Past project's Collaborators
Alexandre HARARI (to June 2013)
Selena VIGANO (to January 2013)
CD8 T-cells play a critical role in antiviral immunity. A large number of studies in both human and murine models of virus infection indicate that virus-specific CD8 T-cells are directly involved in the control of virus replication and thus may prevent or slow down the progression of virus-associated diseases. The aim of this project is to identify specific signatures associated with protective CD8 T-cell responses. We are investigating this issue in acute-treated HIV infection as well as in progressive and non-progressive chronic HIV infection.
Regarding HIV-1 infection, it has already been shown that some immunological characteristics such as some specific HLAs (e.g. HLA-B*27 and B*57), the number of anti-Gag CD8 T-cells specific responses and/or the functional profile are associated to better viral control. Other immunological players are involved in shaping the immunological responses: TCR avidity, exhaustion, survival/proliferation responses, maintenance of a functional CD4 T-cell population. Therefore, the complex relationship between TCR avidity, functional profile, level of exhaustion, and the ability to respond to survival/proliferation stimuli of HIV-1-specific CD8 T-cells in different cohorts of HIV-infected patients has been investigated.
T-cell functional avidity defined by the ability of CD8 T-cells to exert their function at limiting antigen concentrations is one parameter that is thought to be critical for virus control. We try to understand the relationship between CD8 T-cell functional avidity and virus control by studying samples from different cohorts of HIV infected individuals. CD8 T-cell responses generated early after HIV infection are compared to responses present at the chronic phase of the infection. The effects of antiretroviral treatment as well as treatment interruption on the CD8T-cell functional avidity were also investigated.
T-cell activation and effector functions are tightly regulated: CD8T-cells sample their surroundings and constantly integrate the numerous signals they receive through co-stimulatory as well as co-inhibitory molecules. Over-expression of co-inhibitory molecules such as PD-1, Tim3, CD160, Lag3 and 2B4, during viral chronic infections can lead to functional exhaustion, a loss of function of antigen-specific CD8T-cells. The dynamics of transcriptional expression as well as the function of regulatory (inhibitory) molecules during the different phases of HIV infection remains poorly understood. For an improved insight into the expression patterns and dynamics of expression, different cohorts of HIV infected individuals are compared. CD8T-cell responses initiated early after HIV infection are compared to responses present during chronic HIV infection. The influences of antiretroviral treatment as well as treatment interruption are also investigated. In addition, the relative influence of each co-inhibitory molecule on CD8 T-cell function remains poorly understood.