The unilateral involution in the thymus of a 96-year-old male leads to the preservation of structural integrity in one thymic lobe, as assessed by the expression of medullar and cortical antigens and the presence of CD3+ cells.

The process of thymic involution begins soon after birth and continues through adult life. Although evolutionary conserved in all vertebrates, the thymic involution has no defined kinetics. Little is known about the pace of its regression in humans, except that there is a marked increase of thymic involution after puberty.

DING Protein Inhibits Transcription of HIV-1 Gene through Suppression of Phosphorylation of NF-κB p65.

Introduction: Novel plant DING proteins (full-length 38 kDa p38SJ, and 27 kDa p27SJ) exhibit phosphatase activity and modulate HIV-1 gene transcription. Previously, we demonstrated that DING regulates HIV-1 gene transcription by dephosphorylation and inactivation of CTD RNA polymerase II, the major elongating factor of HIV-1 Long Terminal Repeats (LTR). Because the transcription of HIV-1 is controlled by several viral and cellular factors, including p65/p50 subunits of NF-κB, we hypothesized that DING phosphatase can also affect the phosphorylation and activity of p65 NF-κB, in addition to C-terminal Domain (CTD) of RNA Polymerase II (RNAPII), to suppress HIV-1 gene transcription and inhibit HIV-1 infection.

Human X-DING-CD4 mediates resistance to HIV-1 infection through novel paracrine-like signaling.

X-DING-CD4 is a novel phosphatase mediating antiviral responses to HIV-1 infection. This protein is constitutively expressed and secreted by HIV-1 resistant CD4(+) T cells and its mRNA transcription is up-regulated in peripheral blood mononuclear cells from HIV-1 elite controllers. The secreted/soluble X-DING-CD4 protein form is of particular importance because it blocks virus transcription when added to HIV-1 susceptible cells.

DING proteins from phylogenetically different species share high degrees of sequence and structure homology and block transcription of HIV-1 LTR promoter.

Independent research groups reported that DING protein homologues isolated from bacterial, plant and human cells demonstrate the anti-HIV-1 activity. This might indicate that diverse organisms utilize a DING-mediated broad-range protective innate immunity response to pathogen invasion, and that this mechanism is effective also against HIV-1. We performed structural analyses and evaluated the anti-HIV-1 activity for four DING protein homologues isolated from different species.

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.

X-DING-CD4 blocks HIV-1 long terminal repeat (LTR) and pathogen induced pro-inflammatory response. Increased activity of the X-DING-CD4 gene is associated with cellular resistance to virus; therefore, HIV-1 elite controllers (ECs) should have higher X-DING-CD4 and reduced pro-inflammatory mRNA activity than viremic or uninfected individuals. Also, depending on the cell stimulating factor, expression of X-DING-CD4 mRNA in ECs might be autonomous or contingent on IFN signaling.

Cellular resistance to HIV-1 infection in target cells coincides with a rapid induction of X-DING-CD4 mRNA: indication of the unique host innate response to virus regulated through function of the X-DING-CD4 gene.

Clinical reports indicate that some infected individuals control HIV-1 replication through undefined mechanisms. Our group reported that a human protein named X-DING-CD4 holds a potent antiviral activity, blocking transcription of HIV-1 LTR through the inhibition of NF-κB/DNA binding. Based on observations that transformed HIV-1 resistant CD4(+) T cells produce higher levels of soluble X-DING-CD4 protein upon their exposure to virus, we hypothesized that resistance to HIV-1 in these cells may be regulated through function of the X-DING-CD4 gene.

Native X-DING-CD4 protein secreted by HIV-1 resistant CD4+ T cells blocks activity of IL-8 promoter in human endothelial cells infected with enteric bacteria.

Onsets of bacterial infections devastate the compromised immune system in AIDS patients. Damaged gut mucosa permits dissemination of bacterial toxins into deeper layers and hyper-activation of the immune system. We previously reported that the unfractionated supernatants of HIV-resistant CD4(+) T cells impeded the NF-κB/DNA binding in macrophages induced by either HIV-1 or LPS.

Identification of X-DING-CD4, a new member of human DING protein family that is secreted by HIV-1 resistant CD4(+) T cells and has anti-viral activity.

We reported previously the anti-viral activity named HRF (HIV-1 Resistance Factor) secreted by HIV-1 resistant cells. This work describes the identification of HRF from cell culture supernatant of HRF-producing cells (HRF(+) cells). Employing the proteomics and cell based activity assay we recovered ten peptides sharing 80-93% sequence homology with other eukaryotic DING proteins; discrete amino acid characteristics found in our material suggested that HRF is a new member of DING proteins family and consequently we designated it as X-DING-CD4 (extracellular DING from CD4(+) T cells).

Intranasal transmission of hepatitis C virus: virological and clinical evidence.

Intranasal transmission of hepatitis C virus (HCV) via contaminated drug-sniffing implements is a potential but unconfirmed source of viral infection. We demonstrate the virological plausibility of intranasal transmission by confirming that blood and HCV RNA are present in the nasal secretions and drug-sniffing implements of HCV-infected intranasal drug users recruited from a community health clinic in New York City.

The critical role of human transcriptional repressor CTCF mRNA up-regulation in the induction of anti-HIV-1 responses in CD4(+) T cells.

We have employed our CD4(+) T cell model named HIV-1 resistance factor (HRF(+)) to study the inducible anti-HIV-1 responses mediated through novel soluble molecules. We found that exposure to the soluble products of HRF(+) cells activated CCCTC-binding factor (CTCF) mRNA expression in HIV-1 susceptible primary and transformed CD4(+) T cells and overlapped with their acquisition of transient resistance to virus. Conversely, the interference with the expression of CTCF gene in HRF(+) cells reversed the resistant phenotype and eliminated the biological potential of their cell culture supernatant to induce "HRF-like" activity in target cells.

Inhibition of HIV-1 or bacterial activation of macrophages by products of HIV-1-resistant human cells.

We have recently described the molecular basis of HIV-1 resistance factor (HRF)-mediated anti-viral activity in primary and transformed CD4 T cells. HRF+ cell culture supernatants or partially purified HRF were found to incapacitate the formation of the NF-kappaB/DNA complex, which is indispensable for long terminal promoter-driven transcription of virus genes. In this study, we tested whether HRF might have much broader activity against other organisms whose pathogenesis is linked to NF-kappaB activation.

The innate cellular responses to HIV-1 invasion: emerging molecules of ancient defense mechanisms.

Along alternative protective pathways, human cells can synthesize biologically active proteins that interfere with HIV replication, but are not viral antigen specific. HIV is sensitive to several viral inhibitors of cellular origin, such as interferons or interferon-regulated proteins. With the progress of AIDS research it has become evident that the immune cells of some individuals are capable of restricting the virus by secretion of other, yet unidentified factor(s) that can be detected only by their potent antiviral activity.

A soluble factor secreted by an HIV-1-resistant cell line blocks transcription through inactivating the DNA-binding capacity of the NF-kappa B p65/p50 dimer.

The identity and activity of several anti-HIV soluble factor(s) secreted by CD8 and CD4 T lymphocytes have been determined; however, some of them still await definition. We have established an HIV-1-resistant, transformed CD4 T cell line that secretes HIV-1 resistance protein(s). Our studies indicate that this protein(s), called HIV-1 resistance factor (HRF), inhibits transcription of the virus by interfering with the activity of NF-kappaB.

Monoubiquitinated histone H1B is required for antiviral protection in CD4(+)T cells resistant to HIV-1.

Linker histone H1B (H1B) coeluted with an antiviral activity during the purification of HIV-1 resistance factor (HRF) from supernatants of HRF(+) cells. Western blot analysis of the supernatant using alpha-H1 and alpha-ubiquitin antibodies detected the same band of roughly 46 kDa; this band was absent from the control supernatant. Depletion of histone from biologically active material did not affect its potential, suggesting that ubiquitinated H1B is not required for the HRF-mediated antiviral protection in HIV-1 susceptible target cells; however, specific silencing of histone H1B via RNAi in HRF(+) cells reduced the biological activity of cell culture supernatants by 96% and reversed the HIV-1 resistance phenotype of HRF(+) cells.

Microarray analysis of differentially expressed genes in cells resistant to HIV-1.

We have previously isolated two matched transformed human T cell clones: one of which is resistant to HIV-1 replication and secretes an HIV-1 resistance factor(s) (HRF) and the second which retains the susceptibility of the parental cell line to HIV-1 infection. We employed cDNA arrays to investigate the spectrum of changes in cellular gene expression that correlate with the acquisition of HIV-1 resistance and the secretion of HRF. Using a tissue based immunology/hematology array, we identified 29 transcripts that were differentially expressed by HRF(+) and HRF(-) cells.

Detection of hepatitis C virus in the nasal secretions of an intranasal drug-user.

Background: One controversial source of infection for hepatitis C virus (HCV) involves the sharing of contaminated implements, such as straws or spoons, used to nasally inhale cocaine and other powdered drugs. An essential precondition for this mode of transmission is the presence of HCV in the nasal secretions of intranasal drug users.

Methods: Blood and nasal secretion samples were collected from five plasma-positive chronic intranasal drug users and tested for HCV RNA using RT-PCR.

Customized rapid subtraction hybridization (RaSH) gene microarrays identify overlapping expression changes in human fetal astrocytes resulting from human immunodeficiency virus-1 infection or tumor necrosis factor-alpha treatment.

Genes displaying altered expression as a function of human immunodeficiency virus (HIV)-1 infection of cultured primary human fetal astrocytes (PHFA) were previously identified using a rapid subtraction hybridization (RaSH) method. This scheme identified both known and novel genes displaying elevated expression, astrocyte elevated genes (AEG), and decreased expression, astrocyte suppressed genes (ASG), in PHFA as a consequence of infection with HIV-1 or treatment with HIV-1 envelope glycoprotein (gp120). RaSH also identified both known and novel genes displaying enhanced (HR) or reduced (HS) expression in HIV-1 resistant versus HIV-1 susceptible human T-cell clones.

Induction of secreted human immunodeficiency virus type 1 (HIV-1) resistance factors in CD4-positive T lymphocytes by attenuated HIV-1 infection.

This report describes induction of HIV-1 resistance and synthesis of resistance factors in immortal CD4-positive T lymphocytes. SupT1 cells were infected by NL4-3 attenuated by a defect in the vif gene through coculture with infected primary lymphocytes. Cell lines from this infection, termed R1, expressed CD4 and CXCR4, carried low levels of HIV-1 DNA, but expressed no other detectable viral products and were resistant to infection by wild-type HIV-1.