© Institut Pasteur, Charles Dauguet
“HIV controller” patients represent less than 0.5% of all HIV-infected patients. They are proof that in some cases the human immune system can resist the harmful effects of HIV. They are able to maintain a population of functional auxiliary CD4+ T lymphocytes, whereas in patients that have gone on to develop the disease these cells are destroyed or rendered inactive. The patients enrolled in the HIV controller study were recruited from the ANRS CO21 CODEX cohort which includes the few HIV controller patients living in France. Scientists in the team led by Lisa Chakrabarti (Viral Pathogenesis Unit at the Institut Pasteur / Inserm unit U1108), in collaboration with Olivier Lambotte from Bicêtre Hospital, used the cohort to analyze the CD4+ T cell responses of these patients at molecular level.
To trigger the antiviral immune response, the CD4+ T cells of HIV controllers are able to produce numerous cytokines in response to very low doses of HIV antigens. The study revealed that these highly sensitive responses were due to the expression of particular T cell receptors (TCRs) on the surface of the controllers’ CD4+ T cells. In comparison, these TCRs were rarely found on the CD4+ T cells of patients receiving treatment. The scientists showed in particular that the TCRs targeting Gag293, the HIV capsid’s most highly conserved peptide, frequently shared the same sequence in HIV controllers. These “public” TCRs have a strong affinity for the Gag293 peptide, when this peptide is presented at the surface of immune cells. This strong affinity interaction ensures the highly sensitive detection of infected cells in HIV controllers. Transferring these TCRs to healthy cells reproduces the properties typically associated with CD4+ T cells in HIV controllers, with highly sensitive responses and the production of multiple cytokines.
Overall, this research shows that the expression of high-affinity TCRs is linked with spontaneous control of HIV infection. Immunotherapy strategies based on transferring or boosting these TCRs could help restore effective antiviral responses in patients that have gone on to develop the disease.
This research was funded by the ANRS (France REcherche Nord & Sud Sida-HIV Hépatites), the French National Research Agency (ANR), the Institut Pasteur, the Australian Research Council (ARC) and the Australian National Health and Medical Research Council (NHMRC).
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Public T cell receptors confer high-avidity CD4 responses to HIV controllers,
Journal of Clinical Investigation, April 25, 2016
Daniela Benati1, Moran Galperin1, Olivier Lambotte2,3,4,5, Stéphanie Gras6,7, Annick Lim8, Madhura Mukhopadhyay1, Alexandre Nouël1, Kristy-Anne Campbell6, Brigitte Lemercier8, Mathieu Claireaux1, Samia Hendou9, Pierre Lechat10, Pierre de Truchis11, Faroudy Boufassa9, Jamie Rossjohn6,7,12, Jean-François Delfraissy2,3,4, Fernando Arenzana-Seisdedos1,13, and Lisa A. Chakrabarti1, 13