HIV mutates faster than the human immune system can produce new antibodies, and some B cells—the cells that make antibodies—become exhausted and stop working properly during long-term infection. This matters because even after years of trying, many HIV-positive individuals produce highly-mutated antibodies that still cannot stop the virus. Researchers already know that exhausted B cells exist, but they were assumed to be irrelevant casualties of infection. Recent work on malaria suggests otherwise: exhausted B cells there carry genetic blueprints for highly-mutated antibodies, meaning they may have participated in the same arms race seen in HIV. This project tests whether exhausted B cells in HIV patients are the source of those highly-mutated antibodies, and whether their numbers rise when the virus gains the upper hand. If the hypothesis holds, it would point to a new strategy: re-invigorating exhausted B cells to restore normal antibody production. This is fundamental science—it does not promise a therapy tomorrow. But understanding why B cells fail could eventually guide vaccine design or treatments that keep the immune system in the fight longer.
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During long-term infection the human immune system continually tries to get rid of the infectious agent without success. For example, during HIV infection which is life-long. One of the ways the immune system tries to overcome HIV is by producing antibodies that block the virus from entering new cells. However, HIV then rapidly mutates within the person and becomes resistant to their antibodies. Our immune system tries to keep up, and mutates the antibodies so that they can block the new version of HIV. This mutational arms race between antibodies and virus continues over many years. In some HIV+ individuals the result is highly-mutated antibodies but these are still unable to halt the virus. This is partly because the virus can mutate faster than the antibodies, but given the antibodies catch up repeatedly during infection it's likely the virus uses other tactics counteract human antibodies as a safeguard. I hypothesise that one of these tactics is to interfere with normal behaviour of the cells, called B cells, that make antibodies so that less antibody is present in the body to act against the virus. It is already known that during long-term infections some B cells become exhausted and can't complete the role they need to play in the body's defense. This exhaustion can be tested for in the laboratory by measuring the amount of particular proteins on the surface of individual B cells. Previously it was thought that these cells had no role in the ongoing immune response and were just casualties of the relentless infection. However, studies in malaria infection have shown that the exhausted B cells have the genetic blueprints for very highly-mutated antibodies against the parasite, suggesting they have participated in the same kind of mutational arms race between pathogen and antibodies seen in HIV infection. Therefore, I want to test whether highly-mutated antibodies that target HIV during long-term infection come from exhausted B cells. I also want to know if numbers of exhausted B cells increase at times in the mutational arms race when the virus gains the upper-hand. If this is true, then it would suggest a way to make antibodies more effective against HIV would be to re-invigorate the exhausted B cells and bring them back to a normal level of activity.
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