded DCs, providing an explanation for shape and size of the memory compartment.

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“…the abundance of the major T-cell antigen pp65 (Varnum et al, 2004), renders these particles attractive for the development of a vaccine. However, recent studies showed that non-structural antigens, such as IE proteins, may also contribute significantly to the priming of a natural T-cell response against HCMV in humans ( Elkington et al, 2003;Khan et al, 2005;Manley et al, 2004;Sylwester et al, 2005). It was thus mandatory to show that DB can be modified to include additional antigens not normally present in these particles and that these antigens can be introduced successfully into the MHC class I presentation pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies provided evidence that peptides derived from exogenously delivered, particle-associated HCMV proteins are presented by MHC class I molecules without requiring de novo protein synthesis (Besold et al, 2007;Manley et al, 2004;McLaughlin-Taylor et al, 1994;Pepperl et al, 2000;Reddehase et al, 1984;Riddell et al, 1991). It was previously unknown whether peptides not usually included in viral particles would also be introduced into MHC class I presentation.…”

Section: Mhc Class I Presentation Of the Ie1 Tmy Peptide Derived Frommentioning

confidence: 99%

Exogenous introduction of an immunodominant peptide from the non-structural IE1 protein of human cytomegalovirus into the MHC class I presentation pathway by recombinant dense bodies

Mersseman

Besold

Reddehase

et al. 2008

Journal of General Virology

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Exogenous introduction of particle-associated proteins of human cytomegalovirus (HCMV) into the major histocompatibility complex (MHC) class I presentation pathway by subviral dense bodies (DB) is an effective way to sensitize cells against CD8 T-cell (CTL) recognition and killing. Consequently, these particles have been proposed as a platform for vaccine development. We have developed a strategy to refine the antigenic composition of DB. For proof of principle, an HCMV recombinant (RV-VM3) was generated that encoded the immunodominant CTL determinant IE1 TMY from the IE1 protein in fusion with the major constituent of DB, the tegument protein pp65. To generate RV-VM3, a bacterial artificial chromosome containing the HCMV genome was modified by applying positive/negative selection based on the expression of the bacterial galactokinase in conjunction with l Red-mediated homologous recombination. This method allowed the efficient and seamless insertion of the DNA sequence encoding IE1 TMY in frame into the pp65 open reading frame (UL83) of the viral genome. RV-VM3 expressed its fusion protein to high levels. The fusion protein was packaged into DB and into virions. Its delivery into fibroblasts by these viral particles led to the loading of the MHC class I presentation pathway with IE1 TMY and to efficient killing by specific CTLs. This demonstrated that a heterologous peptide, not naturally present in HCMV particles, can be processed from a recombinant, DB-derived protein to be subsequently presented by MHC class I. The results presented here provide a rationale for the optimization of a vaccine based on recombinant DB. INTRODUCTIONInfection with human cytomegalovirus (HCMV; family Herpesviridae, subfamily Betaherpesvirinae) may cause significant morbidity and mortality in individuals with immature or compromised immune-defence functions, but proceeds asymptomatically in most healthy adults (Pass, 2001). Prevention of HCMV infection or disease by a vaccine has been ranked as a high-priority goal (Stratton et al., 2001). Although several vaccine approaches have been developed, none have yet entered routine clinical practice (Pepperl-Klindworth & Plachter, 2006;Plotkin, 2004;Schleiss & Heineman, 2005;Zhong & Khanna, 2007). We have demonstrated that HCMV dense bodies (DB) provide a promising basis for vaccine development (Pepperl et al., 2000;Pepperl-Klindworth et al., 2002). DB are enveloped, subviral particles devoid of capsids and viral DNA. They are released from infected fibroblast cultures and enter cells presumably via the normal HCMV entry processes. The major constituent of DB is pp65 (ppUL83) (Varnum et al., 2004), which is a prominent target of the CD4 and CD8 T-cell (CTL) responses following natural infection (Beninga et al., 1995;McLaughlin-Taylor et al., 1994;Wills et al., 1996). Although pp65 by itself appears to be an attractive antigen for the design of a vaccine, other HCMV proteins may also be important and should thus be considered (Reddehase, 2002). One of these, as far as the CTL response is co...

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Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection

Cited by 100 publications

References 54 publications

Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection

Suppression of CD8+ T-cell recognition in the immediate-early phase of human cytomegalovirus infection

Interplay between human cytomegalovirus and dendritic cells in T cell activation

Exogenous introduction of an immunodominant peptide from the non-structural IE1 protein of human cytomegalovirus into the MHC class I presentation pathway by recombinant dense bodies

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