Genetic analyses reveal key mechanism of HIV control

1 December 2010. Related: Basic science and immunology.

Richard Jefferys, TAG

A new study published online in Science Express last week reports a breakthrough in understanding the association between particular immune response genes and the ability of some individuals to control HIV replication without treatment. [1]

The research was conducted through the International HIV Controllers Study, a huge collaborative effort initiated by Bruce Walker from the Ragon Institute of Massachusetts General Hospital in Boston. [2] The study collects samples from individuals who control viral load without treatment, either to less than 50 copies (elite controllers) or less than 2,000 copies (viremic controllers). A team led by Harvard geneticist Paul De Bakker conducted the analyses that led to the latest findings.

The findings relate to immunological alarms called class I HLA receptors, which display protein fragments (called peptides) from pathogens on the outside of infected cells in order to flag the cell for destruction by CD8 T cells (aka “killer” T cells). All cells in the human body except red blood cells are adorned with thousands of class I HLA receptors, and they are continually shuttling from the inside to the outside of the cell carrying peptides for passing CD8 T cells to inspect. Most of the time these peptides are from our own body’s proteins–essentially cellular trash–and CD8 T cells allow the cell to go about its business. But if a class I HLA receptor emerges with peptide from a pathogen, CD8 T cells will typically respond by destroying it.

There are a wide variety of different genes that make (or in genetics language “encode”) class I HLA receptors, all located in the MHC region of the human genome on chromosome six. The specific HLA genes an individual possesses are inherited from their parents. Different HLA genes make class I HLA receptors with slightly different structures, which determines the types of peptide structures the receptor can present, which in turn can influence the ability of CD8 T cells to recognize the presented peptide.

It has been known for more than a decade that certain HLA genes make receptors that seem particularly adept at presenting HIV peptides to CD8 T cells, and that possessing these HLA genes greatly increases the chances of becoming an elite controller. Conversely, some other HLA genes are associated with high HIV viral loads and rapid disease progression. However the detailed mechanisms underlying these associations had not been figured out.

The new study in Science drills down to specific structural features that are shared by class I HLA receptors encoded by the HLA genes associated with elite control. The paper includes a visual representation of a class I HLA receptor showing the locations pf these features, which consist of different amino acids (the building blocks out of which proteins are made). The image is reproduced the receptor looks a little like a pair of jaws; the mouthpart is referred to as a “binding pocket” that peptides slot into.

The crux of the new finding is that the type of amino acid located at the numbered positions has a huge impact on the likelihood of an HIV-infected person controlling their viral load without treatment. Exactly why this is has yet to be fully explained, but some previous evidence that suggests these class I HLA receptors are able to present parts of HIV that cannot mutate without compromising the ability of the virus to replicate. There are also studies showing that the functionality of CD8 T cells can be influenced by the specific viral epitope they recognise; in other words, CD8 T cells that recognise
viral epitopes presented by these class I HLA receptors may simply work better than others. Gaining a better understanding of exactly how these specific amino acids confer benefit is now a priority for the research team.

Another important aspect of the study is that it provides a unifying explanation for the associations between several different HLA genes and HIV control that have been reported previously. What the genes all have in common is that they encode class I HLA receptors with one or more of the structural features De Bakker and colleagues identified.

The publication of the paper last week garnered a great deal of well-deserved coverage in the mainstream media. However, as is always the case, some stories are more accurate than others. One aspect that may not have come through clearly is that while possessing these class I HLA receptor variants massively increases the chances of becoming an elite controller, it does not mean that it is certain; some individuals who have them do not control viral load, and conversely they are absent in some elite controllers. This is not really surprising, as CD8 T cells work in concert with other components of the immune system such as CD4 T cells, and these other immune responses can also impact how well HIV is controlled. Another recent paper by Hendrick Streeck from Bruce Walker’s group–just published online in the Journal of Virology–provides an example by showing that HIV-specific CD4 T cells that produce IL-21 influence the function of HIV-specific CD8 T cell responses and are associated with lower viral loads.

What can be stated with certainty is that the International HIV Controllers Study is providing crucial insights into the mechanisms that underlie immune control of HIV. Close to four pages of the Science Express paper are taken up by the names of individuals and institutions that have referred people to the study, indicating the broad support for this research. Although they can’t be named in the paper, the many altruistic study participants who donated samples must be saluted also.

Source: TAG basic science blog. (12 November 2010). http://tagbasicscienceproject.typepad.com/tags_basic_science_vaccin/2010/11/genetic-analyses-reveal-key-mechanism-of-hiv-control.html

References:

1. The International HIV Controllers Study. The Major Genetic Determinants of HIV-1 Control Affect HLA Class I Peptide Presentation.
   Science Express DOI: 10.1126/science.1195271. Published Online 4 November 2010. http://www.sciencemag.org/cgi/content/abstract/science.1195271
2. International HIV Controllers Study. http://www.hivcontrollers.org