Immunization with Human Immunodeficiency Virus Type 1 rgp120W61Din QS21/MPL Adjuvant Primes T Cell Proliferation and C‐C Chemokine Production to Multiple Epitopes within Variable and Conserved Domains of gp120W61D

Jones, Gareth; Hoegen, Paul von; Weber, Jonathan; Rees, A.

doi:10.1086/314626

Cited by 16 publications

(13 citation statements)

References 44 publications

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“…Cells which produced IFN-␥ in response to APCs pulsed with gp120 in the presence of MAbs to gp120 CD4BD (654-D and 559-64D) or C5 (450-D) were enumerated. The gp120-specific, HLA-DR1-restricted CD4 T-cell line DMg26, which had been tested in previous studies and shown to produce Th1 cytokines (7,9), was used. Figure 1 shows that the DMg26 T cells produced FIG.…”

Section: Resultsmentioning

confidence: 99%

“…gp120-specific CD4 T-cell lines DMg26 and 027-563 were used in the study. The generation and maintenance of these T-cell lines were reported previously (7,9,26). DMg26 is specific for a DR1-restricted epitope in the C2 domain (within gp120 residues 221 to 240) and recognizes gp120 from various HIV-1 strains, including SF2, IIIB, NL4.3, and W61D.…”

Section: Methodsmentioning

confidence: 96%

See 1 more Smart Citation

Inhibition of Human Immunodeficiency Virus Type 1 gp120 Presentation to CD4 T Cells by Antibodies Specific for the CD4 Binding Domain of gp120

Hioe

Tuen

Jones

et al. 2001

J Virol

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Human immunodeficiency virus (HIV)-specific CD4T-cell responses, particularly to the envelope glycoproteins of the virus, are weak or absent in most HIV-infected patients. Although these poor responses can be attributed simply to the destruction of the specific CD4 T cells by the virus, other factors also appear to contribute to the suppression of these virus-specific responses. We previously showed that human monoclonal antibodies (MAbs) specific for the CD4 binding domain of gp120 (gp120 CD4BD ), when complexed with gp120, inhibited the proliferative responses of gp120-specific CD4 T-cells. MAbs to other gp120 epitopes did not exhibit this activity. The present study investigated the inhibitory mechanisms of the anti-gp120 CD4BD MAbs. The anti-gp120 CD4BD MAbs complexed with gp120 suppressed gamma interferon production as well as proliferation of gp120-specific CD4 T cells. Notably, the T-cell responses to gp120 were inhibited only when the MAbs were added to antigen-presenting cells (APCs) during antigen pulse; the addition of the MAbs after pulsing caused no inhibition. However, the anti-gp120 CD4BD MAbs by themselves, or as MAb/gp120 complexes, did not affect the presentation of gp120-derived peptides by the APCs to T cells. These MAb/gp120 complexes also did not inhibit the ability of APCs to process and present unrelated antigens. To test whether the suppressive effect of anti-gp120 CD4BD antibodies is caused by the antibodies' ability to block gp120-CD4 interaction, APCs were treated during antigen pulse with anti-CD4 MAbs. These treated APCs remained capable of presenting gp120 to the T cells. These results suggest that anti-gp120 CD4BD Abs inhibit gp120 presentation by altering the uptake and/or processing of gp120 by the APCs but their inhibitory activity is not due to blocking of gp120 attachment to CD4 on the surface of APCs.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 96%

Inhibition of Human Immunodeficiency Virus Type 1 gp120 Presentation to CD4 T Cells by Antibodies Specific for the CD4 Binding Domain of gp120

Hioe

Tuen

Jones

et al. 2001

J Virol

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“…In most HIV-1-seropositive subjects, either chronically or acutely infected, CD4 T cell responses to C4, and other gp120 epitopes are usually weak or undetectable (46, 66 -69) and thus are not likely to exert sufficient selective pressure for the emergence of escape mutants. Nevertheless, robust CD4 T cells specific for the C4 epitopes were stimulated in an HIV-seronegative recipient of the recombinant gp120 vaccine (70), and upon exposure with the virus challenge, these cells may contribute to the generation of escape mutants. The data presented here show that one effective strategy that the virus can exploit to escape immune surveillance by CD4 T cells is by disposing of a glycan, such as the N448-linked glycan, which does not substantially affect virus-receptor interactions and may even enhance virus infectivity.…”

Section: Discussionmentioning

confidence: 99%

Identification of an N-Linked Glycosylation in the C4 Region of HIV-1 Envelope gp120 That Is Critical for Recognition of Neighboring CD4 T Cell Epitopes

Chien

Tuen

et al. 2008

The Journal of Immunology

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The heavy glycosylation of HIV-1 envelope gp120 shields this important Ag from recognition by neutralizing Abs and cytolytic CD8 T cells. However, very little work has been done to understand the influence of glycosylation on the generation of gp120 epitopes and their recognition by MHC class II-restricted CD4 T cells. In this study, three conserved glycans (linked to N406, N448, and N463) flanking the C4 region of gp120 that contains many known CD4 T cell epitopes were disrupted individually or in combination by asparagine-to-glutamine substitutions. The mutant proteins lacking the N448 glycan did not effectively stimulate CD4 T cells specific for the nearby C4 epitopes, although the same mutants were recognized well by CD4 T cells specific for epitopes located in the distant C1 and C2 regions. The loss of recognition was not due to amino acid substitutions introduced to the mutant proteins. Data from trypsin digestion and mass spectrometry analyses demonstrated that the N448 glycan removal impeded the proteolytic cleavage of the nearby C4 region, without affecting more distant sites. Importantly, this inhibitory effect was observed only in the digestion of the native nondenatured protein and not in that of the denatured protein. These data indicate that the loss of the N448 glycan induces structural changes in the C4 region of gp120 that make this specific region more resistant to proteolytic processing, thereby restricting the generation of CD4 T cell epitopes from this region. Hence, N-linked glycans are critical determinants that can profoundly influence CD4 T cell recognition of HIV-1 gp120.

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“…Previously tested HIV DNA vaccines have demonstrated excellent human safety profiles [4][5][6][7][8][9]. Recombinant protein-based HIV vaccines formulated with QS21 adjuvant have reported local reactions, but have shown limited systemic adverse events in humans [10][11][12][13][14][15]. The current report summarizes the phase 1 clinical safety and tolerability data, highlighting local and *Address correspondence to: Jeff Kennedy, M.D., Division of Molecular Medicine, Wadsworth Center, Biggs Laboratory, ESP, C606, NYS Department of Health, P.O.…”

Section: Hiv; Vaccine; Adverse Event; Vasculitismentioning

confidence: 99%

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

Kennedy

Green

et al. 2008

Vaccine

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This report describes the safety observations following administration of a polyvalent DNA primeprotein boost HIV-1 vaccine formulated with adjuvant QS21. Local injection site reactionswere the most common (65% of subjects), and included type IV delayed-type hypersensitivity (DTH) reactions at prior DNA inoculation sites in 12 of 28 (43%) subjects following protein vaccination. Systemic reactions revealed two cases of vasculitis temporally related to inoculation with recombinant Env protein + QS21 adjuvant. Questions remain regarding the cause of the vasculitis, but the unique DTH observation may have contributed to the high level of immune responses previously reported for this vaccine. Keywords HIV; vaccine; adverse event; vasculitisOver the past two decades, various HIV vaccines have been tested for safety and several for efficacy in humans. However, the majority have not reproduced, in humans, the high immunogenicity seen in preclinical testing. Recently, we reported that a novel multi-gene, polyvalent DNA prime-recombinant protein boost HIV vaccine formulation, DP6-001, elicited strong and balanced humoral and cell-mediated immunity in healthy, HIV-1-negative adult subjects [1]. Preclinical testing of DP6-001 demonstrated no significant adverse reactions in either rabbits or non-human primates despite the induction of robust immunity [2,3]. Previously tested HIV DNA vaccines have demonstrated excellent human safety profiles [4][5][6][7][8][9]. Recombinant protein-based HIV vaccines formulated with QS21 adjuvant have reported local reactions, but have shown limited systemic adverse events in humans [10][11][12][13][14][15]. The current report summarizes the phase 1 clinical safety and tolerability data, highlighting local and *Address correspondence to: Jeff Kennedy, M.D., Division of Molecular Medicine, Wadsworth Center, Biggs Laboratory, ESP, C606, NYS Department of Health, P.O. Box 509, Albany, New York 12201-0509, P: 518-473-8421, F: 518-473-2900, E: jsk07@health.state.ny.us. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. The clinical trial was an open-label, 3-arm design requiring each subject to receive two vaccine components; three sequential inoculations using a DNA plasmid vaccine administered either intradermally (ID) or intramuscularly (IM) followed by two sequential inoculations using a protein vaccine as shown in Table 1. Healthy HIV-negative adults (aged 18-50) were enrolled under informed consent as previously described [1]. This study involved 2 dose levels of DNA vaccines (1.2mg (Groups A and B); 7.2mg (Group C)) expressing five gp120 Env ant...

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Immunization with Human Immunodeficiency Virus Type 1 rgp120_W61Din QS21/MPL Adjuvant Primes T Cell Proliferation and C‐C Chemokine Production to Multiple Epitopes within Variable and Conserved Domains of gp120_W61D

Cited by 16 publications

References 44 publications

Inhibition of Human Immunodeficiency Virus Type 1 gp120 Presentation to CD4 T Cells by Antibodies Specific for the CD4 Binding Domain of gp120

Inhibition of Human Immunodeficiency Virus Type 1 gp120 Presentation to CD4 T Cells by Antibodies Specific for the CD4 Binding Domain of gp120

Identification of an N-Linked Glycosylation in the C4 Region of HIV-1 Envelope gp120 That Is Critical for Recognition of Neighboring CD4 T Cell Epitopes

The safety and tolerability of an HIV-1 DNA prime–protein boost vaccine (DP6-001) in healthy adult volunteers

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