A Somerville student has co-authored a paper that has been published in Science. Publishing in Science is a great achievement, for anyone and most especially for an early career researcher. Hannah Sharpe, who is from Fareham, is a third year student studying biological sciences. She has very kindly provided us with a short summary of the paper, which looks at one promising approach toward an HIV-1 vaccine.
Broadly targeted CD8+ T cell responses restricted by Major Histocompatibility Complex-E.
HIV is a globally significant virus, with serious impacts on global health. Over 35 million people worldwide are infected with HIV, and the unusually high levels of genetic heterogeneity mean it is a complex infection to treat. Because of this, no previous attempts at vaccine development have been successful. However, in 2013, Hansen et al detailed the creation of a vaccine for SIV. SIV is the equivalent virus to HIV that infects non-human primates, including rhesus macaques, and is often used as a model for HIV infection. This vaccine was made using another virus as a vector to deliver antigenic peptides found in SIV to the host, in order to initiate an immune response. The virus vector used was developed from rhesus macaque cytomegalovirus (RhCMV). RhCMV, and its human equivalent HCMV, persist as lifelong infection inside hosts, but often do not present any clinical symptoms.
This RhCMV:SIV vaccine design was able to protect 50% of macaques from further infection with SIV. These protected macaques were able to clear the virus, and were then resistant to reinfection. This level of protection had never been seen before in any HIV/SIV vaccine trials. The question is, could this RhCMV:SIV vaccine design be replicated using HCMV for the development of a vaccine for HIV? It is important to determine exactly how the vaccine works, in order to understand whether it would have the same effect in humans. This paper, Broadly targeted CD8+ T cell responses restricted by Major Histocompatibility Complex-E, outlines the discovery of how the RhCMV:SIV vaccine provides a unique level of immune protection to SIV.
In the immune system, there is a type of cell known as a CD8+ T cell. These cells are cytotoxic, and are involved in the killing of cells infected with viruses. Normally, they recognize antigenic peptides with the help of major histocompatibility complex class Ia (MHC-Ia) immune molecules, which are found on the surface of most cells. MHC-Ia molecules are highly polymorphic in their sequence, which allows them to bind a lot of different peptides from pathogens, to stimulate a CD8+ T cell response. This is often beneficial, as it means a lot of different pathogens will be recognized by the immune system. However, it can have serious implications in vaccine design as different members of a population can respond differently to the same vaccine.
The vaccine created by Hansen et al did not follow this pattern of CD8+ T cell stimulation. All peptides from the SIV virus in the vaccine stimulated an equal response across all protected rhesus macaques, suggesting that it was not MHC-Ia molecules that were assisting in the recognition and response to the peptides. This paper shows that it was MHC class II molecules, and an MHC class Ib molecule known as MHC-E that stimulated the CD8+ T cell responses. MHC-E is found in both humans and rhesus macaques across a wide variety of cells in the body. MHC-E binds peptides presented by MHC-Ia molecules, which up-regulates MHC-E expression on the cell surface. Previously to this paper, it was thought that MHC-E could only bind a very limited number of peptides, as it has very limited polymorphism in comparison to MHC-Ia molecules. However, it turns out that MHC-E can actually bind a much more diverse range of peptides than previously thought.
MHC-E preferentially binds peptides with a conserved nine amino acid sequence (typically VMAPRTLLL), known as VL9. The part of the paper that I assisted with showed that both human and rhesus cytomegalovirus contain genes which contain the VL9 peptide, known as UL40 and Rh67 respectively. Even though the genes are non-homologous in origin (they do not share a common ancestral gene, and therefore have very different genetic sequences), they are both contain this nonameric peptide which interacts with MHC-E.
It was concluded that MHC-E up-regulation is important in the vaccine’s success, as it could produce such a strong CD8+ T cell response in Rhesus macaques. Even though there is still a long way to go before we can be certain that a similar vaccine could be developed in humans, this is a positive step towards the potential development of a vaccine for HIV.
The paper was published in Science on the 12th Feb 2016: Vol. 351, Issue 6274, pp. 714-720
It is also available to read online.