Potent and broad neutralizing activity of a single chain antibody fragment against cell-free and cell-associated HIV-1

Zhang, MY; Borges, AR; Rg, Ptak; Wang, Y; Dimitrov, AS; Alam, S. Munir; Wieczorek, Lindsay; Bouma, Peter; Fouts, Timothy; Jiang, Shantong; Polonis, VR; Haynes, BF; Gv, Quinnan; Montefiori, DC; Ds, Dimitrov

doi:10.4161/mabs.2.3.11416

Cited by 20 publications

(23 citation statements)

References 45 publications

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“…For example, antibodies can block infection by free virions, but they can also direct the killing of infected cells that express cell surface gp160 or its fragments by antibody-dependent cell-mediated cytotoxicity/antibodydependent cell-mediated viral inhibition (ADCC/ADCVI) (40,41). In addition, antibodies may be able to block synapse formation and subsequent cell contact-mediated viral transmission (42)(43)(44). To determine whether the antibodies used in this study can interfere with cell contact-mediated transmission of HIV-1 YU2 , we compared their activity in established cell-free and cell contact-permitting transmission assays (45) in vitro (Fig.…”

Section: Resultsmentioning

confidence: 99%

HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

Horwitz

Halper-Stromberg

Mouquet

et al. 2013

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

245

250

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Effective control of HIV-1 infection in humans is achieved using combinations of antiretroviral therapy (ART) drugs. In humanized mice (hu-mice), control of viremia can be achieved using either ART or by immunotherapy using combinations of broadly neutralizing antibodies (bNAbs). Here we show that treatment of HIV-1-infected hu-mice with a combination of three highly potent bNAbs not only resulted in complete viremic control but also led to a reduction in cell-associated HIV-1 DNA. Moreover, lowering the initial viral load by coadministration of ART and immunotherapy enabled prolonged viremic control by a single bNAb after ART was withdrawn. Similarly, a single injection of adeno-associated virus directing expression of one bNAb produced durable viremic control after ART was terminated. We conclude that immunotherapy reduces plasma viral load and cell-associated HIV-1 DNA and that decreasing the initial viral load enables single bNAbs to control viremia in hu-mice.CD4bs | glycan | gp160

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Section: Resultsmentioning

confidence: 99%

HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

Horwitz

Halper-Stromberg

Mouquet

et al. 2013

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

245

250

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show abstract

“…For this to occur, the immune system must be presented with the target in the desired conformation and then create antibodies at an affinity that outcompetes the native function at a level that eliminates reservoirs of the pathogen. An example of this in HIV vaccines is gp120 as a target for a neutralizing antibody response (25, 26). Here, the key function of the target is binding and entrance to cells via the CD4 / gp120 interaction (27).…”

Section: Neutralization and Breadth Of The Antibody Responsementioning

confidence: 99%

Role of adjuvants in modeling the immune response

Carter

Reed

2010

Current Opinion in HIV and AIDS

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Purpose of review Recent clinical trial results have indicated that it may be possible for vaccines to induce protection against HIV. To build on this result, strategies should be designed to enhance duration, breadth, and magnitude of antibody production. Strategic formulation of agonists of the innate immune system and carriers that selectively present the target antigen yield a class of pharmaceuticals, “adjuvants”, which greatly influence immunity resulting from vaccination. As researchers begin to focus not only on creating an immune response to an antigen, but also on the quality of that response, the role of adjuvants is becoming increasingly significant. This review is intended to give an overview of recent findings on how adjuvants model the immune response to antigens with a focus on the field of vaccines for HIV. Recent findings It is clear that innate and adaptive immunity are linked by communication channels that allow innate signals to influence the quality of adaptive responses as well as adaptive signals that temper innate responses. Adjuvants take advantage of this bridge to shape the immune response to antigens. In this review we will discuss the different classes of adjuvants currently available; recent findings on the relationship between adjuvants and the type of immune profile generated; and the breadth of neutralizing antibodies as influenced by adjuvants. Summary Because adjuvants influence the breadth of antibodies generated and the type of cells that proliferate in response to a vaccine this review is relevant for scientists clinicians involved in creating a new HIV vaccine.

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“…In a recent study, Zhang et al used a sequential antigen panning (SAP) method and successfully isolated broadly cross-reactive antibodies with two-to threefold lower IC 50 s than the parent HIV-1-neutralizing antibody scFv X5 (41). Upon further characterization, they found that the highly potent m9 antibody not only exhibited broad neutralizing activity but also suppressed the generation of escape mutants upon immune selection (40). Addi-tional studies on broadly neutralizing antibodies to HIV from memory B cells also suggest that affinity has an important role in breadth and potency of neutralization (23,31).…”

Section: Discussionmentioning

confidence: 99%

Increased Antibody Affinity Confers Broad In Vitro Protection against Escape Mutants of Severe Acute Respiratory Syndrome Coronavirus

Rani

Bolles

Donaldson

et al. 2012

J Virol

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f Even though the effect of antibody affinity on neutralization potency is well documented, surprisingly, its impact on neutralization breadth and escape has not been systematically determined. Here, random mutagenesis and DNA shuffling of the singlechain variable fragment of the neutralizing antibody 80R followed by bacterial display screening using anchored periplasmic expression (APEx) were used to generate a number of higher-affinity variants of the severe acute respiratory syndrome coronavirus (SARS-CoV)-neutralizing antibody 80R with equilibrium dissociation constants (K D ) as low as 37 pM, a >270-fold improvement relative to that of the parental 80R single-chain variable fragment (scFv). As expected, antigen affinity was shown to correlate directly with neutralization potency toward the icUrbani strain of SARS-CoV. Additionally, the highest-affinity antibody fragment displayed 10-fold-increased broad neutralization in vitro and completely protected against several SARS-CoV strains containing substitutions associated with antibody escape. Importantly, higher affinity also led to the suppression of viral escape mutants in vitro. Escape from the highest-affinity variant required reduced selective pressure and multiple substitutions in the binding epitope. Collectively, these results support the hypothesis that engineered antibodies with picomolar dissociation constants for a neutralizing epitope can confer escape-resistant protection.

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Potent and broad neutralizing activity of a single chain antibody fragment against cell-free and cell-associated HIV-1

Abstract: (2010) Potent and broad neutralizing activity of a single chain antibody fragment against cell-free and cellassociated HIV-1, mAbs, 2:3, 266-274,

Cited by 20 publications

References 45 publications

HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

HIV-1 suppression and durable control by combining single broadly neutralizing antibodies and antiretroviral drugs in humanized mice

Role of adjuvants in modeling the immune response

Increased Antibody Affinity Confers Broad In Vitro Protection against Escape Mutants of Severe Acute Respiratory Syndrome Coronavirus

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