Alternative components of the cellular immunity to SARS-COV-2 and HIV infection: beyond the classical CTL
- Autores: Luis Romero Martin
- Directores de la Tesis: Alexandre Olvera van der Stoep (dir. tes.), Christian Brander (codir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2022
- Idioma: inglés
- Tribunal Calificador de la Tesis: M. Eloisa Yuste Herranz (presid.), Meritxell Genescà i Ferrer (secret.), Jörg Seebach (voc.)
- Programa de doctorado: Programa de Doctorado en Inmunología Avanzada por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Two viral agents, human immunodeficiency virus (HIV) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), are responsible for two biggest pandemics that have hit the human population over the last few years, causing more than 36 HIV- and 6 million SARS-CoV2-associated deaths, respectively. Although AIDS and COVID-19 associated mortality has been dramatically reduced by combined antiretroviral therapy for HIV and vaccination against SARS-CoV-2, both have significant limitations. For HIV, antiretroviral therapy requires lifelong adherence and is linked to long-term side effects. For SARS-CoV-2, emerging variants have compromised herd immunity achieved by vaccination. In addition, global social and economic differences result in unequal access to those treatments. Understanding the underlying mechanisms of viral control will be essential in order to limit the further spread of these infections and develop novel preventive and therapeutic strategies.
Research on the immune response to infectious diseases has been focused on two important components of viral immunity, the elicitation of neutralizing antibodies and cytotoxic T cells (CTL). Other components of the cellular immune response have been less well investigated, including i) NK cells with innate antiviral properties and ii) alternatively polarized T-cells with effector functions beyond those of classical CTL.
In the present thesis, we aimed to provide a better understanding of cellular mechanisms that support HIV and SARS-CoV-2 viral control by comparing individuals with natural control of the infection and individuals with progressive disease. Chapters I and II are focused on the regulation of NK cell activity through the HLA-E/NKG2X axis. We observed common patterns between both infections, including elevated HLA-E expression, reduction of the circulating CD56bright NK cells population and impaired NK cell effector function in individuals with uncontrolled infections, suggesting a common mechanism of ineffective NK cell immunosurveillance linked to worse disease course in both infections. In Chapters III and IV, a novel flow cytometry approach allowed us to identify alternative CD4+ and CD8+ effector functions that might be missed otherwise. In particular, in Chapter III we identified Th1, Th17 and Treg CD4+ responses to SARS-CoV-2 N protein that distinguished individuals with mild or severe course of COVID-19. On the other hand, in Chapter IV we showed increased CD8+ Tfc-like responses in HIV controllers that were linked to humoral responses and to viral control.
Together, this work provides supports an important role of NK cell and alternative T-cell effector function in the natural control of HIV and SARS-CoV-2 infections. This could benefit future research towards new cellular-based immunotherapies in these and other viral infections, including the rescue of exhausted NK cells and the elicitation of specific T-cell profiles that could lead to better disease prognosis.
