Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor

David J. Auerbach, Yin Lin, Huiyi Miao, Raffaello Cimbro, Michelle J. DiFiore, Monica E. Gianolini, Lucinda Furci, Priscilla Biswas, Anthony S. Fauci, Paolo Lusso

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The natural history of HIV-1 infection is highly variable in different individuals, spanning from a rapidly progressive course to a longterm asymptomatic infection. A major determinant of the pace of disease progression is the in vivo level of HIV-1 replication, which is regulated by a complex network of cytokines and chemokines expressed by immune and inflammatory cells. The chemokine system is critically involved in the control of HIV-1 replication by virtue of the role played by specific chemokine receptors, most notably CCR5 and CXCR4, as cell-surface coreceptors for HIV-1 entry; hence, the chemokines that naturally bind such coreceptors act as endogenous inhibitors of HIV-1. Here, we show that the CXC chemokine CXCL4 (PF-4), the most abundant protein contained within the α-granules of platelets, is a broad-spectrum inhibitor of HIV-1 infection. Unlike other known HIV-suppressive chemokines, CXCL4 inhibits infection by the majority of primary HIV-1 isolates regardless of their coreceptor-usage phenotype or genetic subtype. Consistent with the lack of viral phenotype specificity, blockade of HIV- 1 infection occurs at the level of virus attachment and entry via a unique mechanism that involves direct interaction of CXCL4 with the major viral envelope glycoprotein, gp120. The binding site for CXCL4 was mapped to a region of the gp120 outer domain proximal to the CD4-binding site. The identification of a platelet-derived chemokine as an endogenous antiviral factor may have relevance for the pathogenesis and treatment of HIV-1 infection.

Original languageEnglish
Pages (from-to)9569-9574
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number24
DOIs
Publication statusPublished - Jun 12 2012

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Platelet Factor 4
HIV-1
Blood Platelets
Chemokines
HIV Infections
Binding Sites
Phenotype
Virus Attachment
CXC Chemokines
Virus Internalization
Asymptomatic Infections
Chemokine Receptors
Antiviral Agents
Disease Progression
Glycoproteins
HIV
Cytokines

ASJC Scopus subject areas

  • General

Cite this

Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor. / Auerbach, David J.; Lin, Yin; Miao, Huiyi; Cimbro, Raffaello; DiFiore, Michelle J.; Gianolini, Monica E.; Furci, Lucinda; Biswas, Priscilla; Fauci, Anthony S.; Lusso, Paolo.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 24, 12.06.2012, p. 9569-9574.

Research output: Contribution to journalArticle

Auerbach, DJ, Lin, Y, Miao, H, Cimbro, R, DiFiore, MJ, Gianolini, ME, Furci, L, Biswas, P, Fauci, AS & Lusso, P 2012, 'Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 24, pp. 9569-9574. https://doi.org/10.1073/pnas.1207314109
Auerbach, David J. ; Lin, Yin ; Miao, Huiyi ; Cimbro, Raffaello ; DiFiore, Michelle J. ; Gianolini, Monica E. ; Furci, Lucinda ; Biswas, Priscilla ; Fauci, Anthony S. ; Lusso, Paolo. / Identification of the platelet-derived chemokine CXCL4/PF-4 as a broad-spectrum HIV-1 inhibitor. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 24. pp. 9569-9574.
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