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

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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

ASJC Scopus subject areas

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    Auerbach, D. J., Lin, Y., Miao, H., Cimbro, R., DiFiore, M. J., Gianolini, M. E., Furci, L., Biswas, P., Fauci, A. S., & 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, 109(24), 9569-9574. https://doi.org/10.1073/pnas.1207314109