Regulatory T cells (Tregs): A major immune checkpoint to consider in combinatorial therapeutic HIV-1 vaccines

Abstract

The field of immunotherapeutics is living an exceptional time as new antibodies that take brakes off T-cells and unleash them on tumours are being approved by the US-Food and Drug Administration (FDA). For the design and development of an HIV-1 therapeutic-vaccine, one would need preferably to shift the balance T-effectors/T-regulatory cells (Teff/Tregs) towards effectors to improve vaccine-specific immune-responses. Given the success with the new immune-checkpoint-blockers (ICB), it is an appropriate time for HIV-1 field to seize this opportunity and develop new therapeutic vaccine-strategies that take into consideration ICB and other immunomodulators such as cytokines. While the vaccine is important to stimulate HIV-1-specific T-cell responses, cytokines will support the expansion of the stimulated virus-specific T-cells and ICB will reverse exhaustion and unchain cytotoxic T-cells. In this commentary, we will spotlight Tregs as another major brake for T-cell immunity and address the main stumbling-blocks that often blurs HIV-1-specific-Tregs status with regards to their role (beneficial or detrimental) and we will recall some proof-of-concept studies where therapeutic immunization skewed the HIV-1-specific response from Tregs to Teffs which impacts on the magnitude of viral replication. We will also suggest some strategies to shift the balance towards Teffs and potentiate HIV-1-specific immune-responses.

Keywords: CD39; HIV-1-therapeutic vaccine; Immune checkpoint blockers, cytokines; OX40; Treg modulation; combinatorial strategies.

Figure 1.

To potentiate antigen-specific immune responses in the context of HIV-1-therapeutic vaccine. T cell breath and magnitude will be improved by using peptides-loaded-DC (1). Immune response is regulated by inhibitory and co-stimulatory signals mediated by immune-checkpoint. These signals can be modulated using IC blockers (ICB) in order to amplify HIV-1-specific responses and to prevent cell exhaustion (2). T cell proliferation can be boosted using cytokines (IL-2, IL-7 or IL-15) in combination with therapeutic vaccines in order to promote antigen-specific T cell survival and expansion (3). It is important to block Tregs expansion and shift the balance toward effectors (4). To this end, cytokines, i.e IL-7 will modulate Tregs phenotype and function towards and potentiates Teffs differentiation (4a). Vaccines could be combined with other molecules that will suppress Treg-activity (c-Rel inhibitor, anti-CD39) (4b). Antibodies, i.e anti-CD25 (Daclizumab), Fc-optimized anti-CD25, anti-CD127 or anti-CD39 may be used to efficiently deplete Tregs (4c).