While trying to develop a vaccine for AIDS, researchers have uncovered a biological catch-22 that's been hindering their chances of success. They say that while the immune system can produce cells with the potential to manufacture HIV-blocking antibodies, it also works equally hard to eliminate those cells before they have a chance to mature.

Over the years, scientists have assumed that B cells – one of the first lines of defense against infection – are simply not able to "see" the HIV virus. HIV has the ability to hide its most vulnerable parts from immune system surveillance, and researchers generally assumed that
helped explain why B cells often took weeks and even months to arise following infection.

 But several years ago, researchers hypothesized that the antibodies required to broadly neutralize HIV may not be produced in the first place because the immune system "sees"
them as a potential threat – due to their similarity to antibodies that promote autoimmune disease – and destroys them.

To see if this is indeed what happens, Duke University scientists genetically engineered a mouse that could only produce B cells containing a rare but potent broadly neutralizing human antibody that is able to block HIV infection.

They found that the mouse's immune system produced plenty of early stage B cells bearing
this human neutralizing antibody on their surface but eliminated most of them before they had a chance to fully evolve into more mature B cells capable of secreting the antibody.
 
"This work may mean that we need to think and act very differently in envisioning how a
successful vaccine may work," said Laurent Verkoczy, Ph.D., lead author of the study. "The good news is that while about 85 percent of the "right" kind of B cells are eliminated, about 15 percent survive and wind up in circulating blood, but are turned off.  One goal in vaccine design may be to figure out how to wake them up so they can go to work."

"We have now unveiled a major reason why members of this class of neutralizing antibodies are not routinely made:  Our own immune systems block their production because they are perceived as potentially harmful, when in reality, they are not," said co-author Barton Haynes M.D. "This is a very unusual way the virus has developed to evade the immune system."

The researchers say they will next try to teach the immune system how to enable the production of the HIV-blocking antibodies.