HIV p17 enhances T cell proliferation by suppressing autophagy through the p17‐OLA1‐GSK3β axis under nutrient starvation

Abstract

Nutrient starvation is a common phenomenon that occurs during T cell activation. Upon pathogen infection, large amounts of immune cells migrate to infection sites, and antigen‐specific T cells are activated; this is followed by rapid proliferation through clonal expansion. The dramatic expansion of cells will commonly lead to nutrient shortage. Cellular autophagy is often upregulated as a way to sustain the body's energy requirements. During infection, human immunodeficiency virus (HIV) co‐opts a series of host cell metabolic pathways for replication. Several HIV proteins, such as Env, Nef, and Vpr, have already been reported as being involved in autophagy‐related processes. In this report, we identified that the HIV p17 protein acts as a major factor in suppressing the autophagic process in T cells, especially under glucose starvation condition. HIV p17 interacts with Obg‐like ATPase 1 (OLA1) and disrupts OLA1‐glycogen synthase kinase‐3 beta (GSK3β) complex, leading to GSK3β hyperactivation. Consequently, a prior proliferation of HIV‐infected T cells under glucose starvation will occur. The inhibition of autophagy also aids HIV replication by antagonizing the antiviral effect of autophagy. Our study shows a new cellular pathway that HIV can hijack for viral spreading by a prior proliferation of HIV‐loaded T cells and may provide new therapeutic targets for acquired immunodeficiency syndrome intervention.

OLA1 promotes colorectal cancer tumorigenesis by activation of HIF1α/CA9 axis

“…5 B). Our previous study showed that OLA1 directly interacted with GSK3β and inhibited its activity [ 21 , 22 ], which is also proved by other study [ 23 , 24 ]. Meanwhile, GSK3β can phosphorylate HIF1α and facilitate its degradation [ 25 ], which can explain why HIF1α decreased in OLA1-KO CRC cell lines.…”

HIV-1 Structural Proteins or Cell-Signaling Factors? That Is the Question!

“…The inhibition of apoptosis is not the only mechanism by which the HIV-1 matrix protein alters the biological activities of immune cells, given that it also acts as a major factor in suppressing the autophagic process in immune T cells, especially under glucose starvation conditions. According to Lu et al, HIV p17 interacts with Obg-like ATPase 1 (OLA1), resulting in the hyperactivation of the downstream effector glycogen synthase kinase-3 beta (GSK3β), a critical regulator in the T cell autophagic process ( Figure 3 b) [ 48 ].…”

“…Primary human monocytes AP-1 transcription factor activation Inflammation (MCP-1 secretion) [46] Plasmacytoid dendritic cells (pDCs) Down-regulation of nucleophosmin, heat shock protein 70 and eukaryotic translation initiation factor 5B Cell survival, resistance to apoptotic stimuli, increased proliferation [47] Human T cells Obg-like ATPase 1 (OLA1) and hyperactivation of glycogen synthase kinase-3 beta (GSK3β) Autophagy inhibition [48] Human B cells PTEN/PI3K/Akt pathway activation Apoptosis inhibition, cell cycle promotion and cancer progression [18,49] Breast cancer cells line (MDA-MB231) ERK/MAPK pathway activation Enhance cell migration and invasiveness [50] Human endothelial cells (ECs) PI3K/Akt and MEK/ERK1/2 Angiogenic activity [51] Primary human lymph nodederived lymphoid endothelial cells (LN-LECs) PI3K/Akt and MEK/ERK1/2 Lymphangiogenic activity [52] p24 Dendritic cells (DCs) STAT1 and IRF3 pathways activation Inflammation (INF production) [53] Leukemic monocyte cell line (THP-1)…”