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Biomedical subjects

C Lopez

Publications and source records attributed to C Lopez.

At least 145 records · Page 8Linked to original sources
PubMed1983

Persistent cytomegalovirus infection: association with profound immunodeficiency and treatment with interferon.

Cytomegalovirus (CMV) was repeatedly isolated from urine and saliva of a 20-month-old male child with recurrent episodes of pneumonia, high fever, rash, lymphadenopathy, oral ulceration, and neutropenia. Immunologic evaluation revealed decreased serum IgG and IgA, increased IgM, depressed T- and B-lymphocyte functions, and decreased natural killer (NK) activity for herpes simplex-type I virus-infected targets. NK activity was augmented following exposure of the patient's lymphocytes to interferon (IF) in vitro. The child was treated with interferon (four courses, dosage varying from 2 million U/day to 1 million U three times/week for periods of 10, 28, 80, and 67 days, respectively, interspersed over 9 months) and hyperimmune plasma infusions every 3 weeks. Toward the end of interferon therapy oral Levamisole was started and a feeding gastrostomy was inserted to provide nutritional support. Clinical recovery was associated with reversal of immunologic abnormalities except for the hypogammaglobulinemia. Aggressive antiviral therapy (e.g., with IF) followed by immunostimulation (e.g., with Levamisole) may prove effective in controlling certain viral infections in immunodeficiency disorders.

Agammaglobulinemia↗
PubMed1983

Nucleosides. 123. Synthesis of antiviral nucleosides: 5-substituted 1-(2-deoxy-2-halogeno-beta-D-arabinofuranosyl)cytosines and -uracils. Some structure-activity relationships.

The syntheses of several 2'-halogeno-5-substituted-arabinofuranosylcytosines and -uracils are described, and relationships of structure to anti herpes virus activity in vitro were examined. Those arabinonucleosides containing the 2'-fluoro function exhibit, generally, more potent anti herpes virus (HSV) activity than do their 2'-chloro of 2'-bromo analogues. The importance of the fluorine in the 2'-"up" (arabino) configuration for enhancement of antiviral effectiveness is demonstrated by the superior activity of 2'-fluoro-5-iodo-ara-C [3a, FIAC] to that of 2'-fluoro-5-iodo-ribo-C. Of all the nucleosides tested herein, FIAC exhibited the most potent in vitro activity against HSV. 2'-Chloro-5-iodo- and -5-methyl-ara-C (3b and 4b) were 37 to greater than 500 times more effective in vitro against HSV type 2 than against type 1, suggesting that these latter derivatives might serve clinically as useful probes to distinguish between HSV types 1 and 2 in the diagnosis of HSV infections in man.

Animals↗
PubMed1983

Correlation between low natural killing of fibroblasts infected with herpes simplex virus type 1 and susceptibility to herpesvirus infections.

Natural killer cells capable of lysing herpes simplex virus type 1 (HSV-1)-infected fibroblasts were studied in three groups of patients unusually susceptible to severe herpes-virus infections. Cord blood was evaluated because of the known susceptibility of neonates to disseminated infections due to herpes simplex virus type 2 at birth. Only 30% of the cord blood specimens tested demonstrated normal lysis of HSV-1-infected fibroblasts and a normal increment in the lysis of infected over uninfected cells. Five out of six patients with Wiskott-Aldrich Syndrome (WAS) also were found to have abnormally low responses by these criteria. The one WAS patient with normal responses had had little difficulty with infections and had survived much longer than usual. Five patients with severe herpesvirus infections and no known primary cellular immunodeficiency had natural killer cell function significantly below normal (P less than 0.001). These data suggest that natural killer cells probably play an important role in human resistance to herpesvirus infection and that deficiencies of this system may result in unusual susceptibility to herpesvirus infections.

Adolescent↗
PubMed1983

Severe acquired immune deficiency syndrome in male homosexuals: diminished capacity to make interferon-alpha in vitro associated with severe opportunistic infections.

Natural killer cell function, directed against either K562 tumor targets or herpes simplex virus type 1-infected fibroblasts, was often low in patients with acquired immune deficiency syndrome (AIDS) but failed to distinguish these patients from either male homosexual controls or patients with lymphadenopathy. Mononuclear cells from patients with AIDS and opportunistic infections generated diminished levels of interferon-alpha in response to herpes simplex virus type 1-infected fibroblasts. This deficiency discriminated patients with severe opportunistic infections from most individuals with either generalized lymphadenopathy or Kaposi's sarcoma only and from male homosexual control subjects. The deficiency in interferon-alpha generation may be the consequence of the opportunistic infections that these individuals have contracted or may be a direct manifestation of AIDS itself.

Acquired Immunodeficiency Syndrome↗
PubMed1983

Activity of 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)thymine against herpes simplex virus in cell cultures and rabbit eyes.

A new antiviral compound 1-(2'-fluoro-2'-deoxy-beta-D-arabinofuranosyl)thymine (2'-fluoro-5-methyl-ara-uracil [FMAU]), was compared with acyclovir and idoxuridine in vitro against two strains of both herpes simplex virus type 1 (HSV-1) and HSV-2. Determinations of the 50% effective dose varied slightly with each strain and with the host cells employed. The 50% effective dose for FMAU and acyclovir against HSV-1 ranged from 0.1 microM to 0.5 to 0.6 microM in rabbit kidney cells and from 0.5 microM to 0.6 to 0.78 microM in Vero cells. Beginning 4 days post-inoculation, topical FMAU therapy given five times per day to rabbits with acute herpetic keratitis either suppressed or delayed the severity of corneal epithelial involvement, conjunctivitis, iritis, and corneal clouding. Responses to treatment with FMAU were similar to those obtained with acyclovir and significantly better than those attained with idoxuridine and vidarabine. At 30 to 40 days after the end of treatment, rabbit eyes were subjected to iontophoresis with epinephrine in an attempt to induce reactivation and enhance detection of previously latent HSV-1. Latent HSV-1 was detected in 67 to 92% of trigeminal ganglia in FMAU-treated animals and in 90% of placebo-treated animals.

Acyclovir↗
PubMed1983

Efficacy and selectivity of some nucleoside analogs as anti-human cytomegalovirus agents.

1-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC), 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-methyluridine (FMAU), 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouridine (FIAU), and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-ethyluridine (FEAU) were evaluated for antiviral activities against human cytomegalovirus (HCMV) and compared with 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir) and E-5-(2'-bromovinyl)-2'-deoxyuridine (BVDU). The relative anti-HCMV potencies of these compounds, as determined by calculating the dose of drug which inhibited 50% plaque formation, were in order of decreasing potency: FIAC greater than FIAU greater than FMAU greater than acyclovir greater than FEAU greater than BVDU. The antiviral activity of FIAC occurred at levels much lower than those that caused cytotoxic or cytostatic effects in uninfected fibroblasts. Neither thymidine nor deoxycytidine reversed the anti-HCMV activity of FIAC, indicating that this drug was not acting as an analog of the natural nucleosides. FIAC was not phosphorylated by cytosols of HCMV-infected cells to a greater extent that by those of uninfected cells, indicating that, unlike the antiviral activity against herpes simplex virus type 1, the selectivity of this drug is probably not based on a virus-specified pyrimidine kinase.

Antiviral Agents↗
PubMed1983

Suppression of the immune response in tumor-bearing mice. III. Induction of functionally suppressive antigen-driven macrophages.

A functionally suppressive antigen-driven subpopulation of macrophages has been demonstrated in mice-bearing tumors produced by MSV-transformed BALB/3T3 cells. The suppressor macrophages depressed markedly both allogeneic and syngeneic mixed leukocyte culture responses and functioned even when assayed at low concentrations, suggesting that high concentrations of normal macrophages were not responsible for the suppression. Studies also showed that suppressor macrophages acted to suppress the proliferation of hyperreactive Lyt 1+,2- cells found in the splenic cell suspensions of tumor-bearing mice after the removal of the adherent suppressor cells. Finally, the suppressive activity of macrophages induced in tumorous mice could be augmented by KiMSV or MMSV but not by MuLV antigen. These results suggest that suppression might be a direct response to transformation-associated determinants expressed on the tumor cells as well as on the MSV virions or the result of cellular interactions between suppressor macrophages and other antigen-specific spleen cell populations.

Animals↗
PubMed1983

Phase I evaluation of 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine in immunosuppressed patients with herpesvirus infection.

2'-Fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC) is a potent selective inhibitor of the replication of herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella zoster virus, and cytomegalovirus in cell culture systems. FIAC produces an unequivocal therapeutic effect in mice that have been inoculated with a lethal burden of HSV-1. We have administered FIAC to 32 host compromised patients, 30 with advanced cancer, who were experiencing acute herpesvirus infections (varicella zoster, 29; HSV-1, 2; HSV-2, 1); the drug was given by 20 min i.v. infusion twice a day for 7 days. The dosage levels explored were 60, 120, 240, 400, and 600 mg/sq m/day. Drug-induced myelosuppression became evident at 600 mg/sq m/day; thrombocytopenia exceeded leukopenia. The toxic low dose was 400 mg/sq m/day with mild nausea and rare myelosuppression. All 24 varicella zoster patients with cutaneous disease receiving FIAC, greater than or equal to 120 mg/sq m/day, experienced stabilization of cutaneous lesions within 48 to 72 hr; healing began promptly thereafter.

Antiviral Agents↗
PubMed1983

Heterogeneity of human NK cells: comparison of effectors that lyse HSV-1-infected fibroblasts and K562 erythroleukemia targets.

In this study, we compared the natural killer (NK) cells that lyse HSV-1-infected NK(HSV-1) or uninfected [NK-(FS)] fibroblasts to those that lyse K562 erythroleukemia cells [NK(K562)]. Activity against all three targets was found in Percoll gradient fractions enriched for large granular lymphocytes, which suggests that these effector cells have a common morphology. In competition studies between 51Cr-labeled targets and unlabeled targets, both the infected and the uninfected fibroblasts competed for lysis of NK(HSV-1) and NK(FS) activity, whereas K562 cells competed poorly. In contrast, when 51Cr-labeled K562 cells were used, the unlabeled K562 cells competed well, but HSV-1-infected and uninfected fibroblasts competed poorly. Panning studies and complement elimination experiments using monoclonal antibodies were performed to describe cell surface markers on the NK cell populations. Treatment with an antibody to an la framework antigen reduced NK(HSV-1) but not NK(K562) activity. In contrast, the majority of NK(K562) effectors were recognized by antibodies to the E-rosette receptor (Lyt-3 and OKT11A), whereas NK(HSV-1) activity was much less sensitive to this antibody. OKM1, OKT10, and Leu-7 (HNK-1) markers were found on a portion, but not all, of the cells that lysed both the HSV-FS and K562 targets, while treatment with HLA plus complement totally abrogated both NK activities. Taken together, these data are consistent with the concept that human NK cells are heterogeneous and that we are dealing with at least three subpopulations of effector cells--one that kills the infected or uninfected fibroblasts; one that kills K562 cells; and a third population that may be able to kill all three targets. Patient studies provide additional evidence for heterogeneity within the NK cells that lyse the fibroblasts and K562 cells. We have studied a number of individuals who have normal NK activity with one target (HSV-FS or K562) but have low or no activity against the other. These patients provide strong evidence not only that NK cells are heterogeneous but also that these NK subpopulations can be regulated independently of each other in vivo.

Adult↗
PubMed1983

Fibrous intimal thickening and atheronecrosis of the thoracic aorta. Some background for mathematical theory.

Paraffin sections from the lateral walls of the thoracic aorta, stained with a nigrosin-Gomori trichrome combination, were used to separate subjects into those having (Yes-A) and not having (No-A) atheronecrosis, as operationally defined. In 174 of the 211 No-A subjects, the dispersal of fibrous intimal thickening (FIT) over a carefully selected set of loci was fitted well (goodness of fit p greater than 0.05) by the negative binomial distribution. In 99 of the 125 Yes-A subjects, negative binomial forms were fitted well to the data. The Poisson and positive binomial forms also fitted well in most aortas. In some aortas, departures from the negative binomial, positive binomial, or Poisson forms could be attributed to the presence (among a total of 40 points) of a set of one to five points having accelerated fibroplasia. Atheronecrosis and accelerated fibroplasia tended to coexist in the same subjects and also to be found together in the same loci within aortas. Both features of advanced plaques were characteristic of older subjects. These results taken together affirm that several decades of progression of FIT precede an abrupt emergence of the two features of late phase atherogenesis. The findings suggest that atherosclerosis progresses by a two-phase stochastic process. In phase one, FIT evolves such that a form resembling the negative binomial is generated with approximations of the mean as a linear function of time and the standard deviation as a quadratic function of the mean. In phase two the set of points with greatest FIT acquires either atheronecrosis, or accelerated fibroplasia, or both.

Adult↗
PubMed1982

In vitro metabolism of 1-beta-D-arabinofuranosylcytosine and 1-beta-2'-fluoroarabino-5-iodocytosine in normal and herpes simplex type 1 virus-infected cells.

Phosphorylation of 1-beta-D-2'-F-arabino-5-iodocytosine (FIAC), a newly synthesized pyrimidine nucleoside with potent antiherpesvirus activity, was compared with that of its parent compound, 1-beta-D-arabinofuranosylcytosine (ara-C). While ara-C was phosphorylated extensively by homogenates of normal, rapidly proliferating mouse tissues, FIAC was a poor substrate for the nucleoside kinase occurring in such normal tissues. With cell homogenates of noninfected Vero cells, thymidine (TdR) was phosphorylated about fifty and twenty times more efficiently than FIAC and ara-C, while infection of Vero cells with Herpes Simplex Virus Type 1 (HSV-1) resulted in a 23-fold increase of TdR- and a 1270-fold increase of FIAC phosphorylation. In contrast, phosphorylation of ara-C was increased only by a factor of 2.6. While the reaction products obtained with homogenates of normal mouse tissues were 5'-mono-, di- and triphosphates of ara-C and FIAC, the reaction products with noninfected and infected Vero cell homogenates were predominantly monophosphates. In contrast, TdR was efficiently phosphorylated to its 5'-mono-, di- and triphosphates by such homogenates. In intact HSV-1-infected Vero cells. FIAC was rapidly taken up and phosphorylated to FIACMP and to an as yet unidentified metabolite. In contrast, TdR was taken up and phosphorylated to 5'-mono-, di- and triphosphates and ara-C was taken up moderately but metabolized poorly to its 5'-mono-, di- and triphosphates. Thus, in normal tissues, FIAC was a poorer substrate than ara-C for nucleoside kinases, but in intact HSV- 1-infected Vero cells FIAC was efficiently phosphorylated and thus behaved like a TdR analog, except that it was phosphorylated only to the 5'-monophosphate and a hitherto unidentified metabolite. The greatly increased phosphorylation of FIAC by HSV-1-infected Vero cells probably accounts, at least in part, for its great selectivity of action.

Antiviral Agents↗
PubMed1982

Role of interferon in natural kill of HSV-1-infected fibroblasts.

The production of interferon during natural killer (NK) assays against HSV-1-infected fibroblasts (NK(HSV-1)) was studied to determine whether this interferon was responsible for inducing the preferential lysis of herpes-virus-infected target cells over uninfected target cells. The interferon produced during NK(HSV-1) assays was analyzed and found to have the properties of HU-IFN-alpha. Little or no IFN was produced during NK assays against uninfected fibroblasts (NK(FS)) or K562 (NK(K562)) cells. Although the appearance of interferon in the culture supernatants seemed to parallel the development of cytotoxicity during NK(HSV-1) assays, the levels of cytotoxicity and IFN generated did not correlate, arguing against a strict quantitative dependence of cytotoxicity upon IFN production. NK(K562) and NK(FS) cytotoxicity developed with little or no production of IFN. When IFN-pretreated effector cells were used, there was still a preferential lysis of infected over uninfected target cells. This preferential lysis by IFN-treated effector cells of infected over uninfected targets was seen as early as 2 hr into the assay. Anti-IFN antibodies added to the NK assays, although neutralizing all the IFN produced during the assays, had no effect on NK(FS) or NK(K562) cytotoxic activity and caused a slightly reduction of NK(HSV-1) activity only in one of three experiments. We conclude that although IFN is generated during NK(HSV-1) assays, this IFN cannot solely account for the increased lysis of infected over uninfected cells and that NK(HSV-1) activity is in some other way dependent on the virus infection.

Antigens, Viral↗
PubMed1982

Helper cell function of Leukemic Leu-2a+, histamine receptor+, T gamma lymphocytes.

Leukemic cells from a patient with an 11-yr history of chronic lymphocytic leukemia (CLL) were found to have the surface phenotype Leu-1+, Leu-2a+, Leu-3a-, sheep erythrocyte rosette+, IgGFc receptor+. The cells also bore a receptor for histamine inhibitable by cimetidine (H-2). The clonal nature of the proliferation was documented by the presence of a consistent marker chromosome (22-trisomy) in metaphases elicited by culture with T cell growth factors. Although the surface phenotype suggested that these cells might function as suppressor lymphocytes, they had an enhancing effect on the pokeweed- mitogen- (PWM) driven generation of plasma cells and reverse hemolytic plaque-forming cells in vitro. This helper activity was modified neither by irradiation of the leukemic cells nor by removal of a minor population of Leu-3a+ cells, suggesting that the effects were attributable to the CLL cells themselves. In addition to these functions, the CLL cells were active in antibody-dependent cellular cytotoxicity (ADCC) assays in association with expression of Fc receptors for IgG. The ADCC was diminished when a transient loss of the Fc receptor expression was observed. No activity in natural killer cell assays employing K-562 cells or herpes simplex virus- (HSV) infected cells as targets could be attributed to the leukemic clone. These studies indicate that the cell surface phenotype, as defined by monoclonal antibodies, may not always predict the functional state of a particular cell, and suggest that within the Leu-2a+ (TH-2+) population of human lymphocytes, some helper as well as suppressor/cytotoxic cells are to be found.

Antibody-Dependent Cell Cytotoxicity↗
PubMed1982

Induction of gp70-specific suppressor T-cells in mice inoculated with virus-producing tumor cells.

Inoculation of BALB/c mice with syngeneic, murine leukemia virus (MuLV)-producing (murine sarcoma virus-transformed) Balb/3T3 tumor cells resulted in diminution of alloreactivity as measured in the mixed leukocyte culture (MLC) reaction. Cells that suppressed this response were identified in the spleens of tumor-bearing mice 10--14 days after inoculation. The suppressor cells were adherent, radiosensitive T-lymphocytes of the Lyt 1-, 2, 3+ phenotype. Mice inoculated with Gross MuLV (G-MuLV)-producing tumor cells, but not those inoculated with a nonproducing subclone of the same tumor cells, developed suppressor T-cells. The T-cell-mediated suppression of the MLC could be augmented by the admixture of G-MuLV antigen, similar to that replicated by the tumor cell, but not by the admixture of a Rauscher-type MuLV antigen which lacked the cross-reactive, type-specific antigens of the G-MuLV. Furthermore, this augmented suppression could be abrogated by the addition of monoclonal anti-gp70 antibody. These findings indicated that antigen-specific suppressor T-cells were induced in response to leukemia virus antigen shed from and/or expressed on tumor cells and that the suppressive activity involved the specific recognition of the gp70 portion of the virus.

AKR murine leukemia virus↗
PubMed1981

Severe acquired immunodeficiency in male homosexuals, manifested by chronic perianal ulcerative herpes simplex lesions.

Four homosexual men presented with gradually enlarging perianal ulcers, from which herpes simplex virus was cultured. Each patient had a prolonged course characterized by eight loss, fever, and evidence of infection by other opportunistic microorganisms including cytomegalovirus, Pneumocystis carinii, and Candida albicans. Three patients died; Kaposi's sarcoma developed in the fourth. All were found to have depressed cell-mediated immunity, as evidenced by skin anergy, lymphopenia, and poor or absent responses to plant lectins and antigens in vitro. Natural-killer-cell activity directed against target cells infected with herpes simplex virus was depressed in all patients. The absence of a history of recurrent infections or of histologic evidence of lymphoproliferative or other neoplastic diseases suggests that the immune defects were acquired.

Adult↗