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Biomedical subjects

T G Evans

Publications and source records attributed to T G Evans.

At least 19 recordsLinked to original sources
PubMed2000

Response to immunization with recall and neoantigens after prolonged administration of an HIV-1 protease inhibitor-containing regimen. ACTG 375 team. AIDS Clinical Trials Group.

OBJECTIVES: To ascertain if immunization results in the restoration of responses to recall antigens, in the development of responses to presumed neoantigens, and to identify the virologic and immunologic correlates of these responses in persons with HIV-1 infection. DESIGN AND SETTING: Open-label study carried out at three university-affiliated AIDS Clinical Trials Units in the United States. SUBJECTS AND METHODS: Thirty-one subjects participating in AIDS Clinical Trials Group Protocol 375 who had received zidovudine, lamivudine, and ritonavir for at least 48 weeks. Subjects were immunized with tetanus toxoid (TT) at entry and with inactivated hepatitis A vaccine (hep A) and keyhole limpet hemocyanin (KLH) at entry and 6 weeks. The development of antibody, lymphocyte proliferative assay (LPA), and delayed-type hypersensitivity (DTH) responses after immunization were monitored. RESULTS: The LPA and DTH responses to TT improved in 57 and 68% of participants, respectively; 73 and 65% developed enhanced LPA and DTH responses to KLH. Forty-eight percent of patients developed a four-fold increase in antibody concentration to tetanus. Seventy-three percent of patients without detectable hepatitis A antibodies at baseline developed antibodies after immunization. Eighty-three percent of patients experienced at least a four-fold rise in KLH antibody concentration. Immune activation and viral load predicted poor recall responses and the number of memory CD4+ T-cells predicted good responses to recall antigens. Naïve CD4+ T-cell numbers, decrease in viral load, increases in CD4+ and CD28+ cells, and decreases in immune activation were associated with responses to presumed neoantigens. CONCLUSIONS: Most HIV-infected patients treated with potent combination antiretrovirals develop responses to recall and presumed neoantigens after immunization. Functional immune restoration in response to immunization is related to control of viral replication, decreased immune activation as well as to both quantitative and qualitative restoration of circulating T- lymphocyte subpopulations.

AIDS-Related Opportunistic Infections↗
PubMed2000

Effects of interleukin-15 on in vitro human T cell proliferation and activation.

Interleukin-15 (IL-15) has been reported to have many activities on T cell populations, including a potential role in improving antigen-specific proliferation in HIV-1 disease. We tested this response in healthy adults by studying the response of T cell populations after stimulation with medium, tetanus, cytomegalovirus (CMV) antigens in cultures from 21 volunteers. IL-15 caused a dose-dependent increase in medium and antigen-induced proliferation. The expansion was due to CD8>natural killer (NK)>CD4 lymphocytes and memory > naive cells. The IL-15-stimulated CD8 cells had increased levels of the activation markers CD69 and DR. The published CMV-induced expression of CD57 on CD8+ cells was increased in CMV seronegative and seropositive subjects by IL-15. IL-15 appears to be a stimulator of T cell populations in healthy adults and may be useful in settings to enhance nonspecific NK activity or antigen-specific CD8 activity.

Adult↗
PubMed1999

Primary isolate neutralization by HIV type 1-infected patient sera in the era of highly active antiretroviral therapy.

Sera from highly selected HIV-1-positive patients are known to have the ability to neutralize a diverse array of primary isolates of HIV-1. The human osteosarcoma cell line that expresses CD4 and chemokine receptors (GHOST cells) was adapted to study HIV-1 neutralization in 37 HIV-1-infected individuals who were selected because of slow disease progression or nonprogression. Many of these individuals were receiving combination drug therapy. Molecularly cloned HIV-1 JR-FL and NL4-3 viruses were used as prototypes to define assay conditions. Sera were then tested at a 1:40 dilution against six additional primary isolates, three of which utilized CCR5 and three of which used both CCR5 and CXCR4. The assay was highly reproducible and independent of viral input titer, with a readout at 48 hr equivalent to that at later time points. As previously reported, neutralization sensitivity was entirely independent of coreceptor usage. Only a few sera from slow progressors were able to neutralize a broad array of primary isolates at a 1:40 dilution, and the best clinical predictor of broadly neutralizing antibody for primary isolates was the present use of antiretroviral agents. In further studies it was found that purified antibody accounted for the majority of the measured neutralization. However, experiments with exogenous addition of antiviral agents showed that the use of nucleosides also greatly contributed to the measured neutralization in some patients. Measurement of neutralization of HIV-1 primary isolates by sera from patients receiving antiretroviral therapy must be carried out with some caution.

Anti-HIV Agents↗
PubMed1999

Detection of intracellular antigen-specific cytokines in human T cell populations.

Determination of antigen-specific cytokine responses of T lymphocytes after vaccination is made difficult by the low frequency of responder cells. In order to detect these responses, the profile of intracellular cytokines was analyzed using flow cytometry after antigenic expansion. Peripheral blood mononuclear cells were stimulated with antigens for 5 days, further expanded with interleukin (IL)-2, and then restimulated on day 10. Cytokine production was detected by intracellular staining with monoclonal antibodies after saponin-based permeabilization. Influenza expansion resulted in specific interferon-gamma (IFN-gamma) production of 6%-20%, with less IL-4 production (0%-2%). Tetanus toxoid resulted in even greater production. IL-4 and IFN-gamma were produced mainly by memory cells of the CD45RO+ phenotype. IFN-gamma production was contributed by both CD4 and CD8 populations. These methods were then applied to a clinical trial of a candidate human immunodeficiency virus type 1 vaccine. Antigen-specific increases in IFN-gamma were measured, which corresponded to antibody production, lymphoproliferation, and skin testing.

AIDS Vaccines↗
PubMed1999

A canarypox vaccine expressing multiple human immunodeficiency virus type 1 genes given alone or with rgp120 elicits broad and durable CD8+ cytotoxic T lymphocyte responses in seronegative volunteers.

Induction of CD8+ cytotoxic T cells is considered one of the important correlates for the protective efficacy of candidate human immunodeficiency virus type 1 (HIV-1) vaccines. To induce CD8+ cytotoxic T lymphocytes (CTLs) along with neutralizing antibody and CD4+ T cell help, a live canarypox virus construct expressing gp120, transmembrane gp41, the gag and protease genes, and sequences containing CTL epitopes in nef and pol was given simultaneously with, or followed by, rgp120 SF2. CD8+ CTLs were detected in 61% of volunteers at some time during the trial. Three to 6 months after the last immunization, the gene-specific responses were gag, 26/81; env, 17/77; nef, 12/77; and pol, 3/16. Simultaneous immunization with the canarypox vector and the subunit, beginning with the initial immunization, resulted in earlier antibody responses. In summary, a strategy of immunization with a canarypox vector expressing multiple genes of HIV-1 given with gp120 results in durable CD8+ CTL responses to a broad range of epitopes.

AIDS Vaccines↗
PubMed1999

Granulocyte macrophage colony-stimulating factor as an adjuvant for hepatitis B vaccination of healthy adults.

Granulocyte macrophage colony-stimulating factor (GM-CSF) has shown promise as an adjuvant to improve the kinetics and magnitude of the immune response after vaccination. It was hypothesized that GM-CSF given intramuscularly (IM) with hepatitis B vaccine would result in increased seroconversion rates and antibody titers. In total, 108 healthy volunteers (18-45 years old) received recombinant hepatitis B vaccine IM at 0, 1, and 6 months and were randomized to receive either concurrent GM-CSF (80 or 250 microgram) or placebo IM with the first two vaccinations. The percentages of subjects achieving a protective level of antibody at day 56 were 58.3%, 58.8%, and 58.3% in the placebo and 80- and 250-microgram GM-CSF arms, respectively. The geometric mean titers of antibody measured on days 28, 56, and 189 were not statistically different between arms. GM-CSF given immediately before recombinant hepatitis B vaccination was safe and well tolerated but did not appear to provide significant adjuvant activity at this dose.

Adjuvants, Immunologic↗
PubMed1999

Production of influenza-stimulated tumor necrosis factor-alpha by monocytes following acute influenza infection in humans.

Tumor necrosis factor-alpha (TNF-alpha) is often measured in the serum or plasma of patients with severe infections, and marked elevation correlates with poor outcome. The relationship of TNF-alpha to protection from disease is frequently not observed because prospective studies of infectious agents are difficult to perform. We took advantage of a human antiviral influenza challenge study to correlate TNF-alpha production with seroconversion and symptom development. TNF-alpha production was measured by ELISA in the plasma compartment or was measured by intracellular production at the single cell level in the monocyte gated population. Monocyte TNF-alpha was associated with asymptomatic seroconversion, whereas there was no change in the plasma at the times measured. Measurement of TNF-alpha at the single cell level by flow cytometry may allow for better differentiation of the protective role of this cytokine in future studies.

Adolescent↗
PubMed1999

Cytomegalovirus seropositivity is associated with the expansion of CD4+CD28- and CD8+CD28- T cells in rheumatoid arthritis.

OBJECTIVE: Previous researchers have found expansion of CD4+CD28- T cells in patients with rheumatoid arthritis (RA) compared to age matched controls, and have identified expanded clones of autoreactive cells within this population. We examine the association of prior cytomegalovirus (CMV) infection (positive serum anti-CMV IgG) with the percentage of CD4+CD28- T cells and CD8+CD28- T cells in patients with RA. METHODS: A total of 45 patients (36 women, 9 men), mean age of 59 years, with definite RA were studied. RESULTS: In this group 28 patients were seropositive for CMV and 17 seronegative. Seropositive and seronegative subjects did not differ significantly in age, sex, medication use, or severity of disease. Joint count, Health Assessment Questionnaire, pain score, patient global assessment, physician global assessment, and presence of extraarticular disease served to assess disease severity. Expression of CD4/CD28/CD57 and CD8/CD28/CD57 on lymphocytes was determined by 3 color flow cytometry. (CD28 and CD57 are reciprocally related.) CD4+CD28-CD57+ T cells were expanded only in CMV seropositive patients. CONCLUSION: The "carrier" phenotype that has been hypothesized based on a 2 population model for the distribution of CD4+CD28- T cells in RA can be explained by prior infection with CMV.

Arthritis, Rheumatoid↗
PubMed1998

Induction of immune responses to HIV-1 by canarypox virus (ALVAC) HIV-1 and gp120 SF-2 recombinant vaccines in uninfected volunteers. NIAID AIDS Vaccine Evaluation Group.

OBJECTIVE: To determine the ability of live attenuated canarypox virus expressing HIV antigens to induce CD8+ cytotoxic T-cell responses and to prime for neutralizing antibody responses to boosting with purified recombinant gp120 subunit vaccine. DESIGN: A prospective, double-blind, randomized, immunogenicity and safety study was conducted in healthy adults at low risk for acquiring HIV infection and who were seronegative for HIV. METHODS: CD8+ cytotoxic T-cells directed against Env or Gag expressing target cells were measured after live recombinant canarypox-HIV-1 vaccine priming (vaccine given at days 0, 7, 14 and 21). Neutralizing antibodies were measured after subunit boosting (vaccine given at days 28 and 84). RESULTS: CD8+ CTL were induced in 64% of volunteers by the live recombinant canarypox-HIV-1 vaccine. All volunteers who received two doses of subunit vaccine after live recombinant canarypox priming developed neutralizing antibodies directed against laboratory strains of HIV-1 and seven out of eight volunteers tested developed neutralizing antibodies to the primary isolate, BZ167, but to none of eight other primary isolates. Unprimed controls had low or absent neutralizing antibodies after two doses of subunit vaccine. CONCLUSIONS: The live canarypox vector was safe, stimulated cytotoxic T-cells and primed for a vigorous neutralizing antibody response upon boosting with subunit gp120 vaccine. This vaccine combination should be evaluated further for inducing protection against HIV infection.

AIDS Vaccines↗
PubMed1998

Cytomegalovirus-specific IFNgamma and IL-4 are produced by antigen expanded human blood lymphocytes from seropositive volunteers.

The cytokine responses to cytomegalovirus (CMV) antigen in seropositive and seronegative individuals were measured using a combination of antigenic expansion and intracellular staining. Intracellular IFNgamma and IL-4 were produced in a dose-dependent manner by T cells in response to CMV only in the seropositive population. The potential for individual cells to produce both Th1 and Th2 cytokines simultaneously was clear, as IL-4 was most often produced in those cells with the highest IFNgamma production. The cytokine-specific nature of this response was demonstrated by fluorescence microscopy, which showed granular cytoplasmic staining, and at the mRNA level by ribonuclease protection assays. These methods expand our ability to evaluate the immune response to CMV, and can now be correlated to a number of clinical conditions.

Adult↗
PubMed1998

Highly active antiretroviral therapy results in a decrease in CD8+ T cell activation and preferential reconstitution of the peripheral CD4+ T cell population with memory rather than naive cells.

OBJECTIVE: Highly active antiretroviral therapy (HAART) can produce marked increases in peripheral blood CD4+ T cells and decreases in HIV plasma RNA copy numbers. However, it is not clear whether these absolute changes will be accompanied by a recovery in the known naive CD4+ T cell depletion or a decrease in the marked CD8+ T cell activation. DESIGN: Twenty-nine patients were enrolled in studies of either nucleoside therapy alone or nucleoside therapy combined with a protease inhibitor (zidovudine + lamivudine + indinavir). One hundred and ninety-one examinations were carried out at three baseline time points and during 40 weeks of follow-up to evaluate the effect of HAART on CD4+ memory/naive phenotype and CD8+ T cell activation. METHODS: CD4+ and CD8+ T cell number, CD62L/CD45RA expression on CD4+ T cells and CD38 expression on CD8+ T cells were measured by three-color flow cytometry. RESULTS: Most protease inhibitor treated patients had a significant rise in CD4+ numbers. The marked rise in the CD4+ T cells seen in individuals in this study was not accompanied over a 40-week period by a change in the abnormally low CD4+ naive compartment, and thus was almost completely of memory phenotype. The CD38 expression on CD8+ cells fell during treatment, and decreased to a greater degree than the comparable rise in CD4+ T cell counts. This decrease continued in many patients after the CD4+ T cell rise or viral load decline had plateaued. CONCLUSION: HAART results in changes in activation to a greater extent than absolute changes in CD4+ T cell numbers, but is not accompanied by an increase in naive CD4+ T cells. Measurements of CD4+ T cell numbers alone may not allow appropriate interpretation of immune activation or immune competence in patients receiving those drugs.

Anti-HIV Agents↗
PubMed1998

Th1/Th2 cytokine responses following HIV-1 immunization in seronegative volunteers. The AIDS Vaccine Evaluation Group.

The Th1/Th2 profile that follows human vaccination may profoundly influence the subsequent course of disease after infection. However, the ability to detect IL-4 has been limited outside trials of live vaccination. By using methods in which memory effector cells are allowed to antigenically expand by short term culture, followed by low-dose mitogenic stimulation, we have been able to follow the Th1/Th2 profile in HIV-1 volunteers enrolled in two phase I studies of HIV immunogens (a recombinant gp120 and a multivalent, octomeric V3 loop peptide). Antigen-specific interferon-gamma (IFN-gamma) could be detected in primary stimulation, but IL-4 was observed only after antigenic expansion and restimulation. In both of these studies the responses after initial immunizations were dominated by IFN-gamma, with IL-4 appearing only after multiple rounds of immunization, and IL-4 was temporally related to antibody production. Concomitant with the IL-4 production, the amount of supernatant IFN-gamma declined. Antigen-specific IL-10 was not detected in either study. Such techniques, which have been shown to correlate with outcomes in immunotherapy, may prove useful as future surrogates of human vaccine response.

AIDS Vaccines↗
PubMed1998

Randomized, open-label trial of azithromycin plus ethambutol vs. clarithromycin plus ethambutol as therapy for Mycobacterium avium complex bacteremia in patients with human immunodeficiency virus infection. Veterans Affairs HIV Research Consortium.

Disseminated Mycobacterium avium complex (MAC) infection continues to be a common opportunistic infection in patients infected with human immunodeficiency virus (HIV). The optimal therapy for disseminated MAC infection is unclear. We compared azithromycin plus ethambutol with clarithromycin plus ethambutol in the treatment of disseminated MAC infection in HIV type 1-infected patients, examining the frequency of bacteremia clearance, time to clearance, and study drug tolerance after 16 weeks of therapy. Fifty-nine patients for whom blood cultures were positive for MAC were enrolled in the study from 10 university-affiliated Veterans Affairs Medical Centers. Thirty-seven patients were evaluable for determination of quantitative bacteremia and clinical outcomes. Clearance of bacteremia was seen at the final visit in 37.5% of azithromycin-treated patients and in 85.7% of clarithromycin-treated patients (P = .007). The estimated median time to clearance of bacteremia was also significantly different between the two treatment arms: 4.38 weeks for clarithromycin recipients vs. > 16 weeks for azithromycin recipients (P = .0018). Only one isolate developed macrolide resistance during therapy. Abatement of symptoms, other laboratory-evident abnormalities, and adverse effects were similar in the two groups. At the doses used in this study, clarithromycin/ethambutol produced a more rapid resolution of bacteremia than did azithromycin/ethambutol, and clarithromycin/ethambutol was more effective at sterilization of blood cultures after 16 weeks of therapy.

AIDS-Related Opportunistic Infections↗