Caracterització funcional de limfòcits T en individus VIH+ amb pobra recuperació immunològica. Estudi dels mecanismes implicats en la resposta immunodiscordant al tractament antiretroviral

Abstract

Poor immune recovery after HAART observed in a proportion of HIV+ individuals has been associated with an altered cell maturation profile, elevated inflammation, accelerated senescence and immune hyperactivation. However, the impact that all of these alterations have on the T-cell functionality is unknown. Beside other mechanisms associated with the immunodiscordant response, it has been described that CMV infection contributes to an increased immune activation, although the role of the CMV-specific response among other immunological alterations related to immunodiscordant individuals is unknown. In addition, since apoptosis in CD4 T cells is highly associated with poor immune recovery, the autophagy process, which is involved in inflammation and cell death, may also contribute to the immunodiscordant response. Therefore, the objectives of this thesis were to determine (i) the functional level of the CD4 and CD8 T-cell compartments, (ii) the cellular and humoral immune response against CMV and (iii) the ability of CD4 T cells to activate autophagy in a group of virologically suppressed treated HIV+ individuals with favorable or unfavorable immune response. Our results show that immunodiscordant individuals maintain polyclonal and virus-specific cellular functionality as compared to immunoconcordant individuals or HIV-negative populations. Immunodiscordant individuals have a greater cellular and humoral CMV-specific response that would be driven by repeated asymptomatic reactivations over time. Decreased autophagy has also been observed in CD4 T cells from immunodiscordant individuals, and this fact may be contributing to the high activation and inflammation status of these individuals. Our results show that immunodiscordant individuals exhibit a conserved functional diversity and that the hyperactivation state observed in these individuals could be associated with a greater number of CMV reactivations and impaired autophagy in CD4 T cells, leading to a high CMV-specific immune response and driving the altered maturation profile and the increased risk of clinical progression observed in this group.

Date of Award	29 Jun 2017
Original language	Catalan
Supervisor	Julian Miguel Blanco Arbues (Director) & Cecilia Cabrera Navarro (Director)