"Exploring the Interactions between Neutralizing Antibodies and HIV-1 Sensitive and Resistant Envelopes"
To address the difficult task of developing a HIV vaccine, the International AIDS Vaccine Initiative has established a consortium of investigators with diverse backgrounds to better understand the behavior and vaccine potential of neutralizing antibodies (NAb). To-date, trials using HIV envelope (Env) proteins to elicit NAb responses have failed. This is partly because the conserved epitopes on the HIV Env are heavily shielded and little information is known about how NAbs interact with and neutralize HIV. Recently, the Overbaugh lab has identified two mutations within the HIV-1 Env protein, gp41, that increase the neutralization susceptibility to antibodies that target multiple epitopes throughout both subunits of the Env, including gp120 (Blish, PLos Medicine, 2008). I hypothesize that these specific changes affect the global structure of the Env that leads to exposure of normally shielded epitopes. Since classic virology approaches alone will be insufficient to answer the mechanistic question, I propose to examine 1) how these two amino acid changes affect the viral Env-NAb binding to determine if binding alone is responsible for their neutralization and 2) how other amino acids at these positions affect the Env-NAb binding and viral neutralization of these mutants. The Strong lab has begun investigating the biophysical characteristics of SF162, a Clade B, highly NAb-sensitive variant, allowing me to use analogous strategies for the variants described above. Therefore, I will be the link in a new collaboration between the Overbaugh and Strong labs, which will bridge their expertise in HIV biology and in binding analyses.