The HIV-1 epidemic has resulted in ~2.7 million new infections in 2007 for a total of ~33 million people living with HIV/AIDS. Clinical trials have shown that HIV-1 infection cannot be prevented by immunization with monomeric recombinant forms of viral envelope (Env) proteins. However, it is clear that the HIV-1 Env contains epitopes that can induce neutralizing antibodies and that such antibodies can protect primates from infection. The HIV-1 Env is a transmembrane glycoprotein. Both the external subunit (gp120) and the membrane- proximal external region of Env (located within the gp41 subunit) contain epitopes that are the target of broadly neutralizing monoclonal antibodies (mAbs) isolated from infected patients. Considerable effort has been devoted to creating soluble forms of the Env trimer. The improvements in immunogenicity of these molecules relative to monomeric gp120 are limited at best. Another approach to creating improved Env-based immunogens is to produce virus-like particles (VLP). VLPs are multivalent and often very immunogenic. The full-length HIV-1 Env protein can be presented on the surface of VLPs composed of Gag protein and cellular membrane components. These VLP structures have the potential to represent true mimics of the Env trimer spike. Several challenges must be overcome to create HIV-1 vaccines based on VLPs. They must be produced at high levels. The number of Env molecules on each VLP must be maximized. Processing of the gp160 Env polypeptide must take place, without dissociation of the gp120 subunit, to create a functional form of the Env trimer. It might also be necessary to minimize the immunogenicity of the variable sequences. In preliminary studies on the creation of VLPs carrying HIV-1 Env proteins, we have begun to address the challenges outlined above. The preliminary results are encouraging and provide a basis for more detailed work on preparing VLP-based immunogens as candidates for HIV-1 vaccines. The objective is to create VLPs that carry the Env protein in a form that most resembles the current vision of the functional Env trimer of the virus.
The Specific Aims of this Phase I SBIR proposal are as follows: (1) prepare optimized Env constructs for VLP production;(2) prepare VLP constructs with different Env sequences;and (3) evaluate the ability of various VLPs to induce neutralizing antibodies in rabbits If the VLP-based Env immunogens prove to be superior to soluble gp120 or gp140 constructs in their ability to induce neutralizing antibodies, then additional studies will form the basis of a Phase II SBIR proposal.
The HIV/AIDS epidemic has resulted in 2 million deaths and 2.7 million new infections in 2007, for a total of nearly 33 million people living with HIV/AIDS. Development of a vaccine is considered to be an essential component of the public health measures needed to slow the epidemic. This research proposal is designed to create a vaccine that can induce antibodies capable of preventing infection by the HIV virus.
