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  Reported by jules Levin
CROI 2018 March 4-7 Boston
Christian Deo T. Deguit1, Michelle A. Hough2, Rebecca Hoh2, Melissa Krone2, Christopher D. Pilcher2, Jeffrey N. Martin2, Steven G. Deeks2, Joseph M. McCune2, Peter W. Hunt2, Rachel L. Rutishauser2
1University of the Philippines Manila, Manila, Philippines,2University of California San Francisco, San Francisco, CA, USA
program abstract
Antigen-specific CD8 T cell exhaustion, marked by poor proliferative and effector capacity, occurs in HIV disease and other settings of persistent antigen stimulation such as other chronic infections and cancer. Distinct metabolic features, such as increased mitochondrial mass (MM), decreased mitochondrial membrane potential (MMP), and increased reactive oxygen species (ROS) content are related to greater antigen-specific exhaustion. Yet, the contribution of these pathways to HIV-specific CD8 T cell exhaustion has not been explored. We hypothesized that HIV-specific CD8 T cells with features of exhaustion (e.g. cells from viremic individuals, with increased PD-1 expression and/or with poor proliferative capacity) have a distinct mitochondrial state that is linked to their dysfunction.
Cryopreserved PBMC samples were obtained from 20 HIV-infected individuals in 3 clinical groups: Viremic (VL>2000 copies/mL, ART-naïve, n=6), ART-suppressed (VL<40 copies/mL on stable ART for a median of 11 years, n=8), and Controllers (VL<40 copies/mL, n=6). Using flow cytometry, we evaluated the MM, MMP, and ROS content of MHC Class I tetramer+ HIV-specific CD8 T cells in these individuals. We also characterized the tetramer+ cell expression of co-inhibitory receptors, effector molecules, and proliferative capacity after 6-day in vitro peptide stimulation.
Although the mitochondrial state of HIV-specific tetramer+ CD8 T cells did not vary by clinical group, we found significant differences within tetramer+ subsets identified by PD-1, CD127, and/or CD45RA expression. Total tetramer+ cells expressing PD-1 have greater ROS content (p<0.001) and MM (p=0.007) and lower MMP (p=0.027) than PD-1- cells, but for tetramer+ PD-1+ CD45RA- cells, CD127 expression was associated with decreased ROS content (p=0.033), MM (p<0.001), and MMP (p=0.024). The MM of the tetramer+ cells was also found to negatively correlate with their capacity to proliferate after stimulation (r=-0.681, p=0.013), even after adjustment for %PD-1+ or %CD127+ tetramer+ CD8 T cells (p≤0.025) or for clinical group (p=0.046).
These findings suggest that PD-1+ HIV-specific cells have a state of metabolic stress, which is associated with poor proliferative capacity, that may be attenuated by CD127 expression. While it remains unclear if metabolic stress is a cause or consequence of PD-1 or CD127 expression, these findings highlight a potential role of metabolic stress in HIV-specific CD8 T cell exhaustion.








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