Designed Antigens to Elicit Neutralizing Antibodies against the HIV-1 gp41 N-Trimer Region to Prevent HIV Entry into the Host Cell
HIV protects its conserved entry machinery with a steric block, preventing the binding of most antibodies. The present invention provides the methods of producing and identifying sterically restricted antigens that mimic this steric block for use as an antigen to select for antibodies that circumvent this protection. An exemplary sterically restricted N-trimer mimic of the HIV Env protein was designed and used to elicit antibodies that have the ability to bind to the N-trimer region of HIV gp41 and prevent the merging of the viral and cellular membranes. The gp41 trimer-of-hairpins representing a sterically restricted region of a viral protein that drives fusion through a conformational change, where inhibition of the conformational change may prevent or inhibit viral infection.
The AIDS epidemic has claimed more than 20 million lives worldwide. In the United States, approximately 40,000 individuals become infected with HIV each year. The current anti-HIV drugs target only two viral proteins, reverse transcriptase and protease. Because of the increasing viral resistance caused by high rate of viral mutation and turnover, drugs that target additional step of the viral life cycle, such as viral entry, would be useful. This invention provides the methods of developing antiviral therapeutics that can block HIV-1 entry. Clinically, the methods can be used to produce and identify sterically restricted therapeutic antigens that are capable of inducing neutralizing anti-HIV antibodies in humans. As research tools, the methods can be used in experimental studies to discover antibodies that circumvent steric blocks, specifically against HIV and many enveloped viruses using the same mechanism of entry.
Stage of Development
A formal patent application has been filed under the PCT with nationalization to the United States. This technology is part of an active and ongoing research program. It is available for developmental research support or licensing under either exclusive or non-exclusive terms.
*Hamburger AE, Kim S, Welch BD, Kay MS. (2005) Steric accessibility of the HIV-1 gp41 N-trimer region. J Biol Chem. 280(13):12567-72.
Michael Kay, Brett Welch
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