Abstract
Objective:The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in balancing immunity and host immunopathology. During chronic HIV/SIV infection, there is persistent immune activation accompanied by accumulation of virus-specific cells with terminally differentiated phenotypes and expression of regulatory receptors such as PD1. These observations led us to hypothesize that the PD1/PD-L1 pathway contributes to the functional dysregulation and ineffective viral control, and its blockade may be a potential immunotherapeutic target.Methods:Lymph node biopsies from HIV-infected patients (n = 23) were studied for expression of PD1 and PD-L1. In addition, we assessed the safety and biological activity of a human anti-PD-L1 antibody (Avelumab) in chronically SIV-infected rhesus macaques.Results:PD-L1 expression was observed in cells with myloid/macrophage morphology in HIV-infected lymph nodes. Administration of anti-PD-L1 was well tolerated, and no changes in body weights, hematologic, or chemistry parameters were observed during the study. Blockade of PD-L1 led to a trend of transient viral control after discontinuation of treatment.Conclusion:Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. Overall, these data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans.
Highlights
The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in regulating immune responses against pathogens by controlling the balance between immunity and limiting tissue damage
Administration of anti-PD-L1 in chronic SIV-infected rhesus macaques was well tolerated. These data warrant further investigation to assess the efficacy of anti-PD-L1 treatment on viral control in chronic SIV infection as a prelude to such therapy in humans
Expression of programed death-1/programed death-ligand 1 in human lymph nodes from patients with HIV infection During HIV/SIV infection, there is an increase in PD1 expression on CD4þ and CD8þ T cells in peripheral blood [8,10]
Summary
The programed death-1 (PD1)/programed death-ligand 1 (PD-L1) pathway plays a critical role in regulating immune responses against pathogens by controlling the balance between immunity and limiting tissue damage. In-vitro and in-vivo studies of HIV/ SIV infection have shown that blockade of PD1 is associated with enhanced virus-specific responses and improved viral control [12,13,14,15]. These observations support the hypothesis that PD1/PD-L1 interactions contribute to the functional dysregulation, exhaustion, and ineffective viral control [8,16,17,18]. This evidence suggests that the PD1/PD-L1 pathway may be a potential target for immune intervention in patients with HIV infection
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