Human cytomegalovirus latency, reactivation and immune control
Lead Research Organisation:
University of Cambridge
Department Name: Medicine
Abstract
Human cytomegalovirus (HCMV) is a virus which is carried without symptoms by the majority of the population. However, it can cause serious disease in infants born to mothers who acquire the infection in pregnancy and in people whose immune system is suppressed. Understanding how the virus succeeds in maintaining itself in most people without causing disease and how this relationship breaks down to cause disease should help develop better methods of treating the virus and of designing a vaccine (there is currently no vaccine available). Our research is aimed at determining (i) the mechanism by which the virus maintains silent infection (latency) in specialised cells of the immune system and the factors that reawake it and (ii) how the immune system controls the infection in normal people. In addition to advancing our understanding of HCMV in particular, this research may also lead to a better understanding of other virus infections which persist in the body, and how the human host controls them.
Technical Summary
Abstract
This programme of research focuses on human cytomegalovirus (HCMV), a ubiquitous human herpesvirus which is a major cause of morbidity, especially in the immunocompromised host. Our previous work using models of both natural and experimental latency has shown that dendritic cells, key antigen-presenting cells, are an important site of HCMV latency and reactivation. In this programme of research we propose to use these models to address the following questions which we believe are crucial to understanding HCMV latency, reactivation and immune control.
We will identify viral latency-associated transcripts in natural latency in myeloid lineage cells from healthy HCMV carriers and determine how latency-associated genes are regulated in undifferentiated and differentiated myeloid cells. We will also analyse the function of specific latency-associated transcripts which we have already identified in CD34+ progenitors of healthy HCMV carriers, and determine if these are recognised by the CD8+ T cell response and also determine if T cell specificity for individual HCMV proteins is important for control of reactivation and dissemination.
HCMV-mediated changes in cellular gene expression, during infection of permissive cells, have profound effects on numerous cellular functions but little is known about virus-induced changes in cellular gene expression during latency and reactivation. Consequently, we will compare changes in cellular gene expression associated with latency and reactivation of HCMV and analyse what role these changes may play in virus persistence and determine whether they aid avoidance of immune surveillance.
As there is a high frequency of HCMV-specific revertant memory T cells maintained in virus carriers, which suggests that they are crucial for immune control, we will determine the requirements for activation of these memory T cells and also determine whether they play a particular role in detecting viral reactivation and preventing viral dissemination. Finally, we will determine the phenotype, antigen specificity, activation status, cytokine profile and clonality of T cells recruited to natural sites of reactivation in vivo.
The work proposed will address fundamental questions about the molecular interactions between the virus and the cell which maintain latency and permit reactivation in vivo, and how the immune response then limits virus dissemination. The resultant increased understanding of virus pathogenesis at the level of specific viral gene products and host immune responses, should lead to rational methods of therapeutic intervention, such as novel antiviral strategies and approaches to vaccines.
This programme of research focuses on human cytomegalovirus (HCMV), a ubiquitous human herpesvirus which is a major cause of morbidity, especially in the immunocompromised host. Our previous work using models of both natural and experimental latency has shown that dendritic cells, key antigen-presenting cells, are an important site of HCMV latency and reactivation. In this programme of research we propose to use these models to address the following questions which we believe are crucial to understanding HCMV latency, reactivation and immune control.
We will identify viral latency-associated transcripts in natural latency in myeloid lineage cells from healthy HCMV carriers and determine how latency-associated genes are regulated in undifferentiated and differentiated myeloid cells. We will also analyse the function of specific latency-associated transcripts which we have already identified in CD34+ progenitors of healthy HCMV carriers, and determine if these are recognised by the CD8+ T cell response and also determine if T cell specificity for individual HCMV proteins is important for control of reactivation and dissemination.
HCMV-mediated changes in cellular gene expression, during infection of permissive cells, have profound effects on numerous cellular functions but little is known about virus-induced changes in cellular gene expression during latency and reactivation. Consequently, we will compare changes in cellular gene expression associated with latency and reactivation of HCMV and analyse what role these changes may play in virus persistence and determine whether they aid avoidance of immune surveillance.
As there is a high frequency of HCMV-specific revertant memory T cells maintained in virus carriers, which suggests that they are crucial for immune control, we will determine the requirements for activation of these memory T cells and also determine whether they play a particular role in detecting viral reactivation and preventing viral dissemination. Finally, we will determine the phenotype, antigen specificity, activation status, cytokine profile and clonality of T cells recruited to natural sites of reactivation in vivo.
The work proposed will address fundamental questions about the molecular interactions between the virus and the cell which maintain latency and permit reactivation in vivo, and how the immune response then limits virus dissemination. The resultant increased understanding of virus pathogenesis at the level of specific viral gene products and host immune responses, should lead to rational methods of therapeutic intervention, such as novel antiviral strategies and approaches to vaccines.