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Molecular mechanisms of persistent antigenic stimulation in cytomegalovirus infection

Objective

Cytomegalovirus (CMV) is a ubiquitous herpesvirus, latently persisting in the majority of the adult population worldwide. In these hosts, CMV-specific memory cells dominate the immune memory compartment. It follows that CMV-specific T-cells dominate the memory compartment of the majority of the human population worldwide.
I propose to define within this project the molecular mechanisms driving the inflation of CMV-specific T-cells. My central hypothesis is that expression levels of CMV peptides during latency, along with the avidity of T-cell receptors for peptide MHC complexes, define the amplitude of T-cell responses. A corollary hypothesis is that vigorous T-cell responses in CMV infection are defined by factors that drive CMV gene expression during latency, such as inflammatory stimuli.
This hypothesis will be verified in a model of in vivo CMV latency and immune monitoring. We will benefit from state-of-the-art inducible genetic systems, where recombinant mouse CMV will be deployed in transgenic mice. In latently infected mice, we will induce or suppress the expression of immunodominant CMV genes, and define downstream effects on T-cell response kinetics. In parallel, we will define the T-cell responses to high and low avidity peptides.
Understanding the mechanisms driving the strong T-cell response to CMV is of outstanding biological and clinical relevance. If strong T-cell responses may be redirected to target heterologous antigens of interest, CMV-based vaccine vectors might potentially allow the development of HIV or tumor vaccines. On the other hand, it is speculated that the control of latent CMV may overcommit the aging immune system and exhaust the T-cell repertoire. Given the CMV pervasiveness, discerning the mechanisms of its T-cell induction may define novel molecular targets for rejuvenation strategies. In either case, the proposed research has groundbreaking potential in the field of infection and immunity.

Field of science

  • /medical and health sciences/basic medicine/pharmacology and pharmacy/pharmaceutical drug/vaccines
  • /medical and health sciences/basic medicine/immunology

Call for proposal

ERC-2010-StG_20091118
See other projects for this call

Funding Scheme

ERC-SG - ERC Starting Grant

Host institution

HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH
Address
Inhoffenstrasse 7
38124 Braunschweig
Germany
Activity type
Research Organisations
EU contribution
€ 1 498 456
Principal investigator
Luka Cicin-Sain (Dr.)
Administrative Contact
Michael Straetz (Dr.)

Beneficiaries (1)

HELMHOLTZ-ZENTRUM FUR INFEKTIONSFORSCHUNG GMBH
Germany
EU contribution
€ 1 498 456
Address
Inhoffenstrasse 7
38124 Braunschweig
Activity type
Research Organisations
Principal investigator
Luka Cicin-Sain (Dr.)
Administrative Contact
Michael Straetz (Dr.)