Human immunodeficiency 1 (HIV-1), identified in 1983 , remains a global health threat responsible for a world-wide pandemic. The introduction of the highly active antiretroviral therapy (HAART) in 1996 exhibited the potential of curing acquired immune deficiency syndrome (AIDS). Even though an effective AIDS vaccine is still lacking, HAART has greatly extended survival . AIDS pandemic has stabilized on a global scale in 2008 with an estimated 33 million people infected worldwide (data from UN, 2008).
However, several problems have been encountered since the introduction of HAART, and improvements in the design of drugs for HIV-1 are needed. A drawback of HAART is that the treatment is very expensive with limitation of its use to western countries. HAART has also several serious side effects leading to treatment interruption. Another major concern is related to the emergence of multidrug resistant viruses which has been reported in patients receiving HAART [3–5]. Therefore, new antiviral drugs are needed with activities against both wild type and mutant viruses. Two major cellular targets for HIV-1 are currently known which have critical role in HIV pathogenesis, i.e. CD4+ T lymphocytes and monocytes/macrophages including microglial cells, which are the central nervous system resident macrophages [6–8]. However, several drugs being active in CD4+ T lymphocytes are ineffective in chronically infected macrophages (i.e. several reverse transcriptase inhibitors) , and protease inhibitors have significantly lower activities in macrophages compared to lymphocytes . Finally, many observations strongly suggest that even long term suppression of HIV-1 replication by HAART cannot totally eliminate HIV-1. The virus persists in cellular reservoirs because of viral latency, cryptic ongoing replication or poor drug penetration [11–13]. Moreover, these cellular reservoirs are often found in tissue sanctuary sites where penetration of drugs is restricted, like in the brain [14–16]. All these considerations (existence of several reservoirs, tissue-sanctuary sites and multidrug resistance) urge the search for new and original anti HIV-1 treatment strategies. Currently there are seven classes of antiretroviral (ARV) drugs available in the treatment of HIV-1-infected patients: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), entry/fusion inhibitors (EIs), co-receptor inhibitors (CRIs) and integrase inhibitors (INIs) . The therapy of HIV-1-infected patients is based on a combination of three or more drugs from two or more classes . There have been attempts without success to develop vaccines against HIV- 1 and this field of research needs new directions [19–21]. Improvement of HAART is therefore crucial.
We believe that new drugs should target other steps of the HIV-1 cycle such as transcription since there is no drug currently available targeting this step. An increasing number of studies suggest that inhibitors of cellular LTR-binding factors, such as NF-KB and Sp1 repress LTR-driven transcription [19, 21–24]. Recently, it has been shown that proteins of the DING family are good candidates to repress HIV-1 gene transcription [25, 26].
More than 40 DING proteins have now been purified, mostly from eukaryotes  and personal communication] and most of them are associated with biological processes and some diseases . The ubiquitous presence in eukaryotes of proteins structurally and functionally related to bacterial virulence factors is intriguing, as is the absence of eukaryotic genes encoding DING proteins in databases. However, theoretical arguments together with experimental evidences supported an eukaryotic origin for DING proteins [29, 30]. A member of the DING family proteins, HPBP, was serendipitously discovered in human plasma while performing structural studies on another target, the HDL-associated human paraoxonase hPON1 [31–33]. The structure topology is similar to the one described for soluble phosphate carriers of the ABC transporter family [32–36] that makes HPBP the first potential phosphate transporter identified in human plasma. Moreover, the association with hPON1 has been hypothesized to be involved in inflammation and atherosclerosis processes . Later, the ab initio sequencing of HPBP by tandem use of mass spectrometry and X-ray crystallography confirmed that its gene was missing from the sequenced human genome . Immunohistochemistry studies performed in mouse tissues demonstrate that DING proteins are present in most of tissues, spanning from neurons to muscle cells and their cellular localization is largely variable, being exclusively nuclear in neurons, or nuclear and cytoplasmic in muscle cells . Altogether, these localizations are consistent with the biological function that was associated to these proteins, especially the regulation/alteration of cell cycle.
To test whether HPBP is a potential HIV-1 repressor we carried out experiments in a lymphoblastoid cell line (Jurkat) and in primary cells (Peripherial Blood Lineage and macrophage cultures). We report that HPBP represses HIV-1 replication through the inhibition of its gene transcription. Furthermore, HPBP is also active against mutant viruses. Evidence that HPBP can block HIV-1 LTR promoted expression and replication should lead to the design of new drugs which target a not yet targeted step of the virus cycle i.e. transcription.