University of Washington investigators utilized rare cell enrichment and an HLA-agnostic, proteome-wide approach to expand the library of known HHV-6 T cell antigens from 11 to 60. Several of the newly identified epitopes are among the most prevalent.
A major obstacle in the fight against HHV-6 is the limited effectiveness of current antiviral treatments. While progress has been made in studying cytotoxic CD8 T cells from adoptive T cell therapy, very little was previously known about HHV-6 CD4 T cell targets. Since immunotherapy utilizing both CD4 and CD8 T cells has been effective, a team led by David Koelle, MD, used a genome-wide approach to learn more about HHV-6 specific adaptive immune response, paving the way for possible future virus-specific or transgenic TCR T cell products.
The study of HHV-6 T cell antigens is challenging due to the complex viral proteome and the low frequency of HHV-6-specific T cells in blood, approximately 100 times lower than the frequency of CMV-specific T cells. Studies so far have focused on identifying HHV-6 homologs of known CMV antigenic proteins (HHV-6 U11, U14, U54 and U90) or by testing libraries of peptides predicted to bind to specific HLA alleles.
HHV-6-reactive CD4 T cells were extracted from 18 donors and expanded in vitro. These cells were then exposed to known and suspected HHV-6B proteins. Of the 101 proteins tested, 60 were recognized by at least one donor and the median number of proteins recognized per donor was 9. Of the 60 proteins identified as HHV-6-specific T cell antigens in this study only 11 had been described in previous literature as CD4 T cell targets.
Newly identified antigens recognized by at least 1/3 of healthy donors include: U73, U72, U95, U30, U62 and U63. Some of the new antigens discovered, such as U73 and U72, were broadly reactive across the donor pool and appear to be attractive candidates for future study.
Read the full paper: Hanson 2019