Kaposi Sarcoma Herpesvirus Immunity
Lead Research Organisation:
University College London
Department Name: The Wolfson Inst for Biomedical Research
Abstract
Kaposi sarcoma is a cancer that affects individuals with a damaged immune system (defence to microbes), such as people living with HIV or patients after an organ transplantation. Indeed, Kaposi sarcoma is the most common cancer among people with AIDS, and in certain parts of the world, the most common cancer after an organ transplant. In some parts of Africa, because of the extent of the HIV pandemic, Kaposi sarcoma is the most common cancer in men and second most common in women. This cancer is the result of infection with a virus called Kaposi sarcoma herpesvirus. Our work will discover how the human body normally fights infection with Kaposi sarcoma herpesvirus. We will use this information to develop new therapies that specifically boost immune responses to treat individuals with Kaposi sarcoma. We want to discover which are the components of the virus that trigger a type of defence process, which is specifically dedicated to this virus (termed an adaptive immune response). We will also study other defence mechanisms, which are less specific but equally important, as these constitute the first line of defence against microbes (termed innate immune responses). Following this approach, we hope to discover key players in the protection against Kaposi sarcoma. One such player that we have discovered and we want to further investigate, is a gene called TLR4. The importance of this finding comes from the fact that drugs that boost the activity of this gene are already being used for other diseases. After we identify all these triggers we will develop ways to make them harmless and package them so we can introduce them to people with Kaposi sarcoma and cause beneficial defence reactions without the harm caused by the live virus.
Technical Summary
Kaposi sarcoma herpesvirus (KSHV) is aetiologically linked to the development of Kaposi sarcoma (KS), which is the most common malignancy among HIV-infected individuals, and is common among immunosuppressed organ recipients.
KS treatment regimes take little advantage of our current understanding of KS biology. Furthermore, several areas of KSHV immunobiology are still poorly understood. During the next four years we aim to discover novel mechanisms involved in innate and adaptive immune responses against Kaposi sarcoma herpesvirus (KSHV), and to translate these findings to the clinical setting.
In the proposed research, we will investigate how KSHV escapes host innate immune responses. These studies will be based on our recent findings revealing a central role for Toll-like receptor 4 (TLR4) in innate responses to KSHV, and will focus on the role and regulation of the TLR4 pathway during primary KSHV infection in vitro and in KSHV-related cancer pathogenesis in vivo. As we have already identified lytic KSHV genes that block TLR4 function, we aim to discover how latent KSHV transcripts interfere with TLR signalling. Furthermore, we will investigate how viral and cellular microRNAs (miRNAs) regulate TLR-mediated innate responses. Based on our data revealing the miRNA profiling of KSHV-infected primary human lymphatic endothelial cells, and the use of functional screens, we will investigate the role of cellular and KSHV-encoded miRNAs in innate responses to KSHV.
We will also employ our lentiviral library encoding KSHV ORFs to identify CD4+ T-cell KSHV specific antigens. Following identification of such antigens, we will investigate in vitro and in vivo, a novel, non-viral, delivery method to transduce dendritic cells with these antigens for immunotherapeutic approaches. This method is based on the use of small molecule carriers (SMoCs), a technology exclusively available to our laboratories and with great potential in vaccination approaches. Moreover, after antigen identification we will design and test antigenic KSHV peptides in the form of MHC-II Ultimers in order to phenotypically and functionally characterise the KSHV-specific T-cell response.
We expect that by the end of this 4-year period, these novel and exciting studies will take us closer to effective immunotherapeutic approaches to tackle KS, and may have important implications for other vaccine strategies.
KS treatment regimes take little advantage of our current understanding of KS biology. Furthermore, several areas of KSHV immunobiology are still poorly understood. During the next four years we aim to discover novel mechanisms involved in innate and adaptive immune responses against Kaposi sarcoma herpesvirus (KSHV), and to translate these findings to the clinical setting.
In the proposed research, we will investigate how KSHV escapes host innate immune responses. These studies will be based on our recent findings revealing a central role for Toll-like receptor 4 (TLR4) in innate responses to KSHV, and will focus on the role and regulation of the TLR4 pathway during primary KSHV infection in vitro and in KSHV-related cancer pathogenesis in vivo. As we have already identified lytic KSHV genes that block TLR4 function, we aim to discover how latent KSHV transcripts interfere with TLR signalling. Furthermore, we will investigate how viral and cellular microRNAs (miRNAs) regulate TLR-mediated innate responses. Based on our data revealing the miRNA profiling of KSHV-infected primary human lymphatic endothelial cells, and the use of functional screens, we will investigate the role of cellular and KSHV-encoded miRNAs in innate responses to KSHV.
We will also employ our lentiviral library encoding KSHV ORFs to identify CD4+ T-cell KSHV specific antigens. Following identification of such antigens, we will investigate in vitro and in vivo, a novel, non-viral, delivery method to transduce dendritic cells with these antigens for immunotherapeutic approaches. This method is based on the use of small molecule carriers (SMoCs), a technology exclusively available to our laboratories and with great potential in vaccination approaches. Moreover, after antigen identification we will design and test antigenic KSHV peptides in the form of MHC-II Ultimers in order to phenotypically and functionally characterise the KSHV-specific T-cell response.
We expect that by the end of this 4-year period, these novel and exciting studies will take us closer to effective immunotherapeutic approaches to tackle KS, and may have important implications for other vaccine strategies.
