Retro-Target IS

Identification of the cellular and molecular targets mediating the immunosuppressive properties of retroviral envelope proteins, and of candidate inhibitory compounds

Coordinators: T. Heidmann (Partner 5) and G. Schlecht-Louf (Partner 3)
Starting date: January 2015

Induction of an immunosuppressive environment to allow persistence in the host is a common hallmark of persistent viral infections and cancer. The identification of the mechanisms contributing to immune subversion is a prerequisite for the design of targeted therapeutics that would counteract this immunosuppression. Partner 5 has identified a molecular effector that drives immune subversion and favors both viral persistence and tumor progression through immune response inhibition. This effector is a conserved domain of the envelope (Env) glycoproteins of oncoretroviruses endowed with immunosuppressive properties (IS domain), as assessed in vivo using an inhibition assay of the immune responses in mice. IS domains have been mapped within the Env proteins of endogenous (HERV) and infectious retroviruses, including human, murine and feline oncoretroviruses (HTLV, MLV, FeLV), simian (MPMV) retrovirus, as well as lentiviruses (HIV-1, SIV). Mutations have been defined that specifically abolish the IS functions (IS-negative) without altering the canonical Env fusogenic and infectious properties. Introduction of these mutations within a model oncoretrovirus (Friend mouse leukemia virus, F-MLV) enabled us to demonstrate that the IS domain is absolutely required for retroviral viremia in vivo, and acts on both innate and adaptive immune responses. IS-negative retroviral particles, and recombinant or vectored Env antigens exhibit enhanced immunogenicity, with specific humoral (IgG) and cellular (T CD4 and CD8) responses increased up to an order of magnitude in mice (F-MLV) and cats (FeLV) (Schlecht-Louf et al. 2010, 2014 - Partner 3). Therefore, the IS domain is essential for viral propagation and, if unmutated, critically inhibits the immunogenicity of vaccine preparations. These observations have led to the design of an optimized veterinarian vaccine against the feline leukemia virus (FeLV), licensed and launched on the market by Mérial. Regarding the role of the IS domain in tumorigenesis, we have also shown that the IS domain of endogenous retroviruses expressed de novo by some tumor cells, such as B16 melanoma and Neuro-2a neuroblastoma, is required for tumor growth in mice (Mangeney et al. 2005, Pothlichet et al. 2006). Hence, IS-dependent mechanisms could be also relevant to the pathogenesis of human tumors in which HERV may be involved, such as HERV-K in melanoma.
Therefore, the IS domain is a promising therapeutic target against both persistent retroviral infections and certain cancers. The purpose of the present program is to identify the molecular and cellular pathways involved in the host response to the IS domain of retroviral and lentiviral Env glycoproteins, using human and murine cells ex vivo and experimentally infected mice in vivo, to establish a relevant cellular screening system to search for inhibitors, and to identify anti-IS inhibitory compounds from chemical libraries. An ultimate goal is to evaluate in vivo the inhibitory potency of selected anti-IS compounds using the F-MLV model, which has been instrumental to demonstrate the crucial role of the IS function in retroviral viremia. The complementary expertises of the two biologist partners together with their demonstrated ability to work together and their collaboration with the LERMIT Technical platform network should allow for optimal achievement of the project.