Investigating antibody affinity maturation during B cell exhaustion in viral infection

在长期感染过程中，人体免疫系统不断试图摆脱感染因子，但没有成功。例如，在艾滋病毒感染期间，这是终身的。免疫系统试图克服艾滋病毒的方法之一是通过产生抗体来阻止病毒进入新的细胞。然而，HIV随后在人体内迅速突变，并对抗体产生耐药性。我们的免疫系统试图跟上，并使抗体突变，以便它们可以阻止新版本的艾滋病毒。抗体和病毒之间的这种突变军备竞赛持续了许多年。在一些HIV+个体中，结果是高度突变的抗体，但这些抗体仍然无法阻止病毒。这部分是因为病毒可以比抗体更快地变异，但考虑到抗体在感染过程中反复追赶，病毒很可能使用其他策略抵消人类抗体作为保障。我假设这些策略之一是干扰称为B细胞的细胞的正常行为，这些细胞产生抗体，从而减少体内存在的对抗病毒的抗体。众所周知，在长期感染期间，一些B细胞会耗尽，无法完成它们在身体防御中所需的角色。这种耗竭可以在实验室中通过测量单个B细胞表面上特定蛋白质的量来测试。以前人们认为这些细胞在持续的免疫反应中没有作用，只是无情感染的受害者。然而，对疟疾感染的研究表明，耗尽的B细胞具有针对寄生虫的高度突变抗体的遗传蓝图，这表明它们参与了与艾滋病毒感染中所见的病原体和抗体之间的相同类型的突变军备竞赛。因此，我想测试在长期感染过程中针对HIV的高度突变抗体是否来自耗尽的B细胞。我还想知道，当病毒占上风时，在突变军备竞赛中，耗尽的B细胞数量是否会增加。如果这是真的，那么它将表明一种使抗体对艾滋病毒更有效的方法是重新激活耗尽的B细胞，使它们恢复到正常的活性水平。

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.