Membrane cofactor protein (CD46) and Heparan sulfate proteoglycan (HSPG) (CD46/HSPG)

CD46 (Membrane Cofactor Protein) and Heparan Sulfate Proteoglycans (HSPGs) are cell-surface molecules that function as primary receptors and co-receptors for the entry of various viral vectors into CD34+ hematopoietic stem and progenitor cells (HSPCs) (UniProt P15529, PubMed 15141011). CD46 is a type I transmembrane glycoprotein that normally protects cells from complement-mediated lysis by acting as a cofactor for Factor I (UniProt P15529). HSPGs are glycoproteins containing heparan sulfate chains that facilitate initial viral attachment through electrostatic interactions (PubMed 15141011). In the context of gene therapy, these receptors are targeted by B-group adenoviruses, such as Ad35, to deliver genetic payloads to the hematopoietic system (PubMed 21106747). Once the vector enters the cell, the genetic material is transported to the nucleus where it interacts with host chromatin for either stable integration or episomal maintenance (PubMed 28258190). This interaction with host chromatin is a critical step for long-term transgene expression in therapeutic applications. The efficiency of this process is highly dependent on the expression levels of CD46 and HSPGs on the surface of CD34+ cells. Therapeutic challenges include potential insertional mutagenesis and the host's immune response to the viral capsid. Drugs interacting with this system include engineered adenoviral and lentiviral vectors used in ex vivo gene therapy for blood disorders.

Other names

Membrane cofactor proteinMCPCD46HSPGHeparan sulfate proteoglycanCD34+ cell receptors

Viral attachment to CD46 and HSPG receptors on CD34+ cells, followed by endocytosis and nuclear translocation for interaction with host chromatin to facilitate gene delivery.