Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti–programed death-ligand 1 (Avelumab)

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 chronic viral infections such as HIV/SIV, hepatitis B virus, and hepatitis C virus, failure to completely eliminate virus leads to a sustained inflammatory/activated environment accompanied by the accumulation of T cells with diminished in-vitro effector function, ‘exhausted T cells’ [1–3]. In HIV/SIV infections, chronic T-cell immune activation is reflected by increased expression of a variety of immunomodulatory receptors including, PD1, CTLA-4, LAG3, CD244/2B4, CD160, and others [4–11]. 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 [12–15]. These observations support the hypothesis that PD1/PD-L1 interactions contribute to the functional dysregulation, exhaustion, and ineffective viral control [8,16–18]. This evidence suggests that the PD1/PD-L1 pathway may be a potential target for immune intervention in patients with HIV infection. PD1 is expressed upon activation by T, B, and natural killer (NK) cells, dendritic cells, and activated monocytes, although its function in the latter is not well defined [19]. PD1 interacts with two ligands, PD-L1 and PD-L2. PD-L1 is mainly expressed by hematopoietic cells, such as T and B cells, dendritic cells, macrophages, and some epithelial cells (lung and vascular endothelium) [19–22]. In contrast, PD-L2 expression is more restricted and is inducible in dendritic cells, macrophages, bone marrow–derived mast cells, and some B cells [19,23]. PD1 interaction with its ligands regulates T cell receptor signaling by distinct mechanisms leading to diminished effector function, including cytokine secretion, proliferation, cytotoxicity, motility, and cell survival [24–27]. In addition, engagement of PD1 with its ligands induces reverse signaling on PD-L1/PD-L2 expressing cells [19,28,29]. Lymphoid organs are the primary targets of HIV/SIV infection [30–33]. In HIV/SIV-infected lymph nodes, the germinal center (GC) T follicular helper CD4+ T cells (CD4+ Tfh) exhibit higher expression of PD1 compared with extra follicular CD4+ and CD8+ T cells. PD-L1 expression has been observed inside and outside germinal centers [34,35]. To obtain further insights as to the potential role of PD-L1 blockade in the treatment of HIV infection, we analyzed the expression of PD1 and PD-L1 in human lymph node from 23 patients infected with HIV. In addition, we have evaluated the safety and the effect on SIV viral load of in-vivo PD1/PD-L1 blockade using a fully human anti-PD-L1 mAb (MSB0010718C, Avelumab, EMD-Serono, Inc., Rockland, Massachusetts, USA) in rhesus (Rh) macaques chronically infected with SIVmac239, that had previously received IL-15 [36].