Prevalence of viremia in human immunodeficiency virus-infected patients with renal disease.

BACKGROUND: The prevalence of viremia and its relationship to the pathogenesis of nephropathy in human immunodeficiency virus (HIV)-infected patients with renal disease is unknown. To assess the prevalence of plasma viremia in HIV-infected patients with chronic renal disease, we performed a cohort study in two urban university medical centers. METHODS: Samples of blood from 11 HIV-infected patients with renal failure who were treated with hemodialysis were analyzed concurrently with control samples from three non-HIV-positive patients receiving hemodialysis treatment. Samples from four HIV-infected patients with chronic renal insufficiency were evaluated concurrently. Thirty-three HIV-infected patients with serum creatinine levels of less than 132 mumol/L (1.5 mg/dL), and trace or absent dipstick proteinuria served as controls for the population with renal disease. The patients infected with HIV were staged by CD4 cell counts and the presence of opportunistic infections. Blood samples were analyzed for plasma HIV p24 antigenemia by antigen capture enzyme-linked immunosorbent assay. Blood samples were analyzed for the presence of viremia by infection of normal stimulated peripheral blood mononuclear cell cultures with plasma samples and detection of HIV p24 antigen in culture supernatants. RESULTS: Two of the 11 patients treated with hemodialysis had evidence of HIV p24 antigenemia, while seven of the 11 had evidence of plasma viremia. The proportion of hemodialysis patients with detectable antigenemia and viremia was similar to that in patients with chronic renal insufficiency. A significantly greater proportion of HIV-infected patients with renal disease had plasma viremia and antigenemia, compared with HIV-infected patients without renal disease. In logistic regression analysis, race, CD4 cell count (either on a continuous scale or dichotomized at 0.2 x 10(9)/L), and treatment with zidovudine were not significantly associated with the presence of plasma viremia, but patient age and the presence of renal disease were factors independently associated with viremia. CONCLUSIONS: The similar proportions of HIV-infected patients with viremia in groups of patients with chronic renal insufficiency and with renal disease treated with hemodialysis suggest that dialysis treatment does not increase the prevalence of plasma viremia in HIV-infected patients with renal disease. The similar proportions of HIV-infected hemodialyzed patients and patients with chronic renal insufficiency with plasma viremia, and the greater prevalence of viremia in patients with renal disease compared with HIV-infected patients without clinical renal disease suggest that plasma viremia and renal dysfunction are related. Whether this represents a cause and effect relationship is unknown. The greater prevalence of viremia in HIV-infected patients with renal disease has implications for the pathogenesis of HIV-related renal diseases and for caregivers in clinical settings and dialysis units.

Biomedical applications of tissue engineering technology: regulatory issues.

Novel emerging technologies such as tissue engineering, which utilize the approaches of molecular and cell biology, biotechnology, as well as materials science and engineering, are being used in the development of a wide range of biomedical products developed by industries regulated by the U.S. Food and Drug Administration (FDA). The FDA's mission is to promote and protect the public health by ensuring the safety and effectiveness of pharmaceuticals and medical devices, including those manufactured by novel technology, as assessed by scientific principles and methods. Regulatory review is conducted on a product-by-product basis. To accomplish its mission over the wide range of products in its regulatory purview, the FDA has six centers, each staffed with the scientific and regulatory expertise to evaluate the products in the center's jurisdiction. Recent legislative and regulatory changes are designed to simplify and facilitate the administrative process for evaluating novel combination products emanating from such interdisciplinary technology as tissue engineering and to resolve questions of product regulatory jurisdiction. Under the new procedures, the FDA may designate a lead FDA center for product review based on the primary mode of action of the combination product, with additional center(s) designated to assist in the evaluation in a collaborative or consultative capacity. In addition, FDA centers have increased their cooperation and information sharing with regard to evolving interdisciplinary technology. The FDA InterCenter Tissue Engineering Initiative was established to develop information on intercenter efforts in the evaluation of tissue engineering applications and to identify areas for further consideration. The FDA InterCenter Tissue Engineering Working Group, comprised of staff from the Center for Biologies Evaluation and Research (CBER), Center for Devices and Radiological Health (CDRH), Center for Drug Evaluation and Research (CDER), and Center for Veterinary Medicine (CVM) has developed a Draft Report considering recent developments in tissue engineering and scientific and regulatory issues in the product application areas. The Working Group has identified generic safety and effectiveness issues for consideration by the research and development community in its development of products. The FDA centers are using multiple approaches at their disposal in the evaluation of tissue engineered products including research, data and information monitoring, regulatory guidance, training and education, and cooperation with public and private groups.

Quantitation of human immunodeficiency virus (HIV) with respect to disease stage and zidovudine (AZT) therapy.

Quantitation of HIV in 115 seropositive individuals was undertaken to evaluate the potential for HIV transmission as a nosocomial infection through the use of medical devices that may come in contact with the peripheral blood of HIV-infected individuals. The virus burden in the peripheral blood was estimated from the level of: plasma HIV p24 antigenemia; plasma viremia; p24 antigen in peripheral blood mononuclear cell (PBMC) lysates as indicators of productive infection; and frequency of latently infected cells. Negligible HIV levels were observed in the plasma and PBMC lysates of the majority of samples except for late-stage patients with certain opportunistic infections and/or lack of zidovudine (AZT) therapy. Some individuals on AZT therapy and at late-stage of disease may show antigenemia without plasma viremia or alternatively, plasma viremia may be observed without plasma antigenemia. PBMC lysate data indicated that the frequency of productively infected cells was less than one in 20,000 PBMCs for the majority of samples irrespective of status on AZT therapy or disease stage. HIV was detected in greater than 95% of the cocultures and within 14 days for most of the samples, again regardless of the stage of disease or status on AZT therapy. The frequency of latently infected cells in this cohort ranged from 125 to 3125 per million PBMCs and was calculated to be as high as 2.5% of the helpter T-cell (CD4+ cell) population in the peripheral blood. The average latently infected cell frequency was 2-3-fold higher in early stage patients not on AZT than in late-stage patients on AZT therapy.

Isolation and characterization of interferon-producing reticuloendothelial cells from mouse epidermis.

A homogeneous population of trypsin-resistant epidermal cells has been isolated from newborn ICR mice. These cells are characterized by adherence, receptors for Fc-IgG, ATPase activity, phagocytosis of latex particles and opsonized sheep erythrocytes, and secretion of lysozyme and interferon. The production of interferon by these cells suggests that they may be important in protection against viral infections of the skin as well as in regulation of immune responses. The ultrastructure of these trypsin-resistant epidermal cells shows striking similarity to that of reticuloendothelial cells.

Induction of type-C retrovirus by the tumor promotor TPA.

The tumor promotor 12-0-tetradecanoyl-phorbol-13-acetate (TPA) induced endogenous murine xenotropic type-C retrovirus from A1-2 cells, derived from the BALB/c mouse, as determined by infectious center focus-forming assay on permissive normal rat kidney (NRK) cells. Kinetic dose-response studies showed that the number of cells induced to release virus was dependent on TPA concentration and the time of assay following TPA exposure. Maximal induction occurred when cells were treated with 80 ng/ml of TPA for 24 h and assayed at 24 or 48 h. A 30-min pulsed TPA exposure and 200 ng/ml induced virus levels approximating those observed after a continuous 24-h exposure to 80 ng/ml. The combination of TPA at concentrations of 10 and 20 ng/ml and a suboptimal level of 5-iodo-2-deoxyuridine (IdUrd) enhanced retrovirus induction threefold above that seen by the optimum IdUrd concentration alone. The protease inhibitors, antipain and leupeptin, decreased virus induction by TPA, a protease inducer. The capacity of TPA to induce type-C retrovirus complements results demonstrating the enhancement of Epstein-Barr virus (EBV) and murine mammary tumor virus (MMTV) synthesis by TPA.

Induction of endogenous murine type C virus by ultraviolet-irradiated herpes simplex virus: effect of metabolic inhibitors.

Ultraviolet-irradiated herpes simplex virus (u.v.-HSV) induced endogenous xenotropic type C virus from AI--2 cells, derived from the BALB/c mouse, as determined by infectious centre focus-forming assay on permissive normal rat kidney (NRK) cells. The number of cells induced to release type C virus by irradiated HSV was dependent on the level of u.v. exposure received by the HSV. Optimal induction occurred when cells were infected with irradiated HSV during their exponential growth phase. Virus induction decreased under conditions of simultaneous cellular exposure to hydroxyurea or actinomycin D, inhibitors of DNA and RNA synthesis, respectively, with actinomycin D having a greater inhibitory effect. This suggests that both DNA and RNA synthesis are required for irradiated HSV induction of murine xenotropic virus. Hydroxyurea decreased induction in the first few hours after infection of A1--2 cells with irradiated HSV, suggesting that the biological events involving DNA synthesis which are required for induction by u.v.-HSV occur shortly after infection.

Ultraviolet radiation induction of endogenous murine type C virus.

Induction of endogenous type C RNA virus occurred following exposure of mouse cells to ultraviolet radiation. Irradiation of A1-2 cells, derived from the BALB/c mouse, induced endogenous xenotropic type C virus as determined by infectious center focus-forming assay on normal rat-kidney (NRK) cells. Viral induction by UV radiation was compared to that for the halogenated pyrimidines, 5-iodo-2-deoxyuridine (IdU) and 5-bromo-2-deoxyuridine (BrdU). Although the fraction of A1-2 cells induced to release virus by UV radiation (0.17%) was less than that observed for IdU (3.0%) and BrdU (0.46%), use of the sensitive infectious center assay demonstrated reproducible UV induction. Dose-response studies showed that the level of viral induction by UV was dependent upon cellular UV exposure. Study of A1-2 cell survival following irradiation showed that optimum viral induction occurred at a UV exposure corresponding to the edge of the shoulder of the survival curve, suggesting that UV sensitivity of the host cell may be a factor limiting the level of induction. Since less radiation was required for viral induction than for inactivation of colony-forming ability, viral induction may be a more sensitive dosimeter of in vitro UV bioeffects than cell survival for this system.

The biochemistry of lymphocyte-derived mediators of immunological inflammation.

Evidence is presented to indicate that there exists in lymphoid tissue, as a result of transforming lymphocytes, a new lymphokine which is chemotactically specific for lymphocytes, called 'lymphotactin'. Lymphotactin has been purified to electrophoretic homogeneity; has a molecular weight of 10,500 D and an isoelectric point of 5.9. Its role in amplifying the immune defense system by recruitment of naive lymphocytes into propinquity with the challenging antigens is suggested. Purification of macrophage migration inhibitory factor from thymus extracts to electrophoretic homogeneity leads to a compound of molecular weight of 36,500 D and an IEP of 6.9. Chemically it contains sialic acid and o-methyl glucopyranoside as its only carbohydrates. Purified MIF activates the macrophage phagocytically. Skin reactive factor and lymph node permeability factor have been isolated and purified and are found to be inhibited by pepstatin and antihistamine and to have an isoelectric point of pH 4.2 and a molecular weight of 50,000--100,000 D. It is believed that this anionic permeability increasing agent actually arises from the lysosomes of macrophages and lymphoblasts (the normal small lymphocyte having essentially no lysosomal organelles). The mononuclear cell infiltration characteristic of crude SRF and LNPF may proceed from their being contaminated with lymphotactin.