Evaluation of Monoclonal Antibodies to Human Immunodeficiency Virus Type 1 Primary Isolates by Neutralization Assays: Performance Criteria for Selecting Candidate Antibodies for Clinical Trials

D’Souza, M. Patricia; Livnat, Daniella; Bradac, James; Bridges, Sandra

doi:10.1086/516443

Cited by 146 publications

(131 citation statements)

References 19 publications

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“…To address whether a generalized or inherent neutralization susceptibility of the patients' viruses accounted for this variability, viruses derived from two subjects who did not generate neutralization responses (TN-2 and TN-4) and two subjects who did generate neutralization responses (TN-1 and TN-3) were tested against three well characterized, broadly neutralizing monoclonal antibodies (b12, 2F5, and 2G12) ( Table 5; refs. [22][23][24]. Monoclonal antibody neutralization patterns did not correlate with the presence or absence of an autologous neutralizing antibody response.…”

Section: Investigation Of Poor Autologous Neutralizing Antibody Respomentioning

confidence: 99%

Rapid evolution of the neutralizing antibody response to HIV type 1 infection

Richman¹,

Wrin²,

Little³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

1,079

1,088

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A recombinant virus assay was used to characterize in detail neutralizing antibody responses directed at circulating autologous HIV in plasma. Examining serial plasma specimens in a matrix format, most patients with primary HIV infection rapidly generated significant neutralizing antibody responses to early (0 -39 months) autologous viruses, whereas responses to laboratory and heterologous primary strains were often lower and delayed. Plasma virus continually and rapidly evolved to escape neutralization, indicating that neutralizing antibody exerts a level of selective pressure that has been underappreciated based on earlier, less comprehensive characterizations. These data argue that neutralizing antibody responses account for the extensive variation in the envelope gene that is observed in the early months after primary HIV infection.

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Section: Investigation Of Poor Autologous Neutralizing Antibody Respomentioning

confidence: 99%

Rapid evolution of the neutralizing antibody response to HIV type 1 infection

Richman¹,

Wrin²,

Little³

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

1,079

1,088

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“…Fabs 59.1 and 58.2 have approximately 83% and 65% sequence identity respectively in their V L and V H domains; their C L and C H 1 domains are identical (lgG1, K). The structure was determined using the X-PLOR rotation function and PC refinement [68], and a modified Harada translation function [69] written in our laboratory by D Filman and J Arevalo, with the intact 59.1 as a model. The intact Fab was ■found to be a suitable starting model because its elbow angle (the angle between the pseudo twofold axes of the V L -V H and C L -C H 1 domains) differed from that of the unknown Fab by only 11° (the elbow angle for 58.2 was 144° and for 59.1 was 135°).…”

Section: Methodsmentioning

confidence: 99%

“…First, they provided a means for comparing the neutralizing activity of PAbs with a template MAb. Second, since the neutralization sensitivity of HrV-1 can vary (68,69), a MAb can provide a standard for wider comparisons.…”

Section: Mabmentioning

confidence: 99%

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Conformationally Restricted Synthetic AIDS Vaccine

Satterthwait¹

2001

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Washington Headquarters Services, Directorate for Information Operations and Reports, 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302, and to the Office of Management and Budget,, Washington, DC 20503 AGENCY USE ONLY (Leave blank)2. REPORT DATE February 2 001 REPORT TYPE AND DATES COVEREDFinal (1 Jul 95 -31 Jan 01) TITLE AND SUBTITLE Conformationally Restricted Synthetic AIDS Vaccine AUTHOR(S)Arnold C. Satterthwait, Ph.D. FUNDING NUMBERS DAMD17-95-2-5017 PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)The Burnham ABSTRACT (Maximum 200 Words)It was proposed to develop a structure-based approach for synthetic vaccine development designed to recapitulate the activities of potent neutralizing monoclonal antibodies (MAbs) using constrained peptides as immunogens. We focused on two antibodies, a MAb 58.2 that binds a sequential V3 epitope and IgG bl2 that binds a discontinuous epitope, both on HIV-1 gpl20. We validated the structure-based approach with a V3 mimetic using MAb 58.2 and demonstrated the enormous effect that peptide conformation can have on affinity and immunogenicity. We were unable to mimic the more challenging discontinuous IgG bl2 epitope despite considerable effort.The enormous affinity enhancements we observed for the constrained V3 peptide and dearth of potent HIV-1 neutralizing antibodies, particularly those specific for sequential epitopes, led us to an important discovery. It suggested that new antibodies might be identified with constrained peptides that go undetected with peptides. It was found that several helix-stabilized gpl20 peptides detect new antibodies that go undetected with linear peptides implying a general phenomenon. Constrained peptides, tailored to mimic short, sequential regions of proposed neutralization sites might be used to widen the selection of template antibodies best suited for synthetic vaccine development. SUBJECT TERMSHIV-1, IgG bl2, MAb 58.2, synthetic vaccine, vaccine, peptides cyclic peptides, V3 loop, gpl20, gp41 INTRODUCTIONWe originally hypothesized that HTV-1 had developed a capability for evading immune responses that could be overcome by focusing immune responses to specific targets essential for the virus and defined in part by neutralizing antibodies and T-cell responses.To test this hypothesis, we proposed to identify synthetic mimetics corresponding to neutralizing epitopes recognized by broadly neutralizing antibodies as well as seek new antibodies using mimetics. We proposed to initially focus on two antibodies, MAb 58.2 that binds a sequential epitope on the V3 loop and IgGbl2 that binds a discontinuo...

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“…Several human mAbs specific for various regions of HIV-gp120 have been reported to have potent neutralizing activity against primary isolates (9,10). Passive immunization of SCID-human mice with human mAbs provided protection against infection with primary isolates (11).…”

Section: Mass Spectrometric Characterization Of a Discontinuousmentioning

confidence: 99%

Mass Spectrometric Characterization of a Discontinuous Epitope of the HIV Envelope Protein HIV-gp120 Recognized by the Human Monoclonal Antibody 1331A

Hochleitner

Górny

Zolla‐Pazner

et al. 2000

The Journal of Immunology

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The characterization of a discontinuous epitope in the C5 region of the HIV envelope protein HIV-gp120, recognized by 1331A, a human mAb, is reported. Regions involved in affinity binding in the HIV-gp120 molecule were identified by epitope excision/extraction methods followed by matrix assisted laser desorption-time of flight mass spectrometry. In epitope excision, the protein is bound in its native conformation to an immobilized Ab and then digested with proteolytic enzymes. In epitope extraction, the protein is first digested and subsequently allowed to react with the Ab. A series of proteolytic digestions of the 1331A/HIV-gp120 complex allowed the identification of protected amino acids in two noncontinuous regions of the C5 region of HIV-gp120. Interaction of the Ab with amino acids I487 and E507 of HIV-gp120 is essential for efficient binding. This is the first application of this approach for the identification and characterization of a discontinuous epitope. The results are consistent with molecular modeling results, indicating that these amino acids are located on opposite sides of a hydrophobic pocket. This pocket is thought to be of importance for the interaction of HIV-gp120 with the transmembrane protein HIV-gp41.

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Evaluation of Monoclonal Antibodies to Human Immunodeficiency Virus Type 1 Primary Isolates by Neutralization Assays: Performance Criteria for Selecting Candidate Antibodies for Clinical Trials

Cited by 146 publications

References 19 publications

Rapid evolution of the neutralizing antibody response to HIV type 1 infection

Rapid evolution of the neutralizing antibody response to HIV type 1 infection

Conformationally Restricted Synthetic AIDS Vaccine

Mass Spectrometric Characterization of a Discontinuous Epitope of the HIV Envelope Protein HIV-gp120 Recognized by the Human Monoclonal Antibody 1331A

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