News From The Journal Of Clinical Investigation: May 9, 2011
Key to the success of vaccines that provide protection from infection with viruses is their ability to stimulate immune cells known as CD8+ T cells. By analyzing protein fragments (peptides) derived from HIV, a team of researchers, led by Sylvie Le Gall, at Harvard Medical School, Boston, has now generated data that suggest new ways to modify the CD8+ T cell-stimulating components of a vaccine such that they trigger a more effective protective response.
CD8+ T cells are stimulated to respond to an invading virus when they see viral peptides bound to a cell surface protein complex known as MHC-I. The team analyzed the repertoire of HIV-derived peptides inside primary human cells and found that they persisted for different lengths of time before being degraded (i.e., showed different levels of stability). The sequence of the peptide determined its stability and this in turn determined how effectively it stimulated CD8+ T cells. Further analysis identified ways to modulate the stability of a peptide such that it enhanced CD8+ T cell-recognition and activity, providing a potential new approach to designing the CD8+ T cell-stimulating components of a vaccine.
TITLE: Variable HIV peptide stability in human cytosol is critical to epitope presentation and immune escape
TUMOR IMMUNOLOGY: Immune cells in tumors too exhausted to work
Immune cells known as CD8+ T cells are key components of the antitumor immune response. A team of researchers, led by Daniel Speiser, at the Ludwig Institute for Cancer Research, Lausanne, Switzerland, has now generated a gene expression profile of CD8+ T cells in the blood of patients with melanoma (the most dangerous form of skin cancer) and CD8+ T cells in the distant tumors of individuals with melanoma. Surprisingly, the cells in the blood have the characteristics of functional effector cells, whereas the cells in the tumors have the characteristics of exhausted cells that are functionally impaired. The molecular mechanisms underlying the functional impairment of the exhausted CD8+ T cells could provide new targets for anticancer therapies.
TITLE: Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients
CARDIOLOGY: The protein JMJD2A reprograms the heart for failure
Heart failure is a leading cause of death in Western countries. It is often preceded by a condition known as cardiac hypertrophy (thickening of the walls of the heart). Cardiac hypertrophy and heart failure are accompanied by a change in the genes expressed in the heart muscle cells and it is thought that understanding the mechanisms underlying this genetic reprogramming could provide new targets for drugs to treat these conditions. In this context, a team of researchers, led by Zhi-Ping Liu, at the University of Texas Southwestern Medical Center, Dallas, has now found that the protein JMJD2A promotes the genetic reprogramming that supports cardiac hypertrophy in mouse models of the human condition. Consistent with the mouse data, expression of JMJD2A was found to be upregulated in human patients with hypertrophic cardiomyopathy, leading the authors to suggest that the protein could be a potential target for drugs that treat cardiac hypertrophy and heart failure.
TITLE: The histone trimethyllysine demethylase JMJD2A promotes cardiac hypertrophy in response to hypertrophic stimuli in mice
HIV/AIDS: Distinguishing progression to AIDS from nonprogression in HIV-1 infected individuals
The rate at which individuals infected with HIV-1 progress to AIDS differs dramatically: rapid progressors develop AIDS within 2 years of infection; typical progressors develop AIDS in approximately 10 years; while a small fraction of individuals remain asymptomatic despite high levels of virus being detectable in their blood. A team of researchers - led by Javier Martinez-Picado, at the AIDS Research Institute, Barcelona, Spain, and Amalio Telenti, at University Hospital and University of Lausanne, Lausanne, Switzerland - has now profiled the genes expressed differentially in individuals who progress rapidly to AIDS and those that remain asymptomatic in an attempt to understand more deeply the factors that determine progression to AIDS.
The team defined gene expression profiles characteristic of the two groups of patients and found that they were similar to those obtained from monkeys infected with SIV (the monkey equivalent of HIV) that do and do not develop AIDS-like disease. In addition, a short list of genes relevant to understanding progression to AIDS was identified. These data provide insight into two poorly understood clinical patterns of disease progression that have been minimally studied in the past. They also provide a springboard for future research, as they indicate that studying SIV infection of different species of monkey that do or do not develop AIDS-like disease provides a good model to understand HIV-1 progression to AIDS.
TITLE: Comparative transcriptomics of extreme phenotypes of human HIV-1 infection and SIV infection in sooty mangabey and rhesus macaque
Journal of Clinical Investigation