Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection

Karen Kibler, Akiko Miyazato, Venkat S R K Yedavalli, Andrew I. Dayton, Bertram Jacobs, George Dapolito, Seong Jin Kim, Kuan Teh Jeang

Research output: Contribution to journalArticle

31 Citations (Scopus)

Abstract

Correct endoproteolytic maturation of gp160 is essential for the infectivity of human immunodeficiency virus type 1. This processing of human immunodeficiency virus-1 envelope protein, gp160, into gp120 and gp41 has been attributed to the activity of the cellular subtilisin-like proprotein convertase furin. The prototypic furin recognition cleavage site is Arg-X-Arg/Lys-Arg. Arg-Arg-Arg-Arg-Arg-Arg or longer iterations of polyarginine have been shown to be competitive inhibitors of substrate cleavage by furin. Here, we tested polyarginine for inhibition of productive human immunodeficiency virus-1-infection in T-cell lines, primary peripheral blood mononuclear cells, and macrophages. We found that polyarginine inhibited significantly human immunodeficiency virus-1 replication at concentrations that were benign to cell cultures ex vivo and mice in vivo. Using a fluorogenic assay, we demonstrated that polyarginine potently inhibited substrate-specific proteolytic cleavage by furin. Moreover, we verified that authentic processing of human immunodeficiency virus-1 gp160 synthesized in human cells from an infectious human immunodeficiency virus-1 (HIV-1) molecular clone was effectively blocked by polyarginine. Taken together, our data support that inhibitors of proteolytic processing of gp160 may be useful for combating human immunodeficiency virus-1 and that polyarginine represents a lead example of such inhibitors.

Original languageEnglish (US)
Pages (from-to)49055-49063
Number of pages9
JournalJournal of Biological Chemistry
Volume279
Issue number47
DOIs
StatePublished - Nov 19 2004

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Furin
Virus Diseases
Viruses
HIV-1
Processing
Human Immunodeficiency Virus env Gene Products
Proprotein Convertases
T-cells
Macrophages
Substrates
Virus Replication
polyarginine
Cell culture
Assays
Blood Cells
Blood
Clone Cells
Cell Culture Techniques
Cells
T-Lymphocytes

ASJC Scopus subject areas

  • Biochemistry

Cite this

Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection. / Kibler, Karen; Miyazato, Akiko; Yedavalli, Venkat S R K; Dayton, Andrew I.; Jacobs, Bertram; Dapolito, George; Kim, Seong Jin; Jeang, Kuan Teh.

In: Journal of Biological Chemistry, Vol. 279, No. 47, 19.11.2004, p. 49055-49063.

Research output: Contribution to journalArticle

Kibler, Karen ; Miyazato, Akiko ; Yedavalli, Venkat S R K ; Dayton, Andrew I. ; Jacobs, Bertram ; Dapolito, George ; Kim, Seong Jin ; Jeang, Kuan Teh. / Polyarginine inhibits gp160 processing by furin and suppresses productive human immunodeficiency virus type 1 infection. In: Journal of Biological Chemistry. 2004 ; Vol. 279, No. 47. pp. 49055-49063.
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