Abstract
Immune checkpoints are several co-stimulatory and inhibitory pathways that regulate T cell immune responses. Most of the discoveries about immune checkpoints were made in cancer research where inhibitory immune checkpoints cause immune exhaustion and down-regulate anti-tumor responses. In addition to cancer, immune checkpoints are exploited in chronic infectious diseases. In human immunodeficiency virus (HIV) infection, the immune checkpoint molecule called programmed cell death protein 1 (PD-1) has been determined as being a major regulatory factor for T cell exhaustion. Recent studies with antibodies blocking either PD-1 ligand 1 (PD-L1) or PD-1 show not only promising results in the enhancement of HIV-specific immune responses but even in reducing the latent HIV reservoir. Apart from the therapeutic target for a functional cure of HIV-1, immune checkpoint molecules might be used as biomarkers for monitoring disease progression and therapeutic response. In this review, we will summarize and discuss the inhibitory immune checkpoint molecules PD-1, cytotoxic T-lymphocyte-associated protein 4 (CTLA4), lymphocyte-activation gene 3 (LAG3), and T cell immunoglobulin and mucin-domain-containing-3 (TIM3) as well as the co-stimulatory molecules CD40L and CD70, including their role in immunity, with a particular focus on HIV infection, and being potential targets for a functional HIV cure.
Highlights
Immune checkpoints are the regulators of T cell immune responses in response to invading pathogens or mutated/overexpressed self-antigens by regulating the balance between co-stimulatory and inhibitory signals [1,2]
The “two-signal hypothesis” suggests that T cell activation requires two signals: first, a complex consisting of an antigen (Ag) and major histocompatibility complex class II (MHC II) has to be recognized by the T cell antigen receptor; and second, additional co-stimulatory signals are needed for full activation of naïve T cells [4]
In the inhibitory PD-1 pathway, there was a substantial increase of PD-1 level in VP compared to EC and healthy controls (HC) (p < 0.001 in both the comparisons), but no difference was observed in PD-1 ligand 1 (PD-L1) between the groups, while there was a marginal decrease in PD-L2 in EC compared to VP (p = 0.016)
Summary
Immune checkpoints are the regulators of T cell immune responses in response to invading pathogens or mutated/overexpressed self-antigens by regulating the balance between co-stimulatory and inhibitory signals [1,2]. Many more receptors and ligands with a broad diversity in expression, structure, and function have been identified [6], rendering the two-signal hypothesis more complex This hypothesis has become more extended as co-inhibitory interactions have been characterized. Expression is induced after T cell activation providing a negative feedback loop to suppress activated T cell responses In that way, they modulate the duration and amplitude of a physiological immune response [1,2,6]. PD-1 limits the effector function of activated T cells in peripheral tissues As both co-stimulatory and co-inhibitory pathways consist of membrane-bound and soluble receptor-ligand pairs, they are promising drug targets in immune checkpoint therapy [1,7]. We will summarize and discuss selected immune checkpoints as prognostic biomarkers in HIV-1 infection, their role in immunity, and their potential as therapeutic targets for HIV eradication strategies
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