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Background and Objective: Copper, a wide spectrum biocide, also plays a key role in angiogenesis and wound healing. Antibacterial wound dressings impregnated with copper oxide microparticles (COD) have been recently cleared by the U.S. FDA and other regulatory bodies for the treatment of acute and chronic wounds, including diabetic wounds. Our objective was to evaluate the capacity of COD in stimulating the healing of non-infected stagnated wounds in diabetic patients initially treated with standard of care (SOC) dressings. Materials and Methods: The trial was divided into the three following phases: 1–2 weeks of screening, during which the patients were treated with SOC dressings, 4 weeks of treatment, during which the COD was applied twice weekly, and 2 weeks of follow-up, during which the patients were again treated with SOC dressings. The wound conditions and sizes were assessed by clinical evaluation and a wound imaging artificial intelligence system. Results: Following 1 month of COD treatment, there was a clear reduction in the mean wound area (53.2%, p = 0.003), an increase in granulation tissue (43.37, p &lt, 0.001), and a reduction in fibrins (47.8%, p = 0.002). In patients with non-weight-bearing wounds, the reduction in wound size was even more dramatic (66.9%, 0.001). Conclusions: The results of this study, showing a statistically significant influence of COD on wound healing of hard-to-heal wounds in diabetic patients, strongly supports the notion that copper oxide-impregnated dressings enhance wound healing directly. Further larger controlled studies should be conducted to substantiate our findings.

SARS-CoV-2 can remain viable on the protective face masks surface for several days. Mask touching, reuse and disposal occurs frequently, leading to increased risk of cross-contamination, infection and further transmission. Cuprous-oxide has potent virucidal properties. We determined the capacity of surgical face masks (type IIR) made with nonwoven fabric impregnated with cuprous-oxide microparticles (Test Fabric), to inactivate SARS-CoV-2 when in direct contact with the virus. The Test Fabric reduced the infectious titers of SARS-CoV-2 by 0.73, 3.02 and 4.19 log10 within 5, 30 and 60 minutes, respectively. In contrast, the infectious titers of the virus were reduced by Control Fabric by 0.24, 0.67 and 0.97 within 5, 30 and 60 minutes, respectively. The reductions were significantly higher in the Test Fabric than in the Control Fabric (0.49, 2.35 and 3.22 log difference, accordingly), reaching a statistically significant difference after 5 minutes (p

Copper has two key properties that endow it as an excellent active ingredient to be used in the “wound healing battle”. First, copper plays a key role in angiogenesis, dermal fibroblasts proliferation, upregulation of collagen and elastin fibers production by dermal fibroblasts, and it serves as a cofactor of Lysyl oxidase needed for efficient dermal extracellular matrix (ECM) protein cross-linking. Secondly, copper has potent wide-spectrum biocidal properties. Both gram-positive and gram-negative bacteria, including antibiotic resistant bacteria and hard to kill bacterial spores, fungi and viruses, when exposed to high copper concentrations, are killed. Copper has been used as a biocide for centuries by many different civilizations. Impregnation of copper oxide microparticles in wound dressings allows continuous release of copper ions. This results not only in the protection of the wounds and wound dressings from pathogens, but more importantly, enhances wound healing. The article discusses the molecular mechanisms of enhanced wound healing by the copper oxide impregnated dressings, which include in situ upregulation of pro-angiogenic factors and increased blood vessel formation. It also includes clinical cases showing clearance of infection, induction of granulation and epithelialization of necrotic wounds, reduction of post-operative swelling inflammation and reduction of scar formation, in wounds when they were treated with copper oxide impregnated dressings. We show the positive outcome at all wound healing stages of using the copper impregnated wound dressings, indicating the neglected critical role copper plays in wound healing.

Background Clinical studies demonstrated that continued exposure to copper oxide-embedded textiles, such as pillowcases, significantly reduces depth of facial wrinkles and skin sagging and enhances skin elasticity. Objective Study the mechanisms by which the exposure to copper ions improve the well-being of the skin. Methods Human skin explants, cultured ex-vivo, were exposed topically to saline alone or saline containing 0.02 or 1 µmol/L copper ions. The skin explants viability, histology and secretion of elastin, pro-collagen 1, and TGF-β1 to the culture medium were determined at various time intervals. Results Exposure to saline containing 0.02 or 1 µmol/L copper ions did not affect the viability or morphological profile of the explants as compared to control explants treated with saline only. Notably, exposure of the skin grafts to 0.02 or to 1 µmol/L of copper ions resulted in ~100% and ~20% increases in elastin and pro-collagen 1 concentrations, respectively, in the culture supernatants already after 1 day of incubation, which remained statistically significantly elevated also after 6 days on incubation, as compared to the control explants. In addition, ~2- and ~4-fold increases in TGF-s1 levels in the culture supernatants of explants exposed to the copper ions were detected after 4 and 6 days of culture, as compared to the explants exposed to saline alone. Conclusion This study substantiated the anti-aging effect that copper ions have on the skin and gave insights into the mechanisms by which exposure of the skin to copper ions improves the skin well-being.

Clogging of subsurface drip irrigation (SDI) systems by root penetration into the emitters results in inappropriate water supply, increased replacement rates of SDI systems and increased costs. We found that impregnation of SDI drippers with copper oxide particles inhibits root penetration very significantly. The inhibition of root penetration varied from 24 to 76 % of the control (60–80 % intrusion) depending on the copper oxide concentration of the drippers. The root penetration inhibition was demonstrated at two water flow rates, of 1 and 3.5 l/h, and with new and used drippers after 1750 irrigation hours. Inhibition of root penetration occurred also if sewage water was used. The inhibition of root penetration into drippers was demonstrated with lettuce and tomato plants and reached similar efficacy as compared to the widely used herbicide Stomp® root penetration inhibition treatment. The amount of copper that leached into the water was below detection limit (less than 0.006 ppm). No loss of copper oxide particles was detected in drippers through which 3350 l of water was passed (an amount of water that typically passes in SDI systems during 3–4 years of use), as determined by scanning electronic microscope and X-ray photoelectron spectrum analysis.

Copper has two key properties that are being exploited in consumer and medical device products in the last decade. On the one hand, copper has potent biocidal properties. On the other hand, copper is involved in numerous physiological and metabolic processes critical for the appropriate functioning of almost all tissues in the human body. In the skin, copper is involved in the synthesis and stabilization of extracellular matrix skin proteins and angiogenesis. This manuscript reviews clinical studies that show that the use of textile consumer and medical device products, embedded with microscopic copper oxide particles, improve the well-being of the skin. These include studies showing a) cure of athlete's foot infections and improvement in skin elasticity, especially important for individuals suffering from diabetes; b) reduction of facial fine line and wrinkles; and c) enhancement of wound healing; by copper oxide embedded socks, pillowcases and wound dressings, respectively. The manuscript also reviews and discusses the mechanisms by which the presence of copper in these products improves skin well-being.

Copper has two key properties that make it an attractive component to introduce into textiles and socks in particular – it has potent biocidal properties and is an essential trace element vital for the normal function of skin. The capacity of copper oxide impregnated socks to kill fungi that causes tinea pedis (athlete’s foot) and to enhance skin elasticity has already been demonstrated. In the current study, we assessed the beneficial effect on the skin of the foot in the wider population by supplying socks impregnated with microscopic copper oxide particles to 5,000 individuals that were identified via an internet survey as people who had experienced athlete’s foot within the past 6 months or were concerned about the appearance of their feet. Each individual received 3 complementary pairs of socks and was asked to use them as they would normally use their own socks. After 90 days 3,603 paricipants answered an online questionnaire. The vast majority (82%) of responders that felt uncomfortable showing their bare feet in public before using the socks reported a meaningful improvement to their foot skin following the use of the socks for at least 5 hours a day. 61% of respondents reported elimination or reduction of their foot odor, and 60% reported stopping using a foot care regime or therapy due to using the supplied socks. 51% indicated that the socks improved the appearance of their feet and 58% indicated they were now more comfortable showing their feet in public. In view of the above, it can be concluded that the simple use of copper oxide impregnated socks for at least 5 hours a day helps improve the foot skin well-being and overall appearance of the skin.

Phytochemicals (PHT) are biologically active chemicals produced by plants, non-essential nutrients, with medicinal properties. In this short communication we report the dramatic improvement in the physical and clinical well-being of 9 terminal AIDS patients that received Phyto V7, a PHT mix, for a period of 3 months. All patients living in the Dr. Cruz Jiminian Foundation (hospice) in Santo Domingo, Dominican Republic, were in an emaciated condition—most could not eat, sit down, shower, stand up or dress alone; all had high viremia (from ~50,000 to above 500,000; 243,816 ± 176,724 HIV-1 RNA copies/ml) and very low CD4+ T-cells counts (142 ± 51 counts/mm 3

Copper oxide has potent wide-spectrum biocidal properties. The purpose of this study is to determine if replacing hospital textiles with copper oxide-impregnated textiles reduces the following health care-associated infection (HAI) indicators: antibiotic treatment initiation events (ATIEs), fever days, and antibiotic usage in hospitalized chronic ventilator-dependent patients.A 7-month, crossover, double-blind controlled trial including all patients in 2 ventilator-dependent wards in a long-term care hospital. For 3 months (period 1), one ward received copper oxide-impregnated textiles and the other received untreated textiles. After a 1-month washout period of using regular textiles, for 3 months (period 2) the ward that received the treated textiles received the control textiles and vice versa. The personnel were blinded to which were treated or control textiles. There were no differences in infection control measures during the study.There were reductions of 29.3% (P = .002), 55.5% (P .0001), 23.0% (P .0001), and 27.5% (P .0001) in the ATIEs, fever days (37.6°C), days of antibiotic treatment, and antibiotic defined daily dose per 1,000 hospitalization days, respectively, when using the copper oxide-impregnated textiles.Use of copper oxide-impregnated biocidal textiles in a long-term care ward of ventilator-dependent patients was associated with a significant reduction of HAI indicators and antibiotic utilization. Using copper oxide-impregnated biocidal textiles may be an important measure aimed at reducing HAIs in long-term care medical settings.

Nosocomial infections, especially those caused by antibiotic resistant bacteria, are increasing at an alarming rate over the globe. Unfortunately, standard infection control practices, such as pre-emptive isolation of high-risk patients, wide and targeted surveillance cultures, and proper ventilation systems are lacking in developing countries mainly due to insufficient resources. Patients shed bacteria and contaminate their pyjamas and sheets. The temperature and humidity between the patients and the bed are appropriate conditions allowing for effective bacterial proliferation. Bed making releases large quantities of micro-organisms into the air, which contaminate the immediate and non-immediate surroundings. Personnel in contact with contaminated textiles can also cross-contaminate other surfaces or patients. Thus textiles in hospitals can be an important source of microbes contributing to endogenous, indirect-contact, and aerosol transmission of nosocomial related pathogens. The use of safe wide-spectrum antimicrobial textiles, especially in those textiles that are in close contact with the patients, may significantly reduce bioburden in clinical settings and consequently reduce the risk of nosocomial infections. This is of special significance in resource poor developing countries, where wards are overcrowded and population infection burdens are very high. The use of biocidal textiles is a simple, cost-affordable and feasible measure that may be especially important in developing countries where essential infection control measures are not implemented.

Copper plays a key role in angiogenesis and in the synthesis and stabilization of extracellular matrix skin proteins, which are critical processes of skin formation. We hypothesized that introducing copper into wound dressings would enhance wound repair. Application of wound dressings containing copper oxide to wounds inflicted in genetically engineered diabetic mice (C57BL/KsOlaHsd-Lepr(db)) resulted in increased gene and in situ up-regulation of proangiogenic factors (e.g., placental growth factor, hypoxia-inducible factor-1 alpha, and vascular endothelial growth factor), increased blood vessel formation (p

Diabetic individuals frequently suffer from skin pathologies, especially in their feet. Co-existing peripheral vascular disease and neuropathy exacerbate the capacity of these individuals to cope with infections, minor cuts and wounds, often leading to hard to treat and chronic ulcers. Copper has potent anti-fungal and antibacterial properties. Copper is also an essential trace element vital for the normal function of many tissues and indispensable for the generation of new capillaries and skin. Human skin is not sensitive to copper and the risk of adverse reactions due to dermal exposure to copper is extremely low. We hypothesize that part of the increased risk of developing foot skin pathologies in diabetic patients with compromised blood circulation to the foot is due to low local copper levels. We further hypothesize that copper ions released from copper impregnated socks and absorbed through the skin would improve the well-being of the skin of diabetic patients by inducing angiogenesis and expression and stabilization of extracellular skin proteins, in addition to their biocidal effect of reducing the risk of fungal and bacterial infection of the diabetic foot. Thus, the use of copper impregnated socks may be used as a preventive modality. Furthermore, we hypothesize that the copper released from the socks may even be beneficial in the healing of cuts, wounds and even hard to treat skin pathologies.

In recent years, based on peptide models of HIV-1 RNA binding, NMR structures of Tat-responsive element-ligand complexes and aminoglycoside-RNA interactions, and HIV-1 Tat structure, we have designed and synthesized aminoglycoside-arginine conjugates (AACs) and aminoglycoside poly-arginine conjugates (APACs), to serve as Tat mimetics. These novel molecules inhibit HIV-1 infectivity with 50% effective concentration values in the low micromolar range, the most potent compounds being the hexa-arginine-neomycin B and nona-D-arginine-neomycin conjugates. Importantly, these compounds, in addition to acting as Tat antagonists, inhibit HIV-1 infectivity by blocking several steps in HIV-1 cell entry. The AACs and APACs inhibit HIV-1 cell entry by interacting with gp120 at the CD4-binding site, by interacting with CXCR4 at the binding site of the CXCR4 mAb 12G5, and apparently by interacting with transient structures of the ectodomain of gp41. In the current review, we discuss the mechanisms of anti-HIV-1 activities of these AACs, APACs and other aminoglycoside derivatives in detail. Targeting several key processes in the viral life cycle by the same compound not only may increase its antiviral efficacy, but more importantly, may reduce the capacity of the virus to develop resistance to the compound. AACs and APACs may thus serve as leading compounds for the development of multitargeting novel HIV-1 inhibitors.

Copper oxide (CuO) has broad-spectrum anti-microbial and anti-fungal properties. The aim of this study was to test the acaricidal efficacy of CuO-impregnated fabrics on the common house dust mite, Dermatophagoides farinae. The overall vitality/mobility of the mites was reduced when they were exposed to the CuO-impregnated fabrics and, when possible, the dust mites migrated to fabrics where no CuO was present. The mortality of mites exposed for 10 days to fabrics containing 0.2% (w/w) CuO was significantly higher than the mortality of mites on control fabrics (72 ± 4 and 18.9 ± 0.3%, respectively). The mortality reached 95.4 and 100% with fabrics containing 0.4 and 2% CuO after 47 and 5 days, respectively. The acaricidal effect of copper oxide seems to be due to direct toxicity. The use of fabrics containing copper oxide may thus be an important avenue for reducing house dust mite populations, and for reducing the load of dust mite allergens.

We all hope for healthy, smooth and beautiful looking skin. Many of us spend considerable amounts of money and time looking for products that can keep our skin looking young and radiant. The cosmetic industry is flourishing and new moisturizers, cleansers and beauty products constantly emerge in the market.

We present the design, synthesis, anti-HIV-1 and mode of action of neomycin and neamine conjugated at specific sites to arginine 6- and 9-mers d- and l-arginine peptides (APACs). The d-APACs inhibit the infectivity of X4 HIV-1 strains by one or two orders of magnitude more potently than their respective l-APACs. d-arginine conjugates exhibit significantly higher affinity towards CXC chemokine receptor type 4 (CXCR4) than their l-arginine analogs, as determined by their inhibition of monoclonal anti-CXCR4 mAb 12G5 binding to cells and of stromal cell-derived factor 1α (SDF-1α)/CXCL12 induced cell migration. These results indicate that APACs inhibit X4 HIV-1 cell entry by interacting with CXCR4 residues common to glycoprotein 120 and monoclonal anti-CXCR4 mAb 12G5 binding. d-APACs readily concentrate in the nucleus, whereas the l-APACs do not. 9-mer-d-arginine analogues are more efficient inhibitors than the 6-mer-d-arginine conjugates and the neomycin-d-polymers are better inhibitors than their respective neamine conjugates. This and further structure–function studies of APACs may provide new target(s) and lead compound(s) of more potent HIV-1 cell entry inhibitors.

Copper plays a key role in angiogenesis and in the expression and stabilization of extracellular skin proteins. Copper also exhibits broad biocidal properties. The authors hypothesized that introducing copper into a wound dressing would not only reduce the risk of wound and dressing contamination, but would also stimulate wound repair. To test this hypothesis, non-stick dressings composed of a highly absorbent internal mesh fabric and an external non-woven fabric were fabricated, and each was impregnated with ~2.65% (weight/weight) copper oxide particles. The application to wounds inflicted in genetically engineered diabetic mice resulted in increased gene and in-situ upregulation of proangiogenic factors, increased blood vessel formation, and enhanced wound closure. The present study reports both the potent broad spectrum antimicrobial and antifungal properties of these wound dressings and the lack of adverse reactions as determined in rabbits and a porcine wound model. The prolonged efficacy of the wound dressing is demonstrated by its capacity to reduce the microbial challenge by more than 99.9% even when spiked 5 consecutive times with a high bacterial titer. The dressing's antimicrobial efficacy is exerted within minutes. The dressing did not cause any skin irritation or sensitization to closed skin. Furthermore, no histological differences were found between open wounds exposed to copper oxide containing wound dressings or control dressings. Therefore, copper containing wound dressings hold significant promise in wound healing and their clinical use should be explored .

Impregnation or coating of cotton and polyester fibers with cationic copper endows them with potent broad-spectrum antibacterial, antiviral, antifungal, and antimite properties (Borkow, G. and Gabbay, J. (2004). Putting Copper into Action: Copper-impregnated Products with Potent Biocidal Activities, FASEB Jounal, 18(14): 1728-1730). This durable platform technology enables the mass production of woven and non-woven fabrics, such as sheets, pillow covers, gowns, socks, air filters, mattress covers, carpets, etc. without the need of altering any industrial procedures or machinery, but only the introduction of copper oxide-treated fibers. The biocidal properties of fabrics containing 3-10% copper-impregnated fibers are permanent, are not affected by extreme washing conditions, and do not interfere with the manipulation of the final products (e.g., color, press, etc.). In this article, the authors describe data showing that (i) antifungal socks containing 10% w/w (weight/weight) copper-impregnated fibers alleviate athlete’s foot; (ii) antimicrobial fabrics (sheets) containing 10% (w/w) copper-impregnated fibers decrease bacterial colonization in a clinical setting; and (iii) these products do not have skin-sensitizing properties or any other adverse effects. Taken together, these results demonstrate the wide preventive and curative potential of copper oxide-impregnated apparel products.

Aminoglycoside-arginine conjugates (AACs) inhibit HIV-1 replication and act as Tat antagonists. AACs compete with monoclonal antibody binding to CXCR4, compete with SDF-1alpha and HIV-1 gp120 cellular uptake, indicating that they interfere with initial steps of HIV-1 infection. We here present the selection of HIV-1 isolates resistant to hexa-arginine neomycin B conjugate (NeoR6), the most potent anti-HIV-1 AAC. We found in the NeoR6-resistant isolates the following mutations in gp120: I339T in the C3 region, S372L in the V4 region, and Q395K in the C4 region; and in gp41: S668R and F672Y in the 'heptad repeat' 2 (HR2) region. These findings strongly suggest that NeoR6 obstructs HIV-1 replication by interfering with the fusion step, dependent on both conformational changes in gp120 following CD4 and CXCR4 interaction, as well as by conformational changes in gp41 induced by HR1 and HR2 interaction. The AACs may thus represent a novel family of fusion inhibitors.

We have recently designed and synthesized aminoglycoside-arginine conjugates (AACs) as potential anti-HIV-1 agents. AACs exert a number of activities related to Tat antagonism. We here present a new set of AACs, conjugates of neomycin B, paromomycin, and neamine with different number of arginines (1-6), their (a) uptake by human T-cell lines, (b) antiviral activities, (c) competition with monoclonal antibody (mAb) 12G5 binding to CXCR4, (d) competition with stromal cell-derived factor-1 (SDF-1alpha) binding to CXCR4, and (e) competition with HIV-1 coat protein gp120 cell penetration. The appearance of mutations in HIV-1 gp120 gene in AACs resistant HIV-1 isolates, supports that AACs inhibit HIV-1 infectivity via interference of gp120-CXCR4 interaction. Our results point that the most potent AACs is the hexa-arginine-neomycin conjugate, the other multi-arginine-aminoglycoside conjugates are less active, and the mono-arginine conjugates display the lowest activity. Our studies demonstrate that, in addition to the core, the number of arginines attached to a specific aminoglycoside, are also important in the design of potent anti-HIV agents. The AACs play an important role, not only as HIV-1 RNA binders but also as inhibitors of viral entry into human cells.

Vaccination against HIV-1 of hosts with a dominant Th2 immune profile may fail to induce essential protective Th1 immune responses. By using Schistosoma-infected mice, with a pre-existent Th2 immune background, we demonstrate that oligodeoxynucleotides (ODN) containing unmethylated cytosine-phosphate-guanosine (CpG) immunostimulatory sequences co-administered with inactivated, gp120-depleted HIV-1 viral particles (HIV-1 immunogen) lead to potent Th1 anti-HIV-1 immune responses overcoming the Th2 bias. In contrast, Schistosoma-infected mice immunized with HIV-1 immunogen in incomplete Freund's adjuvant only, induced Th2 anti-HIV-1 immune responses. These findings strongly support the advisability of using CpG ODN as a Th1 inducing adjuvant when immunizing human populations with a strong pre-existent Th2 immune profile.

OBJECTIVE To study the role of cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) during HIV infection. METHODS Intracellular CTLA-4 expression, determined by flow-cytometry, and proliferative responses to HIV antigens, were studied in peripheral blood mononuclear cells (PBMC) from 93 HIV-1-infected [HIV(+)] patients and 40 HIV-1 seronegative controls. RESULTS The proportions of CTLA-4 expressing CD4+ T cells were: (1) significantly higher in HIV(+) patients, 10.95 +/- 0.66%, than in controls, 6 +/- 0.45% (P < 0.0001); (2) inversely correlated to CD4+ counts (r = -0.67, P < 0.005, n = 16, drug-naive patients; r = -0.57, P < 0.0001, n = 77, HAART-treated patients); and (3) positively correlated to proportion of activated (HLA-DR+CD3+) (r = 0.53, P < 0.0001) and memory (CD45RO+CD4+) T cells (r = 0.46, P < 0.001). CD28 median fluorescence intensity in CTLA-4- cells was twice that in CTLA-4+ cells (140 +/- 5.3 versus 70 +/- 2.28, P < 0.00001), whereas cells low in CD28 and CD4, expressed more CTLA-4 (P < 0.0001). Higher proportion of CTLA-4+CD4+ cells expressed CCR5 and Ki-67, in comparison with CTLA-4-CD4+ cells, (65 +/- 11.9 and 25 +/- 7.5% versus 27 +/- 8.9 and 3.7 +/- 2%, P < 0.0001 and P < 0.01, respectively). Among HAART-treated patients, with viral load below detectable levels, CD4+ cells increase was inversely correlated to %CTLA-4+CD4+ cells (r = -0.5, P = 0.003, n = 39). Proliferation of PBMC to anti-CD3, gp-120 depleted HIV-1 antigen or HIV-1 p24 stimulation was inversely correlated with CTLA-4 levels (r = -0.68, P = 0.0035; r = -0.38,P = 0.04; and r = -0.43, P = 0.028, respectively). CONCLUSIONS (1) CTLA-4 is upregulated during HIV infection and may therefore account for CD4 T-cell decline and anergy in HIV-1 infection. (2) Increased levels of CTLA-4 may undermine immune responses and in the HAART-treated patient-immune reconstitution. (3) Blocking of CTLA-4 may offer a novel approach for immune-based therapy in HIV infection.

This study addressed the role of T-cell immune activation in determining HIV-1 plasma viral load and CD4+ T-cell blood levels during HIV-1 infection. A decrease of blood CD4 levels and CD4/CD8 ratios and an increase of CD8 levels in both treated (n = 35) and untreated (n = 19) HIV-positive individuals were more strongly correlated to immune activation (log percentage of HLA-DR+CD3+ cells; R = -0.78, R = -0.77, and R = 0.58, respectively; p

A requisite for vaccines to confer protection against intracellular infections such as Human Immunodeficiency Virus or Mycobacterium tuberculosis is their capacity to induce Th1 immune responses. However, they may fail to do so in Africa and South East Asia, where most individuals have a dominant preexistent Th2 immune profile, due to persistent helminthic parasitic infections, which may undermine any Th1 response. It is well established that DNA vaccines induce strong Th1 biased immune responses against an encoded antigen, depending on the route and mode of immunization. Here, we demonstrate that intradermal immunization with plasmid DNA encoding β-gal (pCMV-LacZ) of Schistosoma-infected mice, with preexistent dominant Th2 immune background, induce a strong Th1 anti-β-gal response, as opposed to immunized with β-gal only. Importantly, the established protective Th2 immune response to schistosomes was not disrupted. These findings strongly support the possibility of using plasmid DNA as a Th1 inducing adjuvant when immunizing populations with a strong preexistent Th2 immune profile.

Helminth infections affect over a quarter of the world's population, especially in the developing countries. These long-lasting parasitic infections cause widespread immune activation and dysregulation, a dominant Th2 cytokine immune profile and an immune hyporesponsiveness state. Considering these profound immune changes and the similar geographic distributions of helminthic infections, HIV and tuberculosis (TB), we suggest that helminthic infections play a major role in the pathogenesis of AIDS and TB. They apparently make the host more susceptible to infection by HIV and Mycobacterium tuberculosis, and impair his/her ability to generate protective immunity against both infections. The implication of these ideas is that without eradication of helminth infections and/or modulation of the immune changes that they cause, HIV and TB vaccines may fail to confer protection against their respective infections in helminth-endemic areas.

Helminthic parasites cause widespread, persistent infections in humans. The immigration of Ethiopians to Israel (a group denoted here by “Eth.”), many of them infested with helminths and in a chronic immune-activation state, enabled us to investigate the effects of such immune activation on immune responses. We studied the immune profile and immune functions of 190 Eth. and Israeli non-Eth. (Isr.) highly, partially, or non‐immune-activated individuals. Immune cells from highly immune-activated individuals were defective in several signaling responses, all of which were restored gradually following anti-helminthic treatment. These cells showed poor transmembrane signaling, as seen by the phosphorylation of various tyrosine kinases and of the MAPK kinases, ERK1/2 and p38; deficient degradation of phosphorylated IκBα; increased expression of cytotoxic T lymphocyte‐associated antigen 4 (CTLA-4), which appears to block proliferative responses in these cells; decreased β-chemokine secretion by CD8 + cells after stimulation; and reduced proliferation to recall antigen stimulation. Highly immune-activated individuals also showed decreased delayed-type skin hypersensitivity responses to recall antigen before deworming. These findings support the notion that chronic helminthic infections cause persistent immune activation that results in hyporesponsiveness and anergy. Such impaired immune functions may diminish the capacity of these individuals to cope with infections and to generate cellular protective immunity after vaccination. J. Clin. Invest. 106:1053‐1060 (2000).

N -[4-Chloro-3-(3-methyl-2-butenyloxy)phenyl]-2-methyl-3-furancarbothioamide (UC781) is an exceptionally potent nonnucleoside inhibitor of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase. We found that a 1:1 molar combination of UC781 and 3′-azido-3′-deoxythymidine (AZT) showed high-level synergy in inhibiting the replication of AZT-resistant virus, implying that UC781 can restore antiviral activity to AZT against AZT-resistant HIV-1. Neither the nevirapine plus AZT nor the 2′,5′-bis- O -( t -butyldimethylsilyl)-3′-spiro-5"-(4"-amino-1",2"-oxathiole-2",2"-dioxide plus AZT combinations had this effect. Studies with purified HIV-1 reverse transcriptase (from a wild type and an AZT-resistant mutant) showed that UC781 was a potent inhibitor of the pyrophosphorolytic cleavage of nucleotides from the 3′ end of the DNA polymerization primer, a process that we have proposed to be critical for the phenotypic expression of AZT resistance. Combinations of UC781 plus AZT did not act in synergy to inhibit the replication of either wild-type virus or UC781-resistant HIV-1. Importantly, the time to the development of viral resistance to combinations of UC781 plus AZT is significantly delayed compared to the time to the development of resistance to either drug alone.

Several important issues must be considered when performing any vaccination in areas with high prevalence of geohelminths. Immunization of populations infected with geohelminths could be sub-optimal if the immune background is not taken into consideration. Immune modulation and deworming might be essential for effective protective vaccination. In addition, further animal models and clinical studies addressing these issues are required. Underscoring the importance of these issues, a recent report has highlighted several vaccination studies in which nematode-infected mice or pigs failed to mount efficient protective immune responses.

In recent publications, oligonucleotides joined by 2',5'-linkages were found to bind to complementary single-stranded RNA but to bind weakly, or not at all, to single-stranded DNA [e.g., P. A. Giannaris and M. J. Damha (1993) Nucleic Acids Res. 21, 4742-4749]. In this work, the biochemical and physicochemical properties of 2',5'-linked oligoribonucleotides containing mixed sequences of the four nucleobases (A, G, C, and U) were evaluated. CD spectra of RNA:2', 5'-RNA duplexes were compared with the spectra of DNA:DNA, RNA:RNA, and DNA:RNA duplexes of the same base sequence. The CD results indicated that the RNA:2',5'-RNA duplex structure more closely resembles the structure of the RNA:DNA hybrid, being more A-form than B-form in character. The melting temperature (Tm) values of the backbone-modified duplexes were compared with the Tm values of the unmodified duplexes. The order of thermal stability was RNA:RNADNA:DNA approximately RNA:DNA approximately DNA:RNARNA:2',5'-RNA2',5'-RNA:2',5'-RNADNA:2',5'-RNA (undetected). RNA:2',5'-RNA duplexes are not substrates of the enzyme RNase H (Escherichia coli, or HIV-1 reverse transcriptase), but they can inhibit the RNase H-mediated cleavage of a natural DNA:RNA substrate. Structural models that are consistent with the selective association properties of 2',5'-linked oligonucleotides are discussed.