This project is a comprehensive look into the CD4 T cell response to human herpesvirus 6 (HHV-6), an emergent / re-emergent human pathogen. In most people infection in childhood resolves uneventfully to a chronic life-long infection held in check by cellular immune responses. However, viral reactivation after immunosuppression can cause serious illness, neurological complications, and even death, and is an important complication following organ transplantation.
One aim of the project is to characterize memory T cell responses to this chronic infection, and compare them to responses to acute infection. CD4 and CDS T cell responses to HHV-6 will be characterized in healthy immune donors and also in kidney transplant recipients experiencing viral reactivation. A possible role for IL-10 in regulating these responses will be investigated. These analysis will involve ex vivo analysis of, peripheral blood and primary cell lines, using functional assays and newly-developed class II MHC oligomers, and will be pursued in collaboration with project 2, which is investigating analogous CD4 T cell functional subsets in mice.
A second aim of the project is to understand the role of NK cells in regulating T cell responses to HHV-6. Preliminary data indicate that NK populations present in peripheral blood regulate CD4 T cells responding to HHV-6. Several mechanistic hypotheses will be explored using ex vivo analysis of human peripheral blood and primary cell lines. This work will be pursued in collaboration with project 1, which is investigating similar NK phenomenon in other systems.
A third aim of the project is to investigate and functionally characterize CD4 T cell responses to HHV-6 that are cross-reactive with other viruses. Several recently identified HHV-6 T cell epitopes are similar to those from other common viral infections. Based on principles established in previous work on CDS cross-reactivity patterns, we predict that the HHV-6 specific CD4 T cell response can recognize heterologous infection by other viruses including EBV, CMV, and lAV. This prediction will be tested using ex vivo analysis of human peripheral blood and primary cell lines, and biochemical and structural analysis of MHC and TCR proteins.
This aim will be pursued in collaboration with project 3.

Public Health Relevance

Human herpesvirus 6 infects most people early in life causing a mild childhood illness that remains present as a life-long chronic infection but which can reactivate after immune suppression to cause serious medical consequences. This project will investigate HHV-6 immune responses in healthy people controlling the virus and in immunosuppressed transplantation recipients in whom the virus has reactivated, to better understand immune control of HHV-6 and to help development of clinically useful diagnostic tools.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109858-01
Application #
8665105
Study Section
Special Emphasis Panel (ZAI1-ZL-I (J1))
Project Start
Project End
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
1
Fiscal Year
2014
Total Cost
$466,992
Indirect Cost
$187,635
Name
University of Massachusetts Medical School Worcester
Department
Type
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Devarajan, Priyadharshini; Bautista, Bianca; Vong, Allen M et al. (2016) New Insights into the Generation of CD4 Memory May Shape Future Vaccine Strategies for Influenza. Front Immunol 7:136

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