Immunology of hepatitis C virus infection.

There is no effective vaccine against Hepatitis C Virus (HCV), a pathogen which is thought to infect 170 million people and is a major cause of liver cirrhosis and hepatocellular carcinoma worldwide. HCV infection is characterized by its high tendency to evolve to chronicity, a feature which is associated with a low or absent T-cell response against viral antigens. By contrast, those individuals who clear viral infection display potent and wide anti viral CD4 and CD8 T-cell responses. Thus, HCV has developed efficient means to escape T-cell immunity, thus causing a high rate of chronic infections. The development of strategies aimed to induce vigorous anti-HCV T-cell responses is considered an important feature of a candidate HCV vaccine. In this scenario, our research focuses in two main objectives:

1.  The study of the mechanisms used by HCV to induce immunosuppression.
2.  The development of vaccines against HCV infection and against other viral infections or against cancer.

1. Immunosuppression caused by HCV infection

We have found, in collaboration with the laboratory of clinical immunology (CIMA), that HCV infection facilitates the induction of Indoleamine 2,3-dioxygenase (IDO) enzyme and the immunosuppressive molecule CTLA4, which might dampen T-cell reactivity to viral antigens in chronic HCV infection. We are analyzing the effects of several molecules that are differentially expressed in HCV infected cells that can contribute to the induction of an immunosuppressive environment and the chronicity of HCV infection. This work will point to novel targets for therapeutic intervention.

2. Development of vaccines against HCV infection and against cancer

One of the main characteristics of the immune system is the presence of highly sophisticated pathways to control the activation of a cellular immune response. Thus, there are a series of immunostimulatory cells and molecules which in turn can be controlled by specific cells and immunosuppressive molecules. Dendritic cells (DC) are the professional antigen presenting cells with a unique ability to stimulate naïve T cells, whereas T regulatory cells (Treg) exert an immunosuppressive activity which, although necessary to protect the host against autoimmune diseases, may hamper the activation of antiviral or antitumoral immune responses. Our research in the field of vaccine development focuses in two strategies:

 2.1. Development of new molecules to target antigens to dendritic cells. We have found that the recombinant protein encompassing the extra domain A from fibronectin (EDA), an endogenous ligand for TLR4, is able to deliver antigens to TLR4-expressing DC and to stimulate their maturation and the production of proinflammatory cytokines. A fusion protein between EDA and an antigen improves the immunogenicity of the antigen in vivo. These data strongly suggest that EDA may serve as a suitable antigen carrier for the development of antiviral or antitumoral vaccines (Patent ES200501412). In this field, we are also testing the capacity of various factors with proinflammatory activities produced by Staphylococcus epidermidis that might favour the induction of adaptive immune responses in vaccine formulations (Patent ES200803441).

 2.2. Development of peptide inhibitors of immunosuppresive molecules. Viral infections and tumours can activate the production of immunosuppresive molecules able to inhibit the activation of efficient immune responses. Our group, in collaboration with the laboratory of experimental immunology (CIMA) is working actively on the development of peptide inhibitors of various immunosuppressive molecules which might be useful for the development of more efficient vaccines and treatments.

T regulatory (CD4+CD25+ FOXP3+) cells (Treg) play an important role on the regulation of immune responses. Thus, down regulation of Treg function might be beneficial to enhance the immunogenicity of viral and tumor vaccines. It has been postulated that TGF- can mediate the immunossupressive activity of Treg. We have demonstrated that peptide inhibitors of TGF- developed in our laboratory are able to inhibit the activity of Treg in vitro and in vivo. These data suggest that these peptides might be very useful for the design of new anti-viral or anti-tumoral vaccination strategies and therapies (Patent ES200302020/9).

The transcription factor FOXP3 is crucial in the development and function of Treg. The analysis of genomic expression profiles on Treg reveals that FOXP3 induce expression of immunosuppresive molecules such us CTLA4, GITR or IL-10, whereas inhibits the expression of the immunostimulatory cytokine IL-2. Our laboratory is also focussed on the development of peptide inhibitors of FOXP3. We have identified a peptide able to bind FOXP3 and to inhibit the immunosuppressive activity of Treg (Patent ES 200703052). We are now analyzing the capacity of this peptide in vivo in different models of immunotherapy.