A fusion intermediate state of HIV-1 gp41, targeted by broadly neutralizing antibodies, for purposes of vaccination
HIV infection generally induces a strong antibody response to the envelope glycoprotein, the sole antigen on the virion surface. Most of the induced antibodies are ineffective in preventing infection, however, as they are either non-neutralizing or narrowly isolate-specific. Only three broadly neutralizing antibodies have been detected that recognize one of tree relatively conserved regions on the envelope protein: the CD4 binding site, carbohydrates on the outer gp120 surface, and a segment of the gp41 ectodomain.
Conformational changes in gp120 result in its dissociation with gp41, leading to a cascade or refolding events in gp41. One of the transitional states of gp41 refolding is known as the "pre-hairpin intermediate." Use of a polypeptide similar to the prehairpin intermediate has been shown to induce broadly neutralizing antibodies against HIV.
Applications
During the past 15 years, several dozen HIV candidate vaccines have entered Phase I clinical trials. The candidate vaccines developed and tested to date have been safe and well tolerated, and nearly all, with varying degrees of success, have produced HIV-specific immune responses; several candidates have undergone, or are undergoing, Phase II evaluation. As of July 2005, two Phase III vaccine trials of first-generation rgp120 vaccine candidates have been completed; these trials failed to show efficacy.
Functionally important epitopes of HIV glycoproteins are masked by glycosylation, trimerisation and receptor-induced conformational changes making it difficult to block with neutralizing antibodies. By focusing on transition state intermediates, such as gp41's pre-hairpin intermediate, broadly neutralizing antibodies may be produced, preventing issues from previous HIV vaccines from developing.
HIV infection generally induces a strong antibody response to the envelope glycoprotein, the sole antigen on the virion surface. Most of the induced antibodies are ineffective in preventing infection, however, as they are either non-neutralizing or narrowly isolate-specific. Only three broadly neutralizing antibodies have been detected that recognize one of tree relatively conserved regions on the envelope protein: the CD4 binding site, carbohydrates on the outer gp120 surface, and a segment of the gp41 ectodomain.
Conformational changes in gp120 result in its dissociation with gp41, leading to a cascade or refolding events in gp41. One of the transitional states of gp41 refolding is known as the "pre-hairpin intermediate." Use of a polypeptide similar to the prehairpin intermediate has been shown to induce broadly neutralizing antibodies against HIV.
During the past 15 years, several dozen HIV candidate vaccines have entered Phase I clinical trials. The candidate vaccines developed and tested to date have been safe and well tolerated, and nearly all, with varying degrees of success, have produced HIV-specific immune responses; several candidates have undergone, or are undergoing, Phase II evaluation. As of July 2005, two Phase III vaccine trials of first-generation rgp120 vaccine candidates have been completed; these trials failed to show efficacy.
Functionally important epitopes of HIV glycoproteins are masked by glycosylation, trimerisation and receptor-induced conformational changes making it difficult to block with neutralizing antibodies. By focusing on transition state intermediates, such as gp41's pre-hairpin intermediate, broadly neutralizing antibodies may be produced, preventing issues from previous HIV vaccines from developing.
Intellectual Property Status: Patent(s) Pending