Optimized antigens for a new lentivirus vaccine strategy – LENTIxIS

The Research Unit UMR8122 led by the Project Coordinator has identified within the envelope protein of oncoretroviruses a domain endowed with immunosuppressive properties (IS domain) assessed in vivo using a test of inhibition of the immune response in mice: expression of this functional domain by tumor cells normally rejected by the mouse immune system leads indeed to neoplastic growth of the grafted cells. The IS domain has been mapped and mutations that inactivate its immunosuppressive functions while preserving the “mechanical” properties of the envelope protein have been discovered. Introduction of these mutations within a model leukemia retrovirus (Friend mouse leukemia virus) enabled us to demonstrate that the IS domain is absolutely required for induction of a persistent viremia in vivo: whereas immunodeficient (irradiated or athymic) mice are infected to the same level by both the mutant and wild-type virus, only the wild-type virus can induce viremia in immunocompetent mice. Moreover, we have shown that envelope proteins whose IS domain has been inactivated by mutation are powerful immunogens, with immunogenicity levels 10 to 100-fold higher than those of the wild-type protein. In conclusion, thanks to the genetic disjunction achieved between the “mechanical” and the IS functions of the retroviral envelope, it appears clearly that: i) the latter is essential for viral invasiveness and the physiopathology of the virus, ii) if unmutated, the IS domain critically inhibits the immunogenicity of vaccine preparations (Patent; Schlecht-Louf et al. PNAS 2010). Altogether, these results open the way to high-performance vaccine approaches, and as a first illustrative step, they already led to the design of an ‘optimized” veterinarian vaccine targeted against the Feline Leukemia Virus FeLV, to be launched on the market by mid-2012 (licensed to Merial by the Viroxis partner). The purpose of the present program is to extend the principles established with oncoretroviruses to the second large class of animal and human retroviruses –the lentiviruses- in order to design vaccines against them and more specifically against HIV –and its feline equivalent FIV- responsible for AIDS. Lentiviruses are more complex viruses, encoding accessory proteins, some of them exhibiting a strong capacity for immune escape by mutation. The UMR8122 team has already characterized within the accessory Nef protein a domain with a sequence closely related to that of the oncoretroviral envelope proteins, also endowed with an IS function whose activity can be abolished by a targeted point mutation (Patent pending). The effect of this mutation has been tested in a “Rhesus macaque” model and allowed us to define an “optimized” antigen for this protein, which is expressed early and constitute a critical initial target to be incorporated into any vaccine protocol. The Research Project aims at generating an “optimized” antigen for the envelope protein from HIV –and FIV- since the Partners have already shown that this protein also exhibits an immunosuppressive activity. A first task will be to pinpoint mutations that inactivate the IS function without interfering with the expression of a properly conformed protein, thus constituting a vaccine antigen optimized both at the structural and immunogenic levels (loss of the IS activity that counteracts an effective vaccination). The antigens thus optimized will be preassessed for their immunogenicity in mice, and then in a macaque model, to constitute together with the mutant Nef antigen the basis for an “optimized” vaccine, prone to be tested in a clinical trial in collaboration with an industrial partner providing an appropriate vaccine vector.