Projects

Cytotoxic follicular CD8+ T lymphocytes (TFCs) that express CXCR5 exhibit homing to the follicle of secondary lymphoid organs, the same location as CD4+ follicular helper T cells (TFH), one of the main reservoirs of HIV. For this reason, it has been proposed that TFCs could play an important role in HIV control by eliminating HIV-infected TFH cells and reducing the viral reservoir, one of the main challenges in achieving an HIV cure. In addition, TFCs can produce IL-4, IL-21 and express CD40L, giving them the potential to regulate B-cell responses, as TFH cells do.

We previously showed that TFC-like cells are more frequent in HIV controllers, and that the presence of TFC responses is linked to IgG isotype switching. Notably, these individuals also displayed higher-avidity IgG, as well as greater plasma neutralization and ADCC capacity, likely due to increased IgG isotype switching. Based on these data, we aim to investigate whether HIV vaccination is able to induce TFC responses that could play a regulatory role and be associated with HIV control.

To achieve our objective in 8FIGHT, we will use samples from two clinical trials that tested the HTI T-cell immunogen. HTI is one of the most promising HIV vaccine candidates to date and has demonstrated unprecedented infection control—40%—in a 24-week analytical treatment interruption. The samples used in 8FIGHT will come from two different clinical trials: one in which HTI will be tested in a prophylactic context (HIV-CORE-051) and another in a therapeutic context (BCN-03). We have unique access to longitudinal samples from these trials to study TFC responses after vaccination in HIV-negative individuals (HIV-CORE-051) and in people with HIV, combining T-cell (HTI) and B-cell (ConM SOSIP.v7 gp140) immunogens. Spectral flow cytometry and scRNA/TCRseq will be used to characterize TFC responses and assess their association with more functional cytotoxic T-cell responses and antibodies, and overall with improved HIV control. Furthermore, we will determine whether T and B cells act synergistically in HIV infection control through the generation of TFC responses. We will also develop a tonsil organoid system to examine the role of TFCs in the development of vaccine-specific cytotoxic T-cell responses.

Taken together, the results generated during the 8FIGHT project will provide crucial guidance for developing vaccine strategies capable of inducing TFC responses, which could be applied to achieve HIV remission.

Grant PID2023-149697OB-I00 funded by:

This HIVRAD program is developing an HIV vaccine that combines fusion peptide (FP)-targeting antibodies with follicle-homing helper and cytotoxic T cells. Using novel immunogens and adjuvants, we aim to elicit durable, high-quality T-cell responses that support broadly neutralizing antibodies. The program includes human and macaque studies and focuses on enhancing antibody-T cell cooperation, T-cell avidity, and protection against clade C HIV.

Behaviours and environment can change the way your genes work through a mechanism known as epigenetics, which act as a switch that turns genes on or off. The EU-funded EPIVINF project aims to understand how acute viral infections alter the epigenetic regulation of host genes that are governing immune control and neurological health. EPVINF will also investigate how pre-existing epigenetics impact immune response to vaccination. The study will focus on HIV and SARS-CoV-2 as two human viral pathogens that affect millions of people around the globe and share common features that require further research. The study also aims to identify the predisposing factors leading to specific clinical symptoms and how these could be employed as novel therapeutic targets.

Funding: This project has received funding from the European Union's Horizon Europe research and innovation programme under grant agreement No 101057548

Flow cytometry is a tool that measures cellular particles in a fluid stream with the aim of gathering information of clinical importance. It has found many uses in biomedicine, such as the analysis of immune cells to diagnose and monitor diseases. The current procedures applied for the measurement of lymphocytes —a type of immune cells— are descriptive. Consequently, these procedures do not evaluate the set of immune functions mediated by these cells, which are essential for the resolution of pathological processes.

This project has developed and patented a methodology called “Boosted Flow Cytometry” tool that captures a more diverse range of pathogen-specific T-cell responses. This has been applied to HIV, Mycobacterium Tuberculosis and SARS-CoV-2 infection, and responses have been detected that are overlooked with current procedures and that play a fundamental role in the management of these diseases.

The objective is to achieve clinical validation and establish a commercially viable diagnostic tool to better identify infections, predict disease course and monitor response to treatment and/or vaccination strategies.

Codi: 101046118