This is the second installment of my review on the recent papers published by Hansen et al, which outline the potential development of a vaccine for HIV. We left off questioning how the RhCMV:SIV vaccine actually works, and whether this vaccine could be replicated in a form suitable for human use. The most recent paper by Hansen et al (2016) outlines a possible explanation for the mechanisms behind this vaccine, by providing a unique level of immune protection against SIV.
It’s all about the CD8+ T cells
The adaptive immune system contains the CD8+ T cell. These cells have cytotoxic capacities, meaning they kill cells infected with pathogens. CD8+ T cells release these killing cytotoxins when stimulated by other tissue cells expressing MHC class Ia molecules on their cell surface. MHC-Ia molcules recognise antigenic parts of the pathogen when it is inside the infected cell, and present the antigens of on the cell surface in a complex, for recognition by CD8+ T cells. MHC-Ia molecules are therefore highly polymorphic, as they need to be able to bind to and present lots of different variations of antigen on the cell surface (Like B cells and antibodies). This is often beneficial, as it means a lot of different antigens from pathogens can be recognised by the immune system. However, it can lead to serious implications in vaccine design, as different members of a population can respond differently to the same vaccine, and sometimes a vaccine will not work as well with some individuals than it does with others (this is important to note!).
So how could this vaccine work?
The RhCMV:SIV vaccine created by Hansen et al did not follow this standard pattern of immune response. All the antigenic peptides from the SIVmac239 in the vaccine stimulated an equal CD8+ T cell response to the vaccine across all the vaccinated macaques, and not the previously-mentioned variation in response. This suggests that it was not MHC-Ia molecules that were assisting in the CD8+ T cells’ response to the viral antigens. Hansen et al (2016) showed that the CD8+ T cells detected the antigens via MHC class II molcules, and MHC-E*, a non-classical class Ib MHC molcule. MHC-E (also known as HLA-E) was mentioned in the previous review.
What does MHC-E do?
MHC-E does not function in the same way as classical class Ia MHC molcules. Class Ia molecules bind antigens from the pathogen inside the cell, and present them on the cell surface as previously described, to be detected by CD8+ T cells and stimulate a response. MHC-E binds to the antigens presented by these class Ia molecules in the cell, which up-regulates MHC-E on the cell surface. This adds an extra step in the chain to getting the antigen to the cell surface. Previously to this paper, it was thought that MHC-E in humans could only bind a very limited number of antigenic peptides presented by MHC-Ia molecules, as it had a very limited polymorphism. However, this theory was proven wrong, and it was shown that MHC-E can actually bind to a lot more antigenic peptides than previously thought. This means it is up-regulated at the cell surface, and therefore interacts with there CD8+ T cells, a lot more than expected.
What does MHC-E preferentially bind to?
Due to its limited polymorphism in humans, MHC-E binds preferentially to a nine amino acid sequence (typically VMAPRTLLL, also known as VL9). This paper shows that both human and rhesus CMV contain genes which contain this peptide sequence, known as UL40 and Rh67 respectively. These genes are non-homologous in origin, meaning they do not share an ancestral common gene. They therefore have very different genetic sequences asides from this sequence. This suggests convergent evolution has occured between the two genes to contain this VL9 peptide sequence. It was shown that both these genes are able to up-regulate HLA-E on the cell surface, despite only sharing this peptide similarity, implying that it must have an important function in immune regulation. Therefore, it seems likely that the CMV vector used for the vaccine is able to contribute towards the success of the vaccine.
What does this mean for the future of vaccine development?
The proof that both HCMV and RhCMV are able to up-regulate HLA-E in the same way indicates that there is a possibility for developing a vaccine for HIV using HCMV as a vector. This is incredibly exciting, given the early success of the vaccine in rhesus macaques. However, there is still a lot of research to do before a human version could be developed. We still don’t know why only 50% of macaques were protected by this vaccine, nor do we fully understand how MHC-E up-regulation protects against viral infection. However, all new findings lead us one step closer to hopefully being able to create a vaccine that will give protection against HIV.
Thanks for reading so far! This review is significant to me, as part of the paper in question (Hansen et al 2016) was an area of research focused on in my undergraduate degree project . This led to me being made a co-author of this paper! Something I will always be super-proud of, even if it is the only research paper that I ever contribute to 🙂
*an all-encompassing term; also known as Mamu-E in macaques, HLA-E in humans
The paper: Hansen et al. Broadly targeted CD8+ T cell responses restricted by major histocompatibility complex-E. 2016. Science. 351 (6274) 714-720.
`Thanks to my supervisors for their assistance with my project