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Journal of Virology, January 2008, p. 471-486, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.00939-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

WFDC1/ps20 Is a Novel Innate Immunomodulatory Signature Protein of Human Immunodeficiency Virus (HIV)-Permissive CD4+ CD45RO+ Memory T Cells That Promotes Infection by Upregulating CD54 Integrin Expression and Is Elevated in HIV Type 1 Infection{triangledown}

R. Alvarez,1 J. Reading,1 D. F. L. King,1 M. Hayes,1 P. Easterbrook,1 F. Farzaneh,1 S. Ressler,2 F. Yang,2 D. Rowley,2 and A. Vyakarnam1*

Department of Infectious Diseases, King's College London, London, United Kingdom,1 Department of Molecular Biology, Baylor College of Medicine, Houston, Texas2

Received 2 May 2007/ Accepted 10 September 2007

Understanding why human immunodeficiency virus (HIV) preferentially infects some CD4+ CD45RO+ memory T cells has implications for antiviral immunity and pathogenesis. We report that differential expression of a novel secreted factor, ps20, previously implicated in tissue remodeling, may underlie why some CD4 T cells are preferentially targeted. We show that (i) there is a significant positive correlation between endogenous ps20 mRNA in diverse CD4 T-cell populations and in vitro infection, (ii) a ps20+ permissive cell can be made less permissive by antibody blockade- or small-interference RNA-mediated knockdown of endogenous ps20, and (iii) conversely, a ps20low cell can be more permissive by adding ps20 exogenously or engineering stable ps20 expression by retroviral transduction. ps20 expression is normally detectable in CD4 T cells after in vitro activation and interleukin-2 expansion, and such oligoclonal populations comprise ps20positive and ps20low/negative isogenic clones at an early differentiation stage (CD45RO+/CD25+/CD28+/CD57–). This pattern is altered in chronic HIV infection, where ex vivo CD4+ CD45RO+ T cells express elevated ps20. ps20 promoted HIV entry via fusion and augmented CD54 integrin expression; both of these effects were reversed by anti-ps20 antibody. We therefore propose ps20 to be a novel signature of HIV-permissive CD4 T cells that promotes infection in an autocrine and paracrine manner and that HIV has coopted a fundamental role of ps20 in promoting cell adhesion for its benefit. Disrupting the ps20 pathway may therefore provide a novel anti-HIV strategy.

* Corresponding author. Mailing address: Department of Infectious Diseases, King's College London, 2nd Floor New Guy's House, Guy's Campus, London SE1 9NU, United Kingdom. Phone: 44 207 18 83077. Fax: 44 207 18 83385. E-mail: anna.vyakarnam{at}kcl.ac.uk

{triangledown} Published ahead of print on 17 October 2007.

Journal of Virology, January 2008, p. 471-486, Vol. 82, No. 1
0022-538X/08/$08.00+0     doi:10.1128/JVI.00939-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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