Variations in peptide stability may alter targeting of infected cells by CD8 T cells
9-May-2011 - A key step in the processing of HIV within cells appears to affect how effectively the immune system's
killer T cells can recognize and destroy infected cells. Researchers at the Ragon Institute of MGH, MIT and Harvard have found that - as HIV
proteins are broken down within cells, a process that should lead to labeling infected cell for destruction by CD8 T cells - there is a great
variability in the stability of resulting protein segments, variations that could significantly change how well cells are recognized by
the immune system. Their report appears in the June Journal of Clinical Investigation.
"We have identified a novel mechanism by which HIV escapes recognition by virus-specific cytotoxic T cells, says
Sylvie Le Gall, PhD, of the Ragon Institute, the paper's senior author. "This discovery may help us better understand the immune-system
failure that characterizes HIV infection and provide information critical to the successful development of immune-system-based therapies."
CD8 T cells that have been programmed to target and destroy HIV-infected cells recognize those cells through
tiny bits of viral protein, called peptides, displayed on the cell surface. Details of how HIV proteins are broken down into peptides
and loaded onto the specialized molecules, called MHC Class I, that carry them to the cell surface are not well understood. Also
unknown is whether particular HIV peptides are more effective than others in flagging cells for destruction.
Le Gall and her team first discovered that HIV peptides reduced to a length of 8 to 11 amino acids within
infected cells varied greatly in their stability, with some breaking down further within seconds and others remaining unchanged for
nearly an hour. Collaborators David Heckerman, MD, PhD, and Carl Kadie from Microsoft Research analyzed the biochemical features
of 166 HIV peptides and identified particular structural patterns associated with either stability or instability. The
researchers then showed that substituting a stability-associated structural motif for an instability motif
significantly increased peptide stability, and vice-versa.
The stability of a peptide within the cell can significantly affect how much peptide is available to be loaded onto MHC Class I molecules
and displayed on the cell surface. The authors found that several known HIV mutations significantly reduced peptide stability - one common
mutation virtually abolished the cell-killing action of CD8 T cells. The Microsoft team members have developed a model to predict the
probable stability of specific HIV peptides, but more research is needed to determine how variations in stability affect the
presentation of the peptide segments called epitopes to CD8 cells and whether changes in peptide stability lead to a more
efficient immune response.
"Efforts to develop T-cell-based vaccines need to focus on producing epitopes that elicit the most protective response," says
Le Gall, an assistant professor of Medicine at Harvard Medical School. "Modulating peptide stability offers a unique way of
regulating epitope presentation in favor of producing the most effective defence against HIV."
Additional co-authors of the Journal of Clinical Investigation report are lead author Estibaliz Lazaro, ,MD; Pamela Stamegna;
Shao Chong Zhang, PhD; Pauline Gourdain, PhD; Nicole Y. Lai; Mei Zhang and Sergio A. Martinez, all of the Ragon Institute. The study was
supported by grants from the Bill and Melinda Gates Foundation and the National Institute of Allergy and Infectious Disease.
The Ragon Institute of MGH, MIT and Harvard was established in 2009 with a gift from the Philip T. and Susan M. Ragon Foundation,
creating a collaborative scientific mission among these institutions to harness the immune system to combat and cure human
diseases. The primary initial focus of the institute is to contribute to the development of an effective AIDS vaccine.
Administratively based at Massachusetts General Hospital, the Ragon Institute draws scientists and engineers from
diverse backgrounds and areas of expertise across the Harvard and MIT communities and throughout the world,
in order to apply the full arsenal of scientific knowledge to understanding mechanisms of immune control
and immune failure and to apply these advances to directly benefit patients.
Contact: Sarah Dionne
Massachusetts General Hospital