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

Abstract

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 ps20 low 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 ps20 positive and ps20 low/negative isogenic clones at an early differentiation stage (CD45RO 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 HIVpermissive 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.

Novel innate immune functions of the whey acidic protein family

“…Conversely, exogenous addition of recombinant ps20 or ectopic expression of full-length ps20 promotes HIV infection of CD4 T cells. This is achieved at least partly by the ability of ps20 to reconfigure the cell surface to become more adhesive [17], consistent with its described functions in regulating extracellular matrix [26,48]. Accordingly, ps20 can upregulate CD54 integrin on CD4 T cells, which is recognized as promoting HIV infection by stabilizing the virus-host fusion process [50] (Figure 5).…”

“…29 No.9 tions have emerged for some of these proteins, including against HIV, and this is discussed in some detail as part of this review [16,17]. Additional diverse functions of this family may include sperm maturation and function [8] and as cancer biomarkers; the latter suggestion is based on the differential expression of WFDC1 and WFDC2 in some cancers [18][19][20].…”

“…29 No.9 Not all WFDC domain proteins are anti-infectives: HIVenhancing properties of ps20 In contrast to SLPI and elafin on ch20, ps20 encoded by the WFDC1 gene on chromosome 16 enhances HIV infection [17]. ps20 is a secreted factor originally cloned from muscle [26], although it can be ubiquitously expressed in several tissue types including memory CD4 T cells (a major in vivo HIV target) [17].…”

Anti-HIV-1 Activity of Elafin Is More Potent than Its Precursor's, Trappin-2, in Genital Epithelial Cells

“…Together with Tr/E, SLPI and ps20 have also been implicated in HIV-1 infection. While SLPI was shown to inhibit infection of HIV-1 permissive cells (39,56), in contrast, ps20 enhanced HIV-1 infectivity and susceptibility of target cells (1). These observations suggest that a balance in SLPI and ps20, as well as other host molecules with documented anti-and pro-HIV-1 activities, might be an integral part in determining host's susceptibility to HIV-1 infection and should be considered in designing anti-HIV-1 interventions.…”

Ethical and Legal Considerations in Human Biobanking: Experience of the Infectious Diseases BioBank at King’s College London, UK

“…These now include those with hepatitis C virus or papillomavirus virus infections and patients with inflammatory diseases (including: as diabetes, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, and, pre-multiple sclerosis syndrome). Some of the currently approved studies are listed (Table 2), and a steady stream of research publications is starting to ensue (Nath et al, 2006(Nath et al, , 2007Alvarez et al, 2008;Thorborn et al, 2010). In addition, publications arising from the contract research work of the IDB are expected to increase significantly (4.8 below).…”