A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals.

Burton, Dennis R.; Barbas, Carlos F.; Persson, Mats A. A.; Koenig, Scott; Chanock, Robert M.; Lerner, Richard A.

doi:10.1073/pnas.88.22.10134

Cited by 595 publications

(406 citation statements)

References 24 publications

(27 reference statements)

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“…In these studies, the focus has been on biz, 2G12, 2F5, and 4E10, which were generated from HIV-1 subtype B-infected individuals (5,7), because a combination of these MAbs, or of just 2G12, 2F5, and 4E10 (also referred to as TriMab), completely protected neonatal rhesus macaques from oral challenge with simian-human immunodeficiency virus 89.6P (13,14). However, because simian-human immunodeficiency virus 89.6P represents only a single strain of virus, and one that is sensitive to neutralization by these antibodies (2,10,17), it is unclear how these findings would translate to vertically transmitted HIV-1 variants, especially those that are not subtype B.…”

mentioning

confidence: 99%

Neutralization Escape Variants of Human Immunodeficiency Virus Type 1 Are Transmitted from Mother to Infant

Wu¹,

Parast²,

Richardson

et al. 2006

J Virol

270

258

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Maternal passive immunity typically plays a critical role in protecting infants from new infections; however, the specific contribution of neutralizing antibodies in limiting mother-to-child transmission of human immunodeficiency virus type 1 is unclear. By examining cloned envelope variants from 12 transmission pairs, we found that vertically transmitted variants were more resistant to neutralization by maternal plasma than were maternal viral variants near the time of transmission. The vertically transmitted envelope variants were poorly neutralized by monoclonal antibodies biz, 2G12, 2F5, and 4E10 individually or in combination. Despite the fact that the infant viruses were among the most neutralization resistant in the mother, they had relatively few glycosylation sites. Moreover, the transmitted variants elicited de novo neutralizing antibodies in the infants, indicating that they were not inherently difficult to neutralize. The neutralization resistance of vertically transmitted viruses is in contrast to the relative neutralization sensitivity of viruses sexually transmitted within discordant couples, suggesting that the antigenic properties of viruses that are favored for transmission may differ depending upon mode of transmission.

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mentioning

confidence: 99%

Neutralization Escape Variants of Human Immunodeficiency Virus Type 1 Are Transmitted from Mother to Infant

Wu¹,

Parast²,

Richardson

et al. 2006

J Virol

270

258

View full text Add to dashboard Cite

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“…RNA isolated from the MCB tissues containing the tumor-infiltrating B cells were also used as starting materials for library construction using the pComb3 and pComb3H M13 surface display systems as previously described (23). Specific Ab clones were selected from the phage libraries by panning on frozen tissue sections (24,25).…”

Section: Library Construction and Phage Selectionmentioning

confidence: 99%

Translocation of an Intracellular Antigen to the Surface of Medullary Breast Cancer Cells Early in Apoptosis Allows for an Antigen-Driven Antibody Response Elicited by Tumor-Infiltrating B Cells

Hansen

Nielsen

Ditzel

2002

The Journal of Immunology

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Tumor-infiltrating lymphoplasmacytic cells are a key feature of medullary carcinoma of the breast (MCB), a distinct subtype of human breast cancer that, despite cytologically anaplastic characteristics, has a more favorable prognosis than other types of breast cancer. Since it has been proposed that the improved clinical outcome is due at least in part to the presence of a prominent lymphoplasmacytic cell infiltrate in the tumor stroma, we recently examined the tumor-infiltrating B cell response in MCB and showed that it is oligoclonal and directed against an intracellular protein translocated to the cell surface upon MCB cell apoptosis. Human Abs cloned from MCB lymphoplasmacytic infiltrate-derived phage display libraries and reflecting the dominant part of the response were used to identify the target Ag as actin. Here, we have characterized in detail the cloned human IgG Abs and the translocation process of actin to the cell surface of apoptotic MCB cells. Our analysis shows that the cloned Abs bind specifically and with high affinity to actin, as determined by ELISA and surface plasmon resonance. Sequence analysis revealed that the Abs are highly somatically mutated, with high replacement to silent ratios, indicative of an Ag-driven, affinity-matured response. Interestingly, the tumor-infiltrating B cells in half the MCB patients mainly exhibited an IgG2 response, while IgG1 dominated in the others. To gain insight to the molecular events that may elicit such an Ab response, we examined the translocation of actin to the cell surface of apoptotic MCB cells using flow cytometry and laser scanning cytometry. Our results show that actin becomes exposed on the cell surface of a large proportion of apoptotic MCB cells as an early apoptotic event. We propose that the Ab response against actin produced by tumor-infiltrating B lymphoplasmacytic cells is Ag-driven, affinity-matured, and elicited due to the increased rate of apoptosis occurring within the MCB tumor that facilitates the translocation and proteolytic fragmentation of intracellular proteins.

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“…Of these, only a handful have been found to be broadly neutralizing across HIV-1 subtypes (8), and have been the result of HIV-1 infection rather than immunization. Two of these are directed against gp120: MAb b12, which binds to an epitope that overlaps a subset of the CD4-binding site (CD4bs) of gp120 (3,10,11,68,94), and MAb 2G12, which recognizes a carbohydrate motif (9,70,72,80). Two broadly neutralizing MAbs, 4E10 and 2F5, recognize gp41 (9,56,77,96).…”

mentioning

confidence: 99%

Llama Antibody Fragments with Cross-Subtype Human Immunodeficiency Virus Type 1 (HIV-1)-Neutralizing Properties and High Affinity for HIV-1 gp120

Forsman

Beirnaert

Aasa-Chapman

et al. 2008

J Virol

111

138

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Members of the Camelidae family produce immunoglobulins devoid of light chains. We have characterized variable domains of these heavy chain antibodies, the VHH, from llamas immunized with human immunodeficiency virus type 1 (HIV-1) envelope protein gp120 in order to identify VHH that can inhibit HIV-1 infection. To increase the chances of isolating neutralizing VHH, we employed a functional selection approach, involving panning of phage libraries expressing the VHH repertoire on recombinant gp120, followed by a competitive elution with soluble CD4. By immunizing with gp120 derived from an HIV-1 subtype B /C primary isolate, followed by panning on gp120 from HIV-1 isolates of subtypes A, B, and C, we could select for VHH with cross-subtype neutralizing activity. Three VHH able to neutralize HIV-1 primary isolates of subtypes B and C were characterized. These bound to recombinant gp120 with affinities close to the suggested affinity ceiling for in vivo-maturated antibodies and competed with soluble CD4 for this binding, indicating that their mechanism of neutralization involves interacting with the functional envelope spike prior to binding to CD4. The most potent VHH in terms of low 50% inhibitory concentration (IC 50 ) and IC 90 values and cross-subtype reactivity was A12. These results indicate that camelid VHH can be potent HIV-1 entry inhibitors. Since VHH are stable and can be produced at a relatively low cost, they may be considered for applications such as HIV-1 microbicide development. Antienvelope VHH might also prove useful in defining neutralizing and nonneutralizing epitopes on HIV-1 envelope proteins, with implications for HIV-1 vaccine design.

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A large array of human monoclonal antibodies to type 1 human immunodeficiency virus from combinatorial libraries of asymptomatic seropositive individuals.

Cited by 595 publications

References 24 publications

Neutralization Escape Variants of Human Immunodeficiency Virus Type 1 Are Transmitted from Mother to Infant

Neutralization Escape Variants of Human Immunodeficiency Virus Type 1 Are Transmitted from Mother to Infant

Translocation of an Intracellular Antigen to the Surface of Medullary Breast Cancer Cells Early in Apoptosis Allows for an Antigen-Driven Antibody Response Elicited by Tumor-Infiltrating B Cells

Llama Antibody Fragments with Cross-Subtype Human Immunodeficiency Virus Type 1 (HIV-1)-Neutralizing Properties and High Affinity for HIV-1 gp120

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