Towards improving cytotoxic T cell function in acute and chronic HIV-1 infection: tackling T cell exhaustion with the help of an in vitro exhaustion system

Abstract

T cell exhaustion is a state of immune dysfunction that is integral to the failure of cytotoxic T cells (CTLs) to control HIV-1 infection. Opposingly, highly functional HIV-specific CTLs are indicative of a good disease prognosis and often lifelong HIV-1 control. In this context, we hypothesize that directly tackling T cell exhaustion could constitute the missing link in the current landscape of HIV-1 cure strategies. Here, we aim to test a wide array of current and novel therapies aimed at reversing or preventing T cell exhaustion – such as checkpoint blockade, exogenous co-stimulation, transcription and epigenetic modulators, and CD4+ T cell help. While some of these therapeutic approaches are well established in other fields (e.g. cancer immunotherapy), little similar progress is achieved in the HIV-1 cure field. As an experimental basis, we will design, optimize, and validate an in vitro exhaustion system that can reliably generate bona fide exhausted HIV-specific CTLs, which will serve as testing platform for the abovementioned treatment strategies. Overall, this project has the potential to identify the best therapeutic approach(es) of tackling T cell exhaustion, which due to the high translational potential of the in vitro exhaustion system, will undoubtedly play an important role in future combinatorial HIV-1 cure strategies. Within the HIV-1 pandemic context, while other options aiming to replace the dysfunctional HIV-specific T cell response are being explored, improving the function of the exhausted T cells is the only research avenue that could lead to an effective, equitable, functional cure that would benefit the key populations most burdened by the HIV-1 pandemic.