Intracellular accumulation of cell cycle regulatory proteins and nucleolin re-localization are associated with pre-lethal ultrastructural lesions in circulating T lymphocytes: The HIV-induced cell cycle dysregulation revisited

Abstract

The HIV-induced demise of CD4-T cells is thought to be a result of the execution of genetically programmed cell death that occurs in lymphoid tissue, where many resident T cells are chronically hyperactivated. Since HIV-induced alterations of cell cycle control has been often indicated as prominent mechanism of immune hyper activation and cause of apoptotic death, the signal pathway involved in cell cycle dysregulation of T lymphocytes from HIV infected patients was extensively studied. Here, we also demonstrate that circulating T lymphocytes leave lymphoid tissues with diffused regressive lesions (vacuolization, blebbing, nuclear evanescence and organelle swelling). Equally diffused are biochemical anomalies that accompany the overall disarrangement of cell structure, particularly the fragmentation and diffusion into the cytoplasm of C23/nucleolin, the intracellular accumulation of short lived regulatory proteins and the decrease in expression of membrane proteins. All this is something more than a cell cycle-related remodelling of cell morphology and biochemical mechanisms, and rather recalls a necrotic/oncotic cell damage. Since these changes are associated with adaptive mechanisms to hypoxia, we give evidence for alteration of cell cycle control developing in conditions of scarce energy supply.

The Cytosolic Protein G0S2 Maintains Quiescence in Hematopoietic Stem Cells

“…The ring-like extranuclear distribution of nucleolin was previously described in nonproliferating leukemic cells of chronic lymphocytic leukemia patients [24]. Similarly, T lymphocytes from HIV-positive patients show a cytosolic expression of nucleolin that is not observed in healthy donors [52]; however, this subcellular localization is associated with apoptosis in CD4 T cells. Our work is the first report to describe a mechanism for the subcellular redistribution of nucleolin and the association of G0S2 with proliferation in hematopoietic cells.…”

Nucleolin stabilizes G-quadruplex structures folded by the LTR promoter and silences HIV-1 viral transcription

“…In addition, NCL can bind HIV-1 Gag protein to promote viral budding ( 64 ), or to enhance Gag release ( 65 ). Further, NCL involvement in the viral life cycle has been corroborated also by evidence that HIV infection modifies the protein's cellular distribution ( 66 , 67 ). The activities performed by NCL in other viruses have also been described in a number of recent papers ( 68 – 72 ).…”

“…In both cases, NCL binding to cellular proteins is a transient response to stress stimuli. These observations prompt the intriguing possibility that when NCL is redistributed by the cellular stress imposed by HIV infection ( 66 , 67 ), it may be then recruited by the G4 structure of viral promoter to transiently down-regulate HIV transcription and enable the virus to prepare for subsequent efficient transcription, when viral proteins, such as Tat, take over. Alternatively, this interaction may be required as a first switch to viral latency and to recruit proteins that further consolidate latency.…”

Vitamin D Status Modulates Inflammatory Response in HIV+ Subjects: Evidence for Involvement of Autophagy and TG2 Expression in PBMC

“…Decreases in CD4+ T lymphocytes were shown as the most relevant change in monitoring pathological conditions associated with HIV [ 16 , 17 ]. Although programmed cell death through apoptosis has been the most commonly described mechanism for lymphocyte depletion, more recent results give evidence of the occurrence of dysfunctional autophagy, which can be associated with both innate and adaptive immunity.…”