Grant: Operating Grant

In the absence of treatment, human immunodeficiency virus (HIV) causes acquired immunodeficiency syndrome (AIDS), which has already killed more than 33 million people worldwide. To be able to spread, HIV needs first to enter human cells. To do so, HIV has developed a unique "key" (envelope glycoproteins, gp120 and gp41) that recognizes a particular "lock" (receptor CD4 and coreceptors CCR5 or CXCR4) in human cells (mainly lymphocytes T CD4 and macrophages). This "key" needs to "move" into the "lock" (conformational changes of gp120 and gp41) to allow viral entry. In the absence of no effective vaccines against HIV and with therapies aimed at HIV eradication remaining a far fetched goal, new ways to fight HIV infection are warranted. Prevention of HIV transmission requires approaches that interrupt the early phase of infection. The first step of the replication cycle is viral entry into target cells. If we could block the "key" of the virus with antibodies or small molecules, the virus will not be able to enter the cell and henceforth, it will be unable to replicate. However, to efficiently block this "key" we must first fully understand how it works. The goal of this proposal is to advance our understanding of how this "key" works, particularly what are the exact "movements" that are required to allow viral fusion and what parts of the "key" are responsible for them. This proposal will advance our understanding of a critical step in the HIV replication cycle and has the potential to develop new inhibitors against the "key" of HIV.