The Level of DING Proteins Is Increased in HIV-Infected Patients: In Vitro and In Vivo Studies

Abstract

DING proteins constitute an interesting family, owing to their intriguing and important activities. However, after a decade of research, little is known about these proteins. In humans, at least five different DING proteins have been identified, which were implicated in important biological processes and diseases, including HIV. Indeed, recent data from different research groups have highlighted the anti-HIV activity of some DING representatives. These proteins share the ability to inhibit the transcriptional step of HIV-1, a key step of the viral cycle that is not yet targeted by the current therapies. Since such proteins have been isolated from humans, we undertook a comprehensive study that focuses on the relationship between these proteins and HIV-infection in an infectious context. Hence, we developed a home-made ELISA for the quantification of the concentration of DING proteins in human serum. Using this method, we were able to determine the concentration of DING proteins in healthy and HIV-infected patients. Interestingly, we observed a significant increase of the concentration of DING proteins in non treated and treated HIV-infected patients compared to controls. In addition, cell cultures infected with HIV also show an increased expression of DING proteins, ruling out the possible role of antiretroviral treatment in the increase of the expression of DING proteins. In conclusion, results from this study show that the organism reacts to HIV-infection by an overexpression of DING proteins.

The interplay between the X-DING-CD4, IFN-α and IL-8 gene activity in quiescent and mitogen- or HIV-1-exposed PBMCs from HIV-1 elite controllers, AIDS progressors and HIV-negative controls

“…The anti-viral activity was detected also in other DING variants derived from human and plant cells; these proteins blocked transcription of HIV-1 LTR with efficiency comparable to X-DING-CD4 34, 47, 48 . While much in their biology is still unknown, this might suggest that DING proteins participate in the innate immunity responses to pathogens in diverse species.…”

DING Proteins from Phylogenetically Different Species Share High Degrees of Sequence and Structure Homology and Block Transcription of HIV-1 LTR Promoter

“…The DING proteins form an intriguing family of biologically active factors contributing to protective [7], [15], [16], [27], [42], [43] or possibly adverse [1], [6] cellular functions. In this work we selected four distinct members of the DING family to ascertain their structural and functional properties with specific interest in their anti-HIV-1 activity.…”

“…The differences in the length of protuberant loops could be connected to the various physiological functions attributed to DING proteins and may be related to their specific protein/protein interactions (PON1, NF-κB, Tat or C/EBPβ) [4], [20], [22], [25], [26], [27], [44], [45]. Nevertheless, the native function of DING proteins, and particularly pDING, is yet to be determined, but plant DING proteins associate with germin-like proteins (GLPs) [46] known to have multiple functions including pathogen elicitation [47].…”

“…Subsequent studies showed the ability of pDING and X-DING-CD4 in regulating various cellular genes including MCP-1 and IL-8 by either C/EBPβ- and/or NF-κB-dependent pathways [25], [26]. In addition to the in vitro studies, the clinical evaluations indicated that HIV-infected patients have an increased concentration of DING proteins [27], and the increased expression of the X-DING-CD4 mRNA correlates with the cellular restriction of HIV-1 replication in human macrophages [21].…”

The DINGGG thermoprotein is membrane bound in the Crenarchaeon Sulfolobus solfataricus

“…No complete gene sequences coding these proteins have been identified in any of the eukaryotic genome databases and only for a prokaryotic DING protein, from P. fluorescens SBW25 [1], the gene, PfluDING, has been cloned and expressed in Escherichia coli [4]. Despite this unresolved question, the complete amino acid sequence of the DING human phosphate-binding protein (HPBP), isolated from human plasma as an apolipoprotein, was identified [5] and was demonstrated to be involved in protection against atherosclerosis and viral infection [5][6][7].…”