Thank you for posting this topic. This is a very interesting issue and a million-dollar question. I, too, have pondered upon this topic quite heavily recently. As a virologist in training, I tried to gather some information about 'immune memory depletion', which I believe will be useful for this session:
Immune memory and the Measles
Measles infection causes severe immune suppression and amnesia, and the direct infection of lymphocytes could be one of the reasons behind it. Still, this was not known to be the definitive norm. This possibility was dismissed based on two major observations during measles infection, a) lymphocyte counts rapidly return to normal after the clearance of the virus, and b) during the peak viremia, only 1-5% of total lymphocytes in the peripheral blood is infected .
In 2012, another seminal animal study investigated the aetiology of measles and measles-related immune suppression. Standing on the supportive foundation established in the previous animal study that showed MeV infection of a high percentage of lymphoid tissues and biased memory T cells. Rhesus macaques were used again in this experiment . In this study, the observations from earlier experiment were corroborated. Lymphoid tissues reveal predominant measles infection even at macroscopic investigation, and the high percentages of B-lymphocytes and CD45RA memory T Cells were infected. In tonsils, peyer’s patches , tracheobronchial lymph nodes and PBMCs, it was seen that memory T cells as compared to naïve T cells were significantly selectively infected. This distinction was not visible for B-cells.
Based on the observations gathered from earlier in vitro and the in vivo experiments, the researchers proposed a measles infection model that is compatible to the ‘measles paradox’. Measles paradox is the phenomenon where individuals retain a strong immunological defense against the measles virus after viral clearance, whereas all other immunological memory against other pathogens is apparently lost. This leads to the condition of measles-induced immune amnesia.
The model suggests that after the measles infection associated viremia, a serious depletion of memory T cells and B cells occurs. After the second week of infection, the lymphocyte population looks as if it is returning to normal just because the number of MV-specific and bystander T and B cells is restored, whereas the number of memory T cells continues to be suppressed for at least six weeks. In this manner, by infecting and eliminating the preexisting memory cells that express high levels of CD150, Measles erases the recollection of past exposures to microbes and ‘resets’ the host’s defence system back to its default.
The findings from the above-mentioned animal models were corroborated by the observations from a large-scale human epidemiological study conducted in the Netherlands after a Measles outbreak in 2013. The study was published in Nature .
Molecular and genetic basis for B-cell repertoire depletion
Next, in 2019, a group of scientists sought to investigate the actual genetic mechanism that might be related to immune amnesia after measles infection. In this study, the group used B cell receptor sequencing to see what changes in the gene were behind the speculated suppression of antibody repertoires against other pathogens after a measles infection. When the cells were sequenced for the B cell receptor Variable region (V-J) gene termed complementarity determining region (CDR3), they found that this region was considerably shortened after measles infection. The V-J gene frequency had a much lower correlation post-infection as compared to pre-infection. This led to an incomplete reconstitution of the naïve B cell pool and compromised the immune capacity to previously encountered pathogens. Moreover, surrogate ferret models of measles infection were also used to demonstrate that the depletion of vaccine-acquired immunity to the influenza virus led to a compromised recall response and increased severity of non-measles diseases .
With this information so far, what can we do next?
Can we edit the naive B cells selectively?
Can we 'engineer' the Measles virus optimally to induce required immune amnesia without the associated pathology?