Investigating antibody affinity maturation during B cell exhaustion in viral infection

在长期感染期间，人类免疫系统不断地试图清除感染剂，但没有成功。例如，在感染艾滋病毒期间，这是终生的。免疫系统试图战胜艾滋病毒的方法之一是产生抗体，阻止病毒进入新细胞。然而，艾滋病毒随后在人体内迅速变异，并对他们的抗体产生抗药性。我们的免疫系统试图跟上，并使抗体发生突变，以便它们能够阻止新版本的艾滋病毒。抗体和病毒之间的这种变异军备竞赛将持续多年。在一些HIV+的个体中，结果是高度突变的抗体，但这些抗体仍然无法阻止病毒。这在一定程度上是因为病毒的变异速度比抗体快，但考虑到抗体在感染期间反复赶上，病毒可能会使用其他策略来中和人类抗体作为一种保护措施。我假设，这些策略之一是干扰制造抗体的细胞(称为B细胞)的正常行为，以便体内出现更少的抗体来对抗病毒。已经知道，在长期感染期间，一些B细胞会变得精疲力竭，无法完成它们在人体防御中所需的角色。这种耗竭可以在实验室通过测量单个B细胞表面特定蛋白质的数量来测试。以前，人们认为这些细胞在持续的免疫反应中没有作用，只是持续感染的受害者。然而，对疟疾感染的研究表明，耗尽的B细胞拥有针对这种寄生虫的高度突变抗体的基因蓝图，这表明它们参与了病原体和抗体之间的同种突变军备竞赛，这在艾滋病毒感染中可以看到。因此，我想测试在长期感染期间针对艾滋病毒的高度突变抗体是否来自耗尽的B细胞。我还想知道，当病毒占据上风时，在突变的军备竞赛中，耗尽的B细胞数量是否会增加。如果这是真的，那么这将表明，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，使它们恢复正常的活动水平。

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.