Browsing by Author "Liu, Michael K. P."

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Increased memory differentiation is associated with decreased polyfunctionality for HIV but not for CMV-specific CD8+ T cells.
(American Association of Immunologists., 2012) Riou, Catherine.; Treurnicht, Florette K.; Abrahams, Melissa-Rose.; Mlisana, Koleka Patience.; Liu, Michael K. P.; Goonetilleke, Nilu.; Koup, Richard A.; Roederer, Mario.; Abdool Karim, Salim Safurdeen.; De Bruyn, Guy.; Williamson, Carolyn.; Gray, Clive M.; Burgers, Wendy A.
The generation of polyfunctional CD8+ T cells, in response to vaccination or natural infection, has been associated with improved protective immunity. However, it is unclear whether the maintenance of polyfunctionality is related to particular cellular phenotypic characteristics. To determine whether the cytokine expression profile is linked to the memory differentiation stage, we analyzed the degree of polyfunctionality of HIV-specific CD8+ T cells within different memory subpopulations in 20 antiretroviral therapy-naive HIV-1–infected individuals at ∼34 wk postinfection. These profiles were compared with CMV-specific CD8+ T cell responses in HIV-uninfected control subjects and in individuals chronically infected with HIV. Our results showed that the polyfunctional abilities of HIV-specific CD8+ T cells differed according to their memory phenotype. Early-differentiated cells (CD45RO+CD27+) exhibited a higher proportion of cells positive for three or four functions (p < 0.001), and a lower proportion of monofunctional cells (p < 0.001) compared with terminally differentiated (TD; CD45RO-CD27-) HIV-specific CD8+ T cells. The majority of TD HIV-specific CD8+ T cells were monofunctional (median 69% [interquartile range: 57–83]), producing predominantly CD107a or MIP1b. Moreover, proportions of HIV-specific monofunctional CD8+ T cells positively associated with proportions of TD HIV-specific CD8+ T cells (p = 0.019, r = 0.54). In contrast, CMV-specific CD8+ T cell polyfunctional capacities were similar across all memory subpopulations, with terminally and early-differentiated cells endowed with comparable polyfunctionality. Overall, these data show that the polyfunctional abilities of HIV-specific CD8+ T cells are influenced by the stage of memory differentiation, which is not the case for CMV-specific responses.
Vertical T cell immunodominance and epitope entropy determine HIV-1 escape.
(American Society for Clinical Investigation., 2012) Liu, Michael K. P.; Hawkins, Natalie.; Ritchie, Adam J.; Ganusov, Vitaly.; Whale, Victoria.; Brackenridge, Simon.; Li, Hui.; Pavlicek, Jeffrey W.; Cai, Fangping.; Abrahams, Melissa-Rose.; Treurnicht, Florette K.; Hraber, Peter.; Riou, Catherine.; Gray, Clive M.; Ferrari, Guido.; Tanner, Rachel.; Ping, Li-Hua.; Anderson, Jeffrey A.; Swanstrom, Ronald.; Cohen, Myron S.; Abdool Karim, Salim Safurdeen.; Haynes, Barton F.; Borrow, Persephone.; Perelson, Alan S.; Shaw, George M.; Hahn, Beatrice H.; Williamson, Carolyn.; Korber, Bette T. M.; Gao, Feng.; Self, Steven G.; McMichael, Andrew.; Goonetilleke, Nilu.
HIV-1 accumulates mutations in and around reactive epitopes to escape recognition and killing by CD8+ T cells. Measurements of HIV-1 time to escape should therefore provide information on which parameters are most important for T cell–mediated in vivo control of HIV-1. Primary HIV-1–specific T cell responses were fully mapped in 17 individuals, and the time to virus escape, which ranged from days to years, was measured for each epitope. While higher magnitude of an individual T cell response was associated with more rapid escape, the most significant T cell measure was its relative immunodominance measured in acute infection. This identified subject-level or “vertical” immunodominance as the primary determinant of in vivo CD8+ T cell pressure in HIV-1 infection. Conversely, escape was slowed significantly by lower population variability, or entropy, of the epitope targeted. Immunodominance and epitope entropy combined to explain half of all the variability in time to escape. These data explain how CD8+ T cells can exert significant and sustained HIV-1 pressure even when escape is very slow and that within an individual, the impacts of other T cell factors on HIV-1 escape should be considered in the context of immunodominance.