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Biomedical subjects

T C Merigan

Publications and source records attributed to T C Merigan.

At least 19 recordsLinked to original sources
PubMed1992

Enhancement of human immunodeficiency virus (HIV)-specific CD4+ and CD8+ cytotoxic T-lymphocyte activities in HIV-infected asymptomatic patients given recombinant gp160 vaccine.

Twenty-six human immunodeficiency virus (HIV)-infected asymptomatic patients with CD4+ lymphocytes > 400 per mm3 were randomly allocated to a range of doses of recombinant gp160 or a control (recombinant hepatitis B vaccine) on a double-blind basis. Each patient received an injection at 0, 4, 12, 24, 36, and 48 weeks. Treatment assignments were decoded when all patients reached 28 weeks of the study period. HIV-1-specific CD4+ and CD8+ cytotoxic T lymphocyte (CTL) activities were assessed in vitro before vaccination and 2 weeks after each injection. There were significant increases in major histocompatibility complex-restricted HIV-1 Env-specific CD4+ and CD8+ CTL activities in 18 of 21 gp160 vaccinees. No control-injected patients showed a significant change. Neither gp160 nor control recipients showed significant changes in HIV-1 Gag- and Pol-specific CTL activities. HIV-1 Env-specific CD4+ and CD8+ CTL precursor frequencies were also measured in three vaccinees before and at 24 weeks after vaccine was started. CTL precursor frequencies also increased in both CD4+ and CD8+ populations. This study shows that this gp160 vaccine is immunogenic in enhancing HIV-1 Env-specific cytotoxic T-cell-mediated immunity in HIV-seropositive individuals.

AIDS Vaccines↗
PubMed1992

A controlled trial of ganciclovir to prevent cytomegalovirus disease after heart transplantation.

BACKGROUND: Because of the immunosuppression required, heart-transplant recipients frequently have complications caused by cytomegalovirus (CMV), including pneumonia, esophagitis, gastritis, and a syndrome of fever, hepatitis, and leukopenia. We undertook a controlled trial to evaluate the prophylactic administration of ganciclovir to prevent CMV-induced disease after heart transplantation. METHODS: This randomized, double-blind, placebo-controlled trial was conducted at four centers. Before randomization, the patients were stratified into two groups: those who were seropositive for CMV before transplantation and those who were seronegative but who received hearts from seropositive donors. Ganciclovir was given intravenously at a dose of 5 mg per kilogram of body weight every 12 hours from postoperative day 1 through day 14, then at a dose of 6 mg per kilogram each day for 5 days per week until day 28. RESULTS: Among the seropositive patients, CMV illness occurred during the first 120 days after heart transplantation in 26 of 56 patients given placebo (46 percent), as compared with 5 of 56 patients treated with ganciclovir (9 percent) (P less than 0.001). Among 37 seronegative patients, CMV illness was frequent in both groups (placebo, 29 percent; ganciclovir, 35 percent; P not significant). From day 15 through day 60, the patients who took ganciclovir had significantly fewer urine cultures positive for CMV, but by day 90 there was no difference. More of the ganciclovir-treated patients had serum creatinine concentrations greater than or equal to 221 mumol per liter (2.5 mg per deciliter) (18 percent vs. 4 percent in the placebo group), but those elevations were transient. CONCLUSIONS: The prophylactic administration of ganciclovir after heart transplantation is safe, and in CMV-seropositive patients it reduces the incidence of CMV-induced illness.

Adolescent↗
PubMed1992

Liposome-formulated interleukin-2 as an adjuvant of recombinant HSV glycoprotein gD for the treatment of recurrent genital HSV-2 in guinea-pigs.

The use of interleukin-2 (IL-2) as an adjuvant to enhance an antigen-induced immunotherapeutic effect was investigated using guinea-pigs with established HSV-2 infection. Animals treated with four weekly doses of liposome-formulated IL-2 (2.7 x 10(5) U kg-1 dose) overlapping two biweekly doses of an HSV-recombinant glycoprotein D (rgD) treatment demonstrated approximately 70% reduction in HSV-2 recurrent disease compared with placebo (p less than 0.005). Combination therapy rgD plus liposome-formulated IL-2 exhibited approximately 30% greater therapeutic effect than either agent alone (p less than 0.05). Liposome formulation of IL-2 was essential to elicit the adjuvant effect. Identical biweekly dosing or more frequent daily dosing of soluble IL-2 did not produce additional therapeutic effects, suggesting the role of liposome targeting to lymph nodes. Although rgD plus liposome-formulated IL-2 induced a marginal early antibody response to rgD, there was no significant increase in overall antibody response. Combination therapy increased the frequency of minimally positive HSV lymphoproliferative response.

Animals↗
PubMed1992

Resistance to interferon-alpha in a mouse B-cell lymphoma involves DNA methylation.

Resistance to interferon-alpha (IFN-alpha) in the 38C13 B-lymphoma cell line results in the loss of antiviral, antiproliferative, and immune regulatory functions of IFN-alpha. Mutagenesis with ethylmethylsulfonic acid (EMS), which can induce point mutations in DNA, increases the frequency of resistance to IFN-alpha 20 to 40-fold. In contrast, treatment with 5-azacytidine, which causes hypomethylation of DNA, reduces the frequency of resistance to 5-10% of control. Furthermore, 5-azacytidine treatment reverts IFN-alpha-resistant cells to the IFN-alpha-sensitive state. Resistance to IFN-alpha occurs spontaneously at a rate of approximately 3 x 10(-6) variants/cell.generation, and is stable for more than 30 passages without selection in IFN-alpha. There is no evidence that gene amplification contributes to the high rate of resistance to IFN-alpha in these cells. These results indicate that DNA mutation and methylation are important in the development of IFN-alpha resistance in these cells.

Animals↗
PubMed1992

CD8+ CD11+ suppressor cells in HIV-infected asymptomatic patients: effect on HIV-specific cytotoxicity.

CD3+CD8+CD11+ cells were present in the peripheral blood of patients infected with asymptomatic human immunodeficiency virus (HIV) in higher percentage (10-20%) than in normal individuals (3-5%) in this study. These cells, through the release of soluble factors, significantly suppressed the effector phase of anti-HIV cytotoxic activities, both human leukocyte antigen (HLA)-class I or class II restricted, and nonrestricted. The effectors were CD8+CD11-, CD4+ T cells, and CD16+ cells for HLA-class I, class II restricted, and nonrestricted cytotoxicities, respectively. The soluble factors also inhibited natural killer cell activity. Thus, this effect was neither HLA-restricted nor antigen-specific. These CD3+CD8+CD11+ cells may be an important immunopathogenic factor in HIV disease.

Antigens, CD↗
PubMed1992

Quantitative RNA and DNA gene amplification can rapidly monitor HIV infection and antiviral activity in cell cultures.

We have developed a quantitative gene amplification procedure to assess the replication of human immunodeficiency virus (HIV) in cell cultures and evaluate the effect of drugs on viral replication. Increases in HIV gag RNA and DNA in phytohemagglutinin-stimulated normal peri-pheral blood mononuclear cells (PBMC) infected with HIV at very low multiplicity of infection paralleled the production of HIV p24 antigen in culture supernatants. Quantitative gene amplification was able to monitor the accumulation of viral nucleic acids in control cultures and demonstrate the effect of various concentrations of azidothymidine (AZT) on the replication of both AZT-sensitive and -resistant strains of HIV. The sensitivity of patient-derived virus strains to AZT could also be successfully measured by these procedures. The results of our studies suggest that quantitative measurement of HIV gag RNA and DNA can be used to monitor the kinetics of viral replication, antiviral activity, viral drug resistance, and mechanism of drug action.

Cells, Cultured↗
PubMed1992

Equivalent recognition of HIV proteins, Env, Gag and Pol, by CD4+ and CD8+ cytotoxic T-lymphocytes.

OBJECTIVES: Cytotoxic T-lymphocytes (CTL) appear to be an important defense mechanism against HIV infection. This study proposes to examine the major histocompatibility complex (MHC)-restricted HIV-1 Env-, Gag- and Pol-specific CTL activities in HIV-infected asymptomatic patients. DESIGN: CD4+ and CD8+ CTL were examined to establish whether the same HIV-1 protein (Env, Gag or Pol) was recognized by both CD4+ and CD8+ CTL with MHC antigen restriction. METHODS: Peripheral blood mononuclear cells, CD4+ and CD8+ T-cells from 17 HIV-infected asymptomatic patients and 10 HIV-seronegative individuals were examined for HIV-1 Env-, Gag- and Pol-specific MHC-restricted cytotoxicity using autologous and heterologous B-lymphoblastoid cell lines infected with vaccinia recombinant expressing HIV-1 Env, Gag and Pol proteins as targets. RESULTS: CD4+ and CD8+ CTL specific for the HIV-1 Env, Gag and Pol were demonstrated in the peripheral blood. DR4 and DQw2 were possible sites of MHC class II restriction of CD4+ CTL. Possible MHC class I restriction sites of CD8+ CTL included A2 and B8 for Env, A1 and A2 for Gag, and A2 and B8 for Pol antigen. CONCLUSIONS: These observations should help to define more precisely the nature and elements of protective immunity and to evaluate AIDS vaccine strategies.

CD4-Positive T-Lymphocytes↗
PubMed1992

Detection and quantification of gene amplification products by a nonisotopic automated system.

We describe in this report the ability to determine human immunodeficiency virus proviral copy number by an automated nonisotopic method. Our system utilizes a FACStarPLUS cell sorter, the GeneAmp PCR System 9600 and a Biomek 1000 robotic workstation. Linking these three machines allows cell populations to be sorted and the DNA amplified and quantitated with minimal technical effort. We have developed this system to quantitate proviral DNA copy number in sorted subpopulations of peripheral blood cells in one day.

Autoanalysis↗
PubMed1991

Cytomegalovirus-specific cell-mediated immune responses in heart and heart-lung transplant recipients are not predictive for the occurrence of symptomatic CMV disease or tissue rejection.

To study the predictive value of interferon-gamma (IFN-gamma) production in vitro for the occurrence of symptomatic CMV disease, 17 healthy adult volunteers were tested and 37 heart or heart-lung transplant recipients (CTRs) were studied at various time intervals after transplantation (Tx) for cell-mediated immune (CMI) responses to cytomegalovirus (CMV). At all intervals post Tx, in vitro IFN-gamma production in CTRs was significantly lower than in control subjects. The occurrence of CMV infection was associated with a trend toward inhibited CMI responses prior to the diagnosis, in comparison with CMI responses measured more than 4 weeks prior to or after the diagnosis of CMV infection. The occurrence of acute tissue rejection was associated with a trend toward enhanced CMV responses prior to the diagnosis, on the other hand. In the early post Tx period, the administration of antithymocyte globulin (ATG) or OKT3 monoclonal antibody and peak dosages of azathioprine were associated with significantly inhibited in vitro IFN-gamma production. Despite the demonstrated trends in vitro, IFN-gamma production does not appear to be uniformly predictive for the occurrence of symptomatic CMV disease or of acute tissue rejection in CTRs.

Adult↗
PubMed1991

Detection of human immunodeficiency virus DNA and RNA in semen by the polymerase chain reaction.

Peripheral blood mononuclear cells (PBMC) and semen of 23 men infected with human immunodeficiency virus (HIV) were examined for the presence of HIV DNA and RNA using the polymerase chain reaction (PCR) and a nonisotopic detection assay. None of the men was receiving antiretroviral therapy at the time of collection. Semen samples were separated into cell-free seminal fluid, nonspermatozoal mononuclear cells (NSMC), and spermatozoa. All of the PBMC samples, 17 (74%) of 23 NSMC samples, and none of the spermatozoal samples were positive for HIV gag gene DNA. Of 23 cell-free seminal fluid samples, 15 (65%) were positive for HIV gag gene RNA by PCR. Cell-free HIV RNA was more likely to be present in the semen of men with less than 400 than in those with greater than or equal to 400 cells/mm3 (P less than .04) and was present in all patient with p24 antigen in serum. The presence of HIV DNA in NSMC samples was not related to CD4 cell count, disease status, or the presence of p24 antigen in the serum. This study shows that HIV nucleic acid can be detected by PCR in either the cell-free seminal fluid or NSMC of 87% of semen samples but not in the DNA of spermatozoa from HIV-infected men.

AIDS-Related Complex↗
PubMed1991

Antibody response to human cytomegalovirus glycoproteins gB and gH after natural infection in humans.

Antibody to the recombinant gB (rgB) and recombinant gH (rgH) glycoproteins of human cytomegalovirus (CMV) was studied in immunocompetent and immunocompromised humans by immunoprecipitating [35S]methionine-labeled CHO cell lines stably expressing rgB and rgH. Antibody to the rgB precursor was present in greater than 60% of immunocompetent individuals. However rgH antibody was detected in less than 10% of these patients. Antibody to both the rgB and rgH was detected during convalescence in three immunocompetent individuals with symptomatic CMV mononucleosis but to a lesser extent in three others who seroconverted to CMV without symptoms. Antibody to rgB and rgH in heart and heart-and-lung transplant recipients was detected in both primary and recurrent CMV infections but not with the same intensity as in immunocompetent individuals. Selected lots of immune serum globulin, administered prophylactically to bone marrow transplant recipients, were frequently deficient in antibody to rgH but not to rgB.

Animals↗
PubMed1991

Reduction in plasma human immunodeficiency virus ribonucleic acid after dideoxynucleoside therapy as determined by the polymerase chain reaction.

Cell-free HIV RNA in plasma was detected and quantitated after antiviral therapy by the polymerase chain reaction. RNA was extracted from plasma, reverse transcribed to cDNA, amplified by polymerase chain reaction, and quantitated by absorbance based on an enzyme-linked affinity assay. 72 HIV antibody-positive subjects had one plasma sample taken. 39 who were not receiving antiretroviral therapy at the time had a mean plasma HIV RNA copy number of 690 +/- 360 (mean +/- SEM) per 200 microliters of plasma, while 33 subjects who had been receiving zidovudine therapy for a minimum of 3 mo had a mean copy number of 134 +/- 219 (P less than 0.05). 27 additional HIV antibody-positive patients had two plasma samples taken before and 1 mo after initiating dideoxynucleoside therapy. Plasma HIV RNA copy number fell from 540 +/- 175 to 77 +/- 35 (P less than 0.05). Finally, nine of these subjects had two baseline samples obtained before initiating therapy and two posttreatment samples 1 and 2 mo after therapy was begun. Mean plasma RNA copy number declined from 794 +/- 274 to less than 40 (below the lower limit of sensitivity) after 1 mo of therapy, with suppression maintained after 2 mo of therapy. These results suggest that gene amplification can be used to detect and quantitate changes in plasma HIV RNA after dideoxynucleoside therapy. Plasma HIV polymerase chain reaction may be a more sensitive marker to monitor antiviral therapy, particularly in asymptomatic patients where measurement of p24 antigen or quantitative plasma cultures are negative.

CD4-Positive T-Lymphocytes↗
PubMed1991

Safety and effects of interleukin-2 plus zidovudine in asymptomatic individuals infected with human immunodeficiency virus.

The safety of continuous i.v. interleukin-2 (IL-2) in conjunction with zidovudine (ZDV) was assessed in asymptomatic patients infected with human immunodeficiency virus. Clinical, immunologic, and viral parameters were monitored in a phase I/II trial with dose escalation and crossover arms. Daily doses of IL-2 from 1.5 to 12 x 10(6) IU/m2 were well tolerated and, in the presence of ZDV, did not induce increases in p24 antigenemia. Significant (p less than 0.05) but transient increases in CD4 cells were observed midway through infusion of IL-2 at all doses, and increases in natural and lymphokine-activated killer activity were seen at higher doses. Circulating hypodense eosinophils and soluble IL-2 receptors increased more than 10-fold. Of nine patients available for long-term follow up 13-25 months from baseline and 4-21 months after stopping IL-2, six still had improved CD4 counts (versus baseline), and the mean increase (135/mm3) for all nine patients was significant (p less than 0.05). Eight of these nine patients were negative for serum p24 at the start of therapy, and none had become p24 antigenemic at long-term follow-up.

Adult↗
PubMed1991

Inverse relationship of CD8+CD11+ suppressor T cells with human immunodeficiency virus (HIV)-specific cellular cytotoxicity and natural killer cell activity in HIV infection.

Profiles of CD8+CD11+ T suppressor cells, human immunodeficiency virus (HIV)-env-specific cytotoxic T-lymphocyte (CTL) activities, and natural killer (NK) cell activity were studied in 12 asymptomatic untreated HIV-infected patients. These patients were followed for 4-7 months. NK activity, HIV-env-specific CTL activities mediated by CD4+, CD8+ T cells and CD8+CD11+ T-suppressor cell number remained stable in seven patients during the study period. Alternatively, NK and HIV-specific CTL activities decreased and CD8+CD11+ cell number increased in five patients whose CD4+ T-cell number fell, and in four of these five patients serum p24 antigen level increased, and they developed minor clinical signs of disease progression during the study period. CD8+CD11+ cells are present in higher percentage (10-45% of peripheral blood mononuclear cells) in these HIV-infected patients as compared to those in normal individuals (3-5%). Our results suggest that CD8+CD11+ cells, NK, and HIV-specific cytotoxic activities may be helpful in monitoring prognosis of HIV infection. These observations also suggest that CD8+CD11+ cells may play an important role in the failure of host immune defences against HIV.

Antigens, CD↗
PubMed1979

Induction and kinetics of natural killer cells in humans following interferon therapy.

Natural killer (NK) cells are non-B, non-T lymphocytes that effect spontaneous cytolysis of both virus-infected and neoplastically transformed target cells. These NK lymphocytes have been detected in several species including man. Interferon is a primary regulator of natural killer activity. Because NK cells have been implicated in the regulation of tumour cell expression and can be induced by interferon in murine models, we have studied patients receiving large doses of interferon to determine (1) whether interferon could induce NK lymphocytes in the peripheral blood of man, and (2) whether there are characteristic kinetics for the appearance, disappearance and reactivation of NK lymphocytes following interferon therapy. We report here the activation of human NK cells by the systemic inoculation of human subjects with interferon. Five patients received interferon as therapy for non-Hodgkin's lymphoma. All showed a marked increase in NK cell activity 12--24 h after inoculation. Peak NK activity occurred 18 h after introducing interferon, and thereafter declined rapidly but remained above pre-interferon levels. Induced NK activity occurred with reintroduction of interferon but at lower levels of activity and with different kinetics.

Humans↗