Human Immunodeficiency Virus Type 1 Nef Induces Programmed Death 1 Expression through a p38 Mitogen-Activated Protein Kinase-Dependent Mechanism

Abstract

Chronic viral infection is characterized by the functional impairment of virus-specific T-cell responses.Recent evidence has suggested that the inhibitory receptor programmed death 1 (PD-1) is specifically upregulated on antigen-specific T cells during various chronic viral infections. Indeed, it has been reported that human immunodeficiency virus (HIV)-specific T cells express elevated levels of PD-1 and that this expression correlates with the viral load and inversely with CD4 ؉ T-cell counts. More importantly, antibody blockade of the PD-1/PD-L1 pathway was sufficient to both increase and stimulate virus-specific T-cell proliferation and cytokine production. However, the mechanisms that mediate HIV-induced PD-1 upregulation are not known. Here, we provide evidence that the HIV type 1 (HIV-1) accessory protein Nef can transcriptionally induce the expression of PD-1 during infection in vitro. Nef-induced PD-1 upregulation requires its proline-rich motif and the activation of the downstream kinase p38. Further, inhibition of Nef activity by p38 MAPK inhibitor effectively blocked PD-1 upregulation, suggesting that p38 MAPK activation is an important initiating event in Nef-mediated PD-1 expression in HIV-1-infected cells. These data demonstrate an important signaling event of Nef in HIV-1 pathogenesis.

Antigen-Independent Induction of Tim-3 Expression on Human T Cells by the Common γ-Chain Cytokines IL-2, IL-7, IL-15, and IL-21 Is Associated with Proliferation and Is Dependent on the Phosphoinositide 3-Kinase Pathway

“…Elevated Tim-3 levels on T cells could potentially negatively impact the immune system's response toward all pathogens. Indeed, another exhaustion marker, PD-1, which exhibits characteristics on T cells similar to those that express Tim-3 in the acute and chronic phases of HIV-1 infection (3, 26-28) was reported to be upregulated by the HIV-1 protein Nef (16). Thus, we determined the effect of in vitro HIV-1 infection on CD4 + T cells' PD-1 or Tim-3 expression up to 72 h postinfection (Fig.…”

“…To elucidate the pathway behind Tim-3 upregulation in chronic HIV-1 infection, we first postulated that a viral gene product could be driving Tim-3 expression. Indeed, HIV-1 protein Nef was shown to directly induce the expression of another exhaustion marker, PD-1, on the surface of HIV-1-infected CD4 + T cells (16). We hypothesized that viral factors, such as HIV-1 gp120, found in the serum of infected individuals, could upregulate Tim-3 by binding to certain receptors on the surface of T cells, such as the CD4 receptor, or that soluble HIV-1 Tat diffusing into T cells to drive HIV-1 replication could also be indirectly responsible (17).…”

HBcAg induces PD-1 upregulation on CD4+T cells through activation of JNK, ERK and PI3K/AKT pathways in chronic hepatitis-B-infected patients

“…One recent study showed Nef to be associated with HIV viral antigens to specifically increase PD-1 expression through a p38 MAPK-dependent mechanism. 41 HBcAg is the major component encoded by HBV DNA, so we focused on the correlation between HBcAg and PD-1 upregulation. In the study on lymphoma, 56 PD-L1 expression was shown to be dependent on the ERK and p38 MAPK signaling pathways.…”

PD-1 and CTLA-4 Mediated Inhibitory Signaling for T cell Exhaustion during Chronic Viral Infections

“…It has been reported that Nef induces PD-1 transcription, while specific inhibitor against p38/MAPK inhibits Nef activity and effectively blocks PD-1 upregulation. This suggests that Nef-mediated PD-1 expression is dependent on p38/MAPK activation [19]. In HBV infected patients, PD-1 expression is increased on CD4 + T cells from peripheral blood compared to those in healthy volunteers.…”