Given the oncogenic capabilities of HHV-8, it has been suggested that an understanding of the viral genes with the potential to induce transformation of cells may contribute towards the elucidation of KS pathogenesis. In addition, such genes may also serve as ideal targets for both therapeutic and vaccine interventions. For this purpose, we have considered HHV-8 genes which are expressed during latency, as tumor 'spindle"""""""" cells of KS and B-cells are latently infected with HHV-8. Of the genes encoded by HHV-8 with transformation potential [K1, glycoprotein; k9, interferon regulatory factor; K12, kaposin; orf73, latency-associated antigen (LANA-1); and orf74, a vlL-8 receptor homolog ], kaposin and LANA-1 are transcribed in latently infected cells along with v-cyclin and v-FLIP. Both v-cyclin and v-FLIP are viral homologs of cellular genes and thus may not be suitable as targets for vaccine strategies due to autoimmunity. This has prompted us to initiate work on Kaposin and LANA-1 as the likely viral target proteins for vaccine approaches to induce immunity against HHV-8. The recent demonstration of CTL epitopes in Kaposin further lends supports to this concept. Vaccines have been successfully used against viral infections (smallpox, polio, varicella) in the past and the correlates of protective immunity may include both the humoral and cellular responses. Based on this, we hypothesize that the expression of Kaposin and LANA-1, in the absence of other HHV-8 proteins, may lead to an induction of potent and durable humoral and cellular immune responses which may be of value in eliminating cells infected with HHV-8 and interfering with the development of KS. Towards this, we propose the following aims: i) to generate DNA vaccine vectors encoding native and modified forms of Kaposin and LANA-1. ii) Characterize the cellular and humoral immune responses against Kaposin and LANA-1 using mice as the animal model, iii) Strategies to enhance the immune responses against Kaposin, and iv) to assess the level of protection induced by latent genes using tumor cells expressing viral proteins as the challenge model. The results from these studies are likely to provide baseline information for further exploration in the development of vaccines against HHV-8.
| Tomkowicz, Brian; Singh, Satya P; Lai, Derhsing et al. (2005) Mutational analysis reveals an essential role for the LXXLL motif in the transformation function of the human herpesvirus-8 oncoprotein, kaposin. DNA Cell Biol 24:10-20 |
