Abstract
During HIV/SIV infection, the upregulation of immune checkpoint (IC) markers, programmed cell death protein-1 (PD-1), cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), T cell immunoglobulin and ITIM domain (TIGIT), lymphocyte-activation gene-3 (LAG-3), T cell immunoglobulin and mucin domain-3 (Tim-3), CD160, 2B4 (CD244), and V-domain Ig suppressor of T cell activation (VISTA), can lead to chronic T cell exhaustion. These ICs play predominant roles in regulating the progression of HIV/SIV infection by mediating T cell responses as well as enriching latent viral reservoirs. It has been demonstrated that enhanced expression of ICs on CD4+ and CD8+ T cells could inhibit cell proliferation and cytokine production. Overexpression of ICs on CD4+ T cells could also format and prolong HIV/SIV persistence. IC blockers have shown promising clinical results in HIV therapy, implying that targeting ICs may optimize antiretroviral therapy in the context of HIV suppression. Here, we systematically review the expression profile, biological regulation, and therapeutic efficacy of targeted immune checkpoints in HIV/SIV infection.
Highlights
T cell exhaustion due to constant antigen stimulation results in chronic cellular dysfunction
How increasing immune checkpoint (IC) markers maintains T cell dysfunction and exhaustion has been extensively investigated in cancer [5,6]; by contrast, the mechanism of how IC markers on T cells affect the disease progression in viral infections, in human immunodeficiency virus (HIV), requires more exploration [2,5,7]
The in vitro response of HIV-specific CD8+ T cells was better restored via blockade of PD1/PD-L1 synergizing with T cell immunoglobulin and immune receptor tyrosine-based inhibitory motif (ITIM) domain (TIGIT)/CD155, 2B4/CD48, T cell immunoglobulin and mucin domain-3 (Tim-3)/galectin-9, or BTLA/herpes virus entry mediator (HVEM) as compared with that from single blockade of PD-1/PD-L1 [30,32,46,52]
Summary
T cell exhaustion due to constant antigen stimulation results in chronic cellular dysfunction. It occurs during chronic infection or cancer when the same antigens repeatedly stimulate T cells, leading to a dysfunctional state [1]. During the process of chronic T cell exhaustion, T cell reactivation gradually declines along with enhanced expression of immune checkpoint (IC) markers. How increasing IC markers maintains T cell dysfunction and exhaustion has been extensively investigated in cancer [5,6]; by contrast, the mechanism of how IC markers on T cells affect the disease progression in viral infections, in human immunodeficiency virus (HIV), requires more exploration [2,5,7]. We systematically compared the expression of T cell checkpoint markers with the stage of HIV infection to assess their potential as therapeutic targets
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