Macaques and MHC- Creating a Vaccine for HIV: Part I

This blog post is on some exciting research that is going into the potential development of a vaccine for HIV. As there is quite a lot of background information, I’m going to be splitting it into two parts (with part II to be released soon!). This first part is on previous research conducted since 2013, and the second part is on a paper published this year.  This research has quite a lot of personal significance- to be revealed in the next part!
What is HIV?
HIV (Human Immunodeficiency Virus) infects over 35 million people worldwide, causing 1.6 million AIDS (Acquired Immune Deficiency Syndrome) related deaths per year. HIV is a complex infection, as the virus has unusually high levels of heterogeneity (viral variation and mutation) within each infected individual, and varying degrees of clinical presentation during the course of an infection.
HIV causes a lifelong and latent infection that attacks the immune system by infecting CD4+ T lymphocytes (which are an essential part of the adaptive immune system, and help ward off infections by pathogens). A reduction in T lymphocytes reduces the individual’s ability to fight other opportunistic infections, leading to the autoimmune disease AIDS.
HIV takes a permanent hold inside the host, and currently even the most effective antiretroviral therapies cannot clear, but merely control, the virus in the infected individual. The mutation and plasticity of the virus allows it to escape from most immune responses, and to remain undetected inside the host. Up until recently, there has been no successful vaccine against HIV that could stimulate the immune system into recognising the virus upon later infection, due to the high mutation rates of HIV during initial infection.

A series of papers published by Hansen et al (2009-2013) highlight the attempted development of a vaccine for HIV. This vaccine had a remarkable success against the closely-related SIV (Simian Immunodeficiency Virus) in macaques, and research is currently underway to test whether this vaccine design would work against HIV in humans.

What’s in this vaccine?

This SIV vaccine works by taking some key proteins from the highly virulent SIVmac239 strain, and expressing them in a Rhesus Cytomegalovirus (RhCMV68-1) vector. Similar to HIV, cytomegalovirus (CMV) persists as a lifelong latent infection within the host, that the immune system can control but not eradicate. This means CMV is not removed from cells upon vaccination, and can target SIV upon infection.
This study by Hansen et al vaccinated rhesus macaques (Macaca mulatta) with the rhesus cytomegalovirus RhCMV  68-1 vectored SIVmac239 vaccine. The vaccinated macaques, alongside an unvaccinated control group, were then infected with the pathogenic SIVmac239 strain. Encouragingly, 50% of the individuals vaccinated with the RhCMV/SIV vector maintained a long-lasting control of the virus for over 2 years post-infection- a figure never before seen in early vaccine trials. This suggests that the RhCMV/SIV vector vaccine assisted clearance of the SIV infection.
It was suggested that this strong immune reaction caused by the vaccine may have been mediated by Mamu-E, the Rhesus macaque orthologue of HLA-E

What is HLA-E?
HLA-E is a non-classical class Ib major histocompatibility complex (MHC) molecule*- lots of words, but basically it’s a molecule of the innate immune system that’s a bit different to other MHC molecules. Class Ia MHC molecules are highly polymorphic and expressed on the surface of a wide range of cells. This polymorphism allows them to detect a wide range of antigens (just like the antibodies), which are presented to CD8+ T cells for activation. HLA-E is a lot less polymorphic, and so researchers thought that it would only recognise a limited number of antigen peptides. Mamu-E is a lot more polymorphic than HLA-E, and looks more similar to MHC class Ia molecules.

Why is this important?

Up until recently, the exact mechanisms behind why this vaccine worked were unclear. What in the vaccine was causing this total repression of viral spread? And why were only 50% of macaques protected by it? The most recent publication by Hansen et al (2016) suggests why HLA-E and the RhCMV-vectored vaccine were so successful, and also sheds some light as to whether this vaccine design could be replicated using human cytomegalovirus (HCMV) for protection against HIV in humans.

The development of a vaccine for HIV would be a massive step-forward in humanity’s advancement in health and disease control, and also reduce the risk of HIV infection for many millions of people worldwide. The effects of this would be immense, and would signify a huge hurdle conquered in the history of the human race, against a highly variable and complex virus.


*Human leukocyte antigen E (HLA-E) means the same a MHC-E, just human-specific (I shall refer to it as HLA-E in humans, Mamu-E in macaques, and MHC-E as a general term) .

Reading and references

  1. HANSEN, S., et al. Effector memory T cell responses are associated with protection of rhesus monkeys from mucosal simian immunodeficiency virus challenge. 2009. Nature Medicine. 15, 293-299.
  1. HANSEN, S., et al. Cytomegalovirus Vectors Violate CD8+ T Cell Epitope Recognition Paradigms. 2013. Science. 340. 940-958)
  1. HANSEN, S., et al. Immune clearance of highly pathogenic SIV infection. 2013. Nature. 502. 100-106

 

Thanks go to my supervisors in the lab, for help with writing parts of this review

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