A means to eradicate HIV infection, along with a vaccine to prevent its acquisition, is the key method by which AIDS will eventually be eliminated worldwide. The two goals are complementary, as several cure strategies incorporate HIV vaccines and drug- or gene therapy-based schemes into their attack on latent HIV reservoirs. amfAR grantees Drs. Alon Herschhorn of Harvard University and Andrés Finzi of Université de Montréal, along with colleagues from McGill University and the University of Pennsylvania, published a report in the March issue of the Journal of Virology defining the structure and interactions of a key target of HIV vaccine design.
They note that HIV, in constantly changing the character of one of its outer envelope proteins known as gp120, effectively evades an infected person’s immune system. But the virus needs to keep some regions of that protein constant to enable it to interact with host cell membrane proteins in order to enter a cell. The balance of these finely tuned processes—HIV gaining entry into a cell while remaining under the radar of the host’s immune system—is what Herschhorn and Finzi sought to exploit.
The gp120 must simultaneously stay loosely joined to the other virus envelope protein, gp41, while it binds to its cell receptor, CD4. That gp120 binding then rapidly initiates a change in the structure of the gp120-gp41 unit, enabling gp120 interaction with another cellular co-receptor, usually CCR5. Only then is the virus capable of infecting a cell.
Herschhorn and associates discovered, by a series of mutations in the HIV envelope, vulnerable sites in gp41. A change in those sites decreased the likelihood of the structural changes in the gp120-gp41 unit and increased the susceptibility of HIV to attack by two drugs—so-called entry inhibitors.
The authors concluded: “Knowledge of the envelope structure and the conformational changes that occur after receptor engagement will help researchers to develop an immunogen able to elicit antibodies that block HIV-1 transmission.”
Or, in simpler terms, it will help design a vaccine component (the “immunogen”) that is better able to prevent HIV infection.
Dr. Laurence is amfAR’s senior scientific consultant.