Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection

Sather, D. Noah; Armann, Jakob; Ching, Lance K.; Mavrantoni, Angeliki; Sellhorn, George; Caldwell, Zachary; Yu, Xuesong; Wood, Blake; Self, Steve; Kalams, Spyros A.; Stamatatos, Leonidas

doi:10.1128/jvi.00283-09

Cited by 121 publications

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“…The scFv fragments were produced by overlapping PCR using variable heavy-and light-chain domain (V H and V L ) genes encoding human anti-gp120, anti-gp41, or a control antibody (mGO53), which does not bind to gp160 and is not polyreactive (Table S1) (59)(60)(61). Specific primers were used to introduce a flexible (G 3 S) 4 linker between V H and V L domains (Fig. S1A).…”

Section: Resultsmentioning

confidence: 99%

“…scFv fragments were generated by classic overlapping PCR using V L and V H DNA fragments cloned into human Ig-expressing vectors (79) as templates, and encoding for anti-gp140 mAbs (59,60) or mGO53 control mAb (61). Briefly, V L and V H DNA fragments were amplified using specific primers introducing a (G 3 S) 4 linker sequence at the 3′ and 5′ ends of V L and V H DNA fragments, respectively (Fig. S1).…”

Section: Methodsmentioning

confidence: 99%

“…Although antibodies that neutralize autologous viruses are common, only a fraction of the patients infected with HIV-1 develop broadly neutralizing serologic activity, and only 2 to 3 y after infection (3)(4)(5)(6)(7)(8)(9). Several broadly neutralizing antibodies (bNAbs) to HIV-1 gp160 have been isolated, including a group that binds to gp120 (10)(11)(12)(13)(14)(15)(16)(17)(18) and a group that is specific for gp41 (19)(20)(21).…”

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confidence: 99%

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Enhanced HIV-1 neutralization by antibody heteroligation

Mouquet

Warncke

Scheid

et al. 2012

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

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Passive transfer of broadly neutralizing human antibodies against HIV-1 protects macaques against infection. However, HIV-1 uses several strategies to escape antibody neutralization, including mutation of the gp160 viral surface spike, a glycan shield to block antibody access to the spike, and expression of a limited number of viral surface spikes, which interferes with bivalent antibody binding. The latter is thought to decrease antibody apparent affinity or avidity, thereby interfering with neutralizing activity. To test the idea that increasing apparent affinity might enhance neutralizing activity, we engineered bispecific anti–HIV-1 antibodies (BiAbs) that can bind bivalently by virtue of one scFv arm that binds to gp120 and a second arm to the gp41 subunit of gp160. The individual arms of the BiAbs preserved the binding specificities of the original anti-HIV IgG antibodies and together bound simultaneously to gp120 and gp41. Heterotypic bivalent binding enhanced neutralization compared with the parental antibodies. We conclude that antibody recognition and viral neutralization of HIV can be improved by heteroligation.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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confidence: 99%

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Enhanced HIV-1 neutralization by antibody heteroligation

Mouquet

Warncke

Scheid

et al. 2012

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

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“…In another study, the critical contribution of aromatic residues (particularly Trp and His) for HIV Env binding has been revealed (Heydarchi et al submitted). The long CDRH3, high level of SHMs and presence of Cys and aromatic residues are parts of the normal bovine immunoglobulin that are comparable to what was observed from human neutralizing immunoglobulins which in contrast, require a long time to develop and are not observed in normal antibodies [1].…”

Section: Aromatic Residues In Bovine Cdrh3 Pave the Wave Toward Hiv Nmentioning

confidence: 54%

“…BrNAbs can emerge in some HIV-infected individuals after several years of infection [1]. The serum immunoglobulin G (IgG) from these "elite neutralizer" patients can neutralize many different HIV-1 strains across various different subtypes [2].…”

Section: Introductionmentioning

confidence: 99%

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

Heydarchi¹,

Quiroz²,

Purcell³

2016

J Vaccines Vaccin

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The idea of using antibodies to restrain HIV viral replication has been a growing interest since many years ago. HIV-patient serum with elite virus-neutralizing breadth has led to the preparation of broadly neutralizing antibodies (BrNAbs) with long and highly mutated CDRH3 domains that can neutralize a broad array of viral strains and prevent transmission in animal models. Recent advances have resulted in the discovery of BrNAbs that are more potent and can neutralize many HIV-1 subtypes. However, elicitation of these antibodies in infected individuals usually requires a long time of antigen exposure. Though BrNAbs are shown to be successful either therapeutically or prophylactically against HIV-1, production of these antibodies in bulk, commercial-sized batches are expensive and non-affordable particularly for poor countries. Therefore, more durable preventative or therapeutic strategies are required. Immunization of the cows with HIV Env is shown to be capable of producing 20 kg purified anti-HIV-1 BrNAbs and this amount could be sufficient for 2 million × 10 mg doses for formulation and pre-clinical testing as an HIV microbicide. In addition, bovine immunoglobulins typically have variable third heavy complementarity determining regions (CDRH3) that may potentially facilitate access to antigenic epitopes that are very difficult for other species to engage. Thus, cows could be engaged to elicit anti-HIV antibodies with the features of human BrNAbs and bovine colostrum could be a promising and cheap resource for the development of combination microbicides.

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Identification of a new epitope for HIV‐neutralizing antibodies in the gp41 membrane proximal external region by an Env‐tailored phage display library

et al. 2012

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HIV controllers are a valuable source for the identification of HIV-neutralizing antibodies, as chronic infection over decades allows extensive affinity maturation of antibodies for improved Ag recognition. We analyzed a small cohort of elite controllers (ECs) for HIVneutralizing antibodies using a panel of standardized HIV-1 pseudovirions on TZM-bl cells. An HIV-1 Env-tailored phage display library was generated to select epitopes targeted by neutralizing antibodies in the EC26 plasma sample showing the broadest neutralizing activity. Selected Env fragments were mostly allocated to the membrane proximal external region of gp41. After preabsorbing the EC26 plasma with the selected phage EC26-2A4, we achieved 50% depletion of its neutralizing activity. Furthermore, antibodies affinity-purified with the EC26-2A4 epitope from EC26 plasma showed neutralizing activity, proving that the selected phage indeed contains an epitope targeted by neutralizing plasma antibodies. Epitope fine mapping of the purified plasma antibodies on peptide arrays identified a new epitope overlapping, but clearly distinct, from the prominent 2F5 epitope. Of note, the purified antibodies did not show autoreactivity with cardiolipin, whereas low reactivity with phosphatidylserine comparable to mAb 2F5 was observed. Thus, this new epitope represents a promising candidate for further analysis in view of HIV vaccine development.Keywords: Elite controllers r Epitopes r HIV-1 r neutralizing antibodies r phage display Additional supporting information may be found in the online version of this article at the publisher's web-site Correspondence: Ursula Dietrich e-mail: ursula.dietrich@em.uni-frankfurt.de IntroductionEliciting broadly neutralizing antibodies (bnAbs) against HIV-1 is a major goal in HIV vaccine development [1]. However, despite the identification of a number of epitopes for bnAbs present in C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 500Mingkui Zhou et al. Eur. J. Immunol. 2013. 43: 499-509 patient sera [2], these epitopes failed so far to induce such antibodies after vaccination in vivo [3][4][5][6][7][8]. The mechanism behind the elicitation of bnAbs during natural infection remains unclear. Emerging evidence indicates that most HIV-1-specific antibodies elicited during early infection fail to neutralize a wide-spectrum of HIV-1 strains and emphasizes the importance of analyzing the Ab profile of patients showing delayed disease progression to allow for sufficient affinity maturation [9]. A subgroup of HIV-1-infected individuals controlling the infection over years in the absence of antiretroviral therapy and maintaining serum viral loads (VL) below the detection limit (<50 copies/mL) is termed "elite controllers" (ECs) [10]. Although virus control is certainly due to a potent HIV-specific immune response [10], few qualitative differences in immune responses have been identified between controllers and viremic individuals. The differences encountered so far mainly concern the cellular immune response an...

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Factors Associated with the Development of Cross-Reactive Neutralizing Antibodies during Human Immunodeficiency Virus Type 1 Infection

Cited by 121 publications

References 0 publications

Enhanced HIV-1 neutralization by antibody heteroligation

Enhanced HIV-1 neutralization by antibody heteroligation

Broad Neutralizing Antibodies to HIV Env and Other Complex Viral Antigens from Vaccinated Cows

Identification of a new epitope for HIV‐neutralizing antibodies in the gp41 membrane proximal external region by an Env‐tailored phage display library

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