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Abstract
Alzheimer's disease is characterized by deposition of beta-amyloid peptide (Abeta) into plaques in the brain, leading to neuronal toxicity and dementia. Human immunodeficiency virus type 1 (HIV-1) infection of the central nervous system can also cause a dementia, and amyloid deposition in the central nervous system is significantly higher in HIV-1-infected individuals compared with uninfected controls. Here we report that Abeta fibrils stimulated, by 5-20-fold, infection of target cells expressing CD4 and an appropriate coreceptor by multiple HIV-1 isolates but did not permit infection of cells lacking these receptors. Abeta enhanced infection at the stage of virus attachment or entry into the cell. Abeta fibrils also stimulated infection by amphotrophic Moloney leukemia virus, herpes simplex virus, and viruses pseudotyped with the envelope glycoprotein of vesicular stomatitis virus. Other synthetic fibril-forming peptides similarly enhanced viral infection and may be useful in gene delivery applications utilizing retroviral vectors. These data suggest that Abeta deposition may increase the vulnerability of the central nervous system to enveloped viral infection and that amyloidogenic peptides could be useful in enhancing gene transfer by enveloped viral vectors.
Highlights
The efficiency of gene delivery using retroviral vectors is often a limiting factor in attempts to express exogenous genes in both cultured mammalian cells and in vivo
Entry of viruses pseudotyped with the human immunodeficiency virus type 1 (HIV-1) envelope glycoproteins is dependent on the presence of CD4 or a chemokine receptor, CCR5 or CXCR4; the viruses pseudotyped with the vesicular stomatitis virus (VSV) or amphotropic murine leukemia virus (A-MuLV) envelope glycoproteins do not require CD4 or chemokine receptor expression on the target cells
Similar results were obtained by infecting a human T-lymphocyte cell line stably expressing CCR5 (SupT1-CCR5) with green fluorescent protein (GFP)-expressing viruses pseudotyped with ADA and YU2 envelope glycoproteins
Summary
The efficiency of gene delivery using retroviral vectors is often a limiting factor in attempts to express exogenous genes in both cultured mammalian cells and in vivo. We report that the amyloidogenic APP fragments A1–40 and A1–42, as well as other synthetic amyloidogenic peptides, significantly enhanced infection by HIV-1 and viruses with other envelope glycoproteins.
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