Biomedical subjects

S Ratto-Kim

Publications and source records attributed to S Ratto-Kim.

10 recordsLinked to original sources

PubMed2000

Anti-CD4-binding domain antibodies complexed with HIV type 1 glycoprotein 120 inhibit CD4+ T cell-proliferative responses to glycoprotein 120.

HIV-specific CD4+ helper T cell responses, particularly to the envelope glycoproteins, are usually weak or absent in the majority of HIV-seropositive individuals. Since antibodies, by their capacity to alter antigen uptake and processing, are known to have modulatory effects on CD4+ T cell responses, we investigated the effect of antibodies produced by HIV-infected individuals on the CD4+ T cell response to HIV-1 gp120. Proliferative responses of gp120-specific CD4+ T cells were inhibited in the presence of either serum immunoglobulin from HIV-infected individuals or human monoclonal antibodies specific for the CD4-binding domain (CD4bd) of gp120. Human monoclonal antibodies to other gp120 epitopes did not have the same effect. The anti-CD4bd antibodies complexed with gp120 suppressed T cell lines specific for varying gp120 epitopes but did not affect T cell proliferation to non-HIV antigens. Moreover, inhibition by the anti-CD4bd/gp120 complexes was observed regardless of the types of antigen-presenting cells used to stimulate the T cells. These results indicate that the presence of anti-CD4bd antibodies complexed with gp120 can strongly suppress CD4+ helper T responses to gp120.

Amino Acid Sequence↗

PubMed2000

A phase I/II trial of HIV SF2 gp120/MF59 vaccine in seronegative thais.AFRIMS-RIHES Vaccine Evaluation Group. Armed Forces Research Institute of Medical Sciences and the Research Institute for Health Sciences.

Fifty-two human immunodeficiency virus type 1, seronegative Thai adults from the community were enrolled in a double-blind, placebo controlled, phase I/II trial of HIV SF2 gp120/MF59 vaccine to determine the safety and immunogenicity of this recombinant, B clade, HIV envelope protein vaccine. Twenty-six subjects were enrolled at each of two sites in Thailand, Bangkok and Chiang Mai. Twelve subjects received placebo and 40 subjects received vaccine (50 microg). Subjects were immunized according to one of two schedules, 0, 1 and 4 or 0, 1 and 6 months. The frequency of adverse reactions was not different between placebo and vaccine subjects, nor between immunization schedules. Of vaccinees, all developed high-titer binding antibody to the immunogen (rgp120), 39 developed neutralizing antibody (NA) responses against homologous virus (HIV-1(SF2)), and 22 developed NA against heterologous virus (HIV-1(MN)). No subject demonstrated intercurrent HIV infection, however screening EIA reactivity occurred in 27% of recipients. Thus, this candidate HIV vaccine was found to be safe and immunogenic in Thai adults, laying the foundation for development of a subtype E construct in this population.

AIDS Vaccines↗

PubMed2000

Efficacy testing of recombinant human immunodeficiency virus (HIV) gp160 as a therapeutic vaccine in early-stage HIV-1-infected volunteers. rgp160 Phase II Vaccine Investigators.

A phase II efficacy trial was conducted with recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein gp160 (rgp160) in 608 HIV-infected, asymptomatic volunteers with CD4+ cell counts >400 cells/mm3. During a 5-year study, volunteers received a 6-shot primary series of immunizations with either rgp160 or placebo over 6 months, followed by booster immunizations every 2 months. Repeated vaccination with rgp160 was safe and persistently immunogenic. Adequate follow-up and acquisition of endpoints allowed for definitive interpretation of the trial results. There was no evidence that rgp160 has efficacy as a therapeutic vaccine in early-stage HIV infection, as measured at primary endpoints (50% decline in CD4+ cell count or disease progression to Walter Reed stage 4, 5, or 6) or secondary endpoints. A transient improvement was seen in the secondary CD4 endpoint for the vaccination compared with the placebo arm, but this did not translate into improved clinical outcome.

AIDS Vaccines↗

PubMed1999

Varicella immunity: persistent serologic non-response to immunization.

OBJECTIVE: Varicella-zoster (VZV) infection is an occupational hazard for health care workers. The "gold standard" for assessing protection is a positive antibody titer. We present a case of persistent serologic non-responsiveness following VZV immunization and discuss a management strategy. METHODS: A 29-year-old woman, immunocompetent pediatric resident was repeatedly removed from her clinical duties because of a negative history of chicken pox and the absence of a VZV antibody titer. She received a total of three doses of the VZV vaccine and continued to have a negative antibody titer as measured by a commercial ELISA assay (Wampole). Subsequently, she had three direct contacts with infectious children and did not develop clinical chicken pox. RESULTS: A lymphocyte proliferation assay was performed using inactivated varicella vaccine and tetanus antigens. The patient's varicella and tetanus stimulation index (SI) were 46.5 and 42, respectively. The SI for the positive control (a patient recently recovered from a wild type infection) were 144 (varicella specific), and 114 (tetanus). The SI secondary to VZV antigens reported in the literature is 30.5 +/- 9.1. We reassessed the varicella antibody titer using more sensitive assays: fluorescent antibody to membrane antigen and latex agglutination. Both tests verified the presence of VZV specific IgG at a titer of 1:8 in our patient. CONCLUSION: This case illustrates that in a subgroup of individuals the antibody response to VZV vaccine may be low despite an adequate cell-mediated response. Commercial VZV ELISA assays were designed to measure higher titers associated with natural infection rather than the lower titer induced by the vaccine. Repeated immunizations plus more sensitive measures of VZV-specific IgG should be used to validate protection rather than the current commonly utilized ELISA screening. Clinicians should be aware of the variability in VZV-specific antibody assays when assessing post VZV vaccine titers prior to determining protection in health care workers.

Adult↗

PubMed1999

Repeated immunization with recombinant gp160 human immunodeficiency virus (HIV) envelope protein in early HIV-1 infection: evaluation of the T cell proliferative response.

This longitudinal study was designed to evaluate cellular immunity in early-stage, asymptomatic human immunodeficiency virus (HIV)-1-infected persons (CD4 cell count,>400/mm3; median, 625/mm3) who were immunized with either recombinant (r) gp160 or placebo every 2 months for 5 years. Proliferative responses were assessed against rgp160, rp24, and a panel of recall antigens and mitogens. Despite good reactivity to recall antigens, at baseline approximately 33% had proliferative responses to gp160, and approximately 42% showed p24 gag responses. There was no statistical difference between vaccine and placebo groups for antigens or mitogens. After 1 year, approximately 73% of the subjects in the vaccine arm had new or boosted responses to gp160, versus approximately 18% in the placebo arm. Statistical significance was maintained throughout the study. Recurrent vaccination with recombinant gp160 was proven to be persistently immunogenic, increasing significantly the ability of HIV-1-infected persons to mount new proliferative responses to the vaccine.

AIDS Vaccines↗

PubMed1999

Proliferative responses to human immunodeficiency virus type 1 (HIV-1) gp120 peptides in HIV-1-infected individuals immunized with HIV-1 rgp120 or rgp160 compared with nonimmunized and uninfected controls.

The proliferative responses to a series of peptides constituting the human immunodeficiency virus type 1 (HIV-1) gp120 sequence were evaluated in 19 HIV-1-infected rgp160 vaccine recipients, 17 HIV-1-infected rgp120 vaccine recipients, 15 HIV-1-infected placebo recipients, and 18 HIV-1-uninfected controls. Many regions of the gp120 molecule were found to contribute proliferative epitopes, although there were clearly regions of relative dominance and silence. Vaccine recipients tended to have broader, more robust, and more frequent peptide recognition than the placebo recipients. Despite the considerable variability in the pattern of peptide recognition among individuals, there was a striking similarity between the rgp160 and rgp120 vaccinee groups as a whole. Low-risk HIV-1-uninfected individuals may react to a few peptides within the gp120 sequence as well, despite a lack of significant response to the whole gp120 protein.

AIDS Vaccines↗

PubMed1999

Preliminary evaluation of human immunodeficiency virus type 1 (HIV-1) immunogen in children with HIV-1 infection.

The safety and preliminary activity of human immunodeficiency virus type 1 (HIV-1) immunogen were evaluated in 10 HIV-1-infected children with disease stage N1,2 or A1,2. Multiple inoculations of 2. 5 or 10 units (U) of HIV-1 immunogen were safe and well tolerated without an acceleration of disease progression. When antiretroviral agents were coadministered, the 10 U dose appeared to be associated with more sustained reduction in plasma HIV-1 RNA than the 2.5 U dose (median log10 HIV-1 RNA at month 18, 3.07 vs. 4.01 copies/mL in 10 U [n=4] vs. 2.5 U [n=3], respectively; P=.034). Levels of regulated-on-activation, normal T cell-expressed and -secreted chemokine produced from HIV-1 immunogen-stimulated lymphocytes in vitro were increased in the children who had HIV-1 immunogen-specific antibody responses (P<.02) and appeared to be inversely correlated with levels of plasma HIV-1 RNA (P<.01). These preliminary data warrant larger studies to determine the effectiveness of adjunctive therapy with HIV-1 immunogen in children with HIV-1 infection.

AIDS Vaccines↗

PubMed1997

Comparison of HIV-1 envelope-specific CD4+ T cell lines simultaneously established from peripheral blood mononuclear cells and lymph node biopsy in HIV-1-infected individuals.

HIV-1 envelope-specific CD4+ T cell lines were established simultaneously from PBMC and lymph node mononuclear cells of two HIV-1-infected patients. Three recombinant envelope proteins were used to establish the CD4+ T cell lines: gp160NL4-3, gp120IIIB, and gp120MN. Six T cell lines were established from the first patient, one for each Ag from each compartment, and four T cell lines, two per compartment, were established from the second patient. Each line was challenged with a panel of overlapping peptides spanning the entire gp120 sequence to define its T cell epitope specificity. The pattern of recognition for all the lines from any given patient was similar between compartments. Each patient had a different pattern of peptide recognition. TCR analysis showed a heterogeneous usage of Vbeta between lines with same peptide specificity and established from different compartments. These data suggest that the cellular immune response does not phenotypically vary between the peripheral blood and lymph node compartments, but demonstrates genotypic heterogeneity, showing possible redundancy of the immune response to HIV-1 gp160.

Acquired Immunodeficiency Syndrome↗

PubMed1997

Delayed-type hypersensitivity skin testing using third variable loop peptides identifies T lymphocyte epitopes in human immunodeficiency virus-infected persons.

Cellular immune responses to human immunodeficiency virus type 1 (HIV-1) infection, particularly in vivo responses, have been difficult to study in large patient cohorts because of technical impediments. By use of small peptide fragments of the HIV-1 gp120 third variable loop, the CD4 T lymphocyte epitopes of 2 HIV-infected persons were mapped using a cutaneous delayed-type hypersensitivity (DTH) assay. The in vivo DTH responses correlated with epitopes previously identified in vitro using CD4 T lymphocyte lines. The ability to determine CD4 T lymphocyte epitopes in large cohorts of patients using this simple in vivo technique would provide important diagnostic and prognostic data regarding effective immunoregulation of HIV-1. This technique should have broad applicability in HIV vaccine development and in the investigation of other immune-mediated human diseases.

Amino Acid Sequence↗

PubMed1997

Evolution of human immunodeficiency virus type 1 env sequence variation in patients with diverse rates of disease progression and T-cell function.

We examined the relationship between env sequence variation and disease progression in 10 human immunodeficiency virus type 1 (HIV-1)-seropositive subjects selected from a longitudinal cohort receiving zidovudine therapy. Five subjects were chosen for stable clinical status and CD4 counts (slow progressors), and five were selected for rapid clinical deterioration and CD4 count decline (rapid progressors). The slow progressors had significantly lower plasma viral RNA loads and greater lymphoproliferative responses to mitogens than the rapid progressors. DNA sequences representing the C1 through C3 regions of env were amplified from two peripheral blood mononuclear cell DNA samples from each subject separated by an average of 2.5 years. Molecular clones of these amplicons were then sequenced, and DNA sequence and deduced amino acid sequence distances were compared. Inter-time point sequence comparison showed a higher rate of sequence evolution for the rapid progressors in three of five matched pairs of rapid progressors and slow progressors and for the slow progressors in the remaining two subject pairs. However, intra-time point sequence comparisons showed that four of five slow progressors developed a more diverse quasispecies over time and one showed no change. In contrast, four of five rapid progressors showed no change in quasispecies diversity over time and one showed a significant decrease in diversity. The overall C1 through C3 region quasispecies diversity in the slow progressors at baseline was lower than that for the rapid progressors, but this difference was not significant at the follow-up time points. These diversity relationships were obscured if sequence analyses were limited to the 300-bp C2 to V3 region. Thus, HIV-1 quasispecies diversity increased over time in subjects with more functional immune systems.

Base Sequence↗