Contributed by guest blogger: Stephanie Mischell ’12
Herpes simplex virus type 1 (HSV-1) is making news due to a paper by Jing et al identifying two promising new candidate antigens for a vaccine. HSV-1 is a widespread public health issue, infecting approximately 60% of Americans and causing symptoms, most likely cold sores or genital sores but on rare occasion blindness or fatal brain damage. Furthermore, finding a vaccine for HSV-1 has proved difficult, in part because of the vital but elusive role of CD8+ T-cells in the HSV-1 immune response. Mice studies suggest that a CD8-response could facilitate memory cell formation and ameliorate chronic disease caused by HSV-1, but human blood does not have many HSV-1 specific CD8+ T-cells and very few CD8 epitopes have been identified. Previous attempts at vaccines most recently using the HSV glycoprotein D (gD2), have focused on CD4+ T-cell specific epitopes. These attempts were unable to stimulate a CD8+ T-cell response, and the vaccine failed during clinical trials. A way to stimulate both CD4+ and CD8+ T-cell responses seems necessary to create an effective vaccine.
Jing et al’s work is significant because it harnesses properties originally used to study HSV-2 to identify HSV-1 epitopes recognized by CD8+ T-cells. An epitope, or antigenic determinant, is the part of an antigen that is recognized by the immune system; this interaction is what triggers a host immune response. Jing et al demonstrated previously that in vitro monocyte-derived dendritic cells (moDC’s), or antigen-presenting cells, can cross-present HSV-2 epitopes to create HSV-2 specific memory T-cells. In this paper, they harnessed this cross-reactivity of moDC’s and applied it to HSV-1, stimulating and identifying HSV-1 specific CD8+ T-cells. 45 distinct CD8+ T-cell epitopes were identified. Furthermore, the genomes of host responder cells were cloned, and HSV-1 epitopes were analyzed for HLA restriction. Proteins from two genes, UL39 and UL46, were identified as most highly restricted, suggesting that they are most involved in the immunogenic response. PMBC assays confirmed these results quantitatively.
Jing et al conclude that the viral proteins coded by UL39 and UL46 are good candidate antigens for an HSV-1 vaccine because of their CD4+ and CD8+ T-cell immunogenicity. However, they also acknowledge that their sample size is small and that subunit vaccines have not been successful vaccines for HSV-1. In fact, the large number of CD8+ T-cell epitopes identified led the authors to conclude that a whole-virus vaccine may be more successful than subunits. Most of the failed vaccines showed similar promise until phase II or phase III of clinical trials, suggesting that the small amount of data from this study is just a start. This discovery is important but not a guaranteed vaccine.
While the identification of UL39 and UL46 are important steps in solving the public health issue posed by HSV-1, as is the identification of other CD8+ T-cell epitopes, perhaps the most significant part of the study is the implications of their novel research methods on the study of viral vaccines. The enrichment techniques used could potentially make studying T-cell responses easier. The authors confirmed the applicability of their methods by using the same techniques to study the vaccinia virus, a microbe with a large genome of over 200 genes. This paper demonstrates a small advancement in HSV-1 research and control, but may have larger implications for this and other large viruses.
Link to original article: http://www.jci.org/articles/view/60556
Stephanie Mischell is a senior at Vassar College, majoring in biology.