Membrane Proximal Region of HIV gp41 Anchored to the Lipid Layer of a Virus-Like Particle Vaccine
The HIV-1 envelope glycoproteins (gp120-gp41), which mediate receptor binding and entry, are the major targets for neutralizing antibodies. Although the envelope glycoproteins are immunogenic and induce a variety of antibodies, the neutralizing antibodies that are induced are strain-specific and the majority of the immune response is diverted to non-neutralizing determinants. Broadly neutralizing antibodies have been isolated only from natural HIV infection, and rarely, as only five broadly-neutralizing antibodies have been identified to date. Three are gp41-directed (2F5, 4E10 and Z13) and the other two (b12 and 2G12) are gp120-directed. The three gp41 neutralizing antibodies recognize the membrane proximal region (MPR) of the HIV-1 gp41 glycoprotein. The MPR region includes a series of amino acids that lie on the HIV virus surface, just before gp41 crosses the viral membrane. The MPR is highly hydrophobic (fifty percent of its residues are hydrophobic) and is highly conserved across many HIV clades. Recently, the hydrophobic context of MPR and the presence of lipid membrane were shown to be important for the optimal binding of 2F5 and 4E10 antibodies. To date, immunization with conserved membrane proximal elements or the core 2F5 epitope in a number of contexts has failed to elicit broadly neutralizing antibodies.
Available for licensing is a technology that uses the immunogenic hepatitis B surface antigen (HBsAg) platform to array epitopes from the conserved, neutralization-sensitive MPR of HIV-1, and use of these constructs to induce an immune response to HIV-1. The replacement of a membrane spanning domain of HBsAg with a membrane spanning domain of gp41 anchors gp41 into HBsAg in virtually the identical orientation as on HIV virions and correctly orients the nearby MPR on the lipid layer. More specifically, HBsAg variant compositions with one or more transmembrane domains of the HBsAg replaced with a gp41 transmembrane domain and one or more gp41 MPRs are available for licensing.
Potential Commercial Applications:
Development of Human Immunodeficiency Virus (HIV) vaccines, therapeutics and diagnostics.
Bill Ronnenberg, JD-MIP, MS
FDA Technology Transfer Program
10903 New Hampshire Ave.
Building WO1, Rm 4214
Silver Spring, MD 20993
OTT Reference No: E-291-2008/0
Updated: August 9, 2015