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Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques.

ABSTRACT: The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.

SUBMITTER: Xu L

PROVIDER: S-EPMC5978417 | biostudies-literature | 2017 Oct

REPOSITORIES: biostudies-literature

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Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques.

Xu Ling L Pegu Amarendra A Rao Ercole E Doria-Rose Nicole N Beninga Jochen J McKee Krisha K Lord Dana M DM Wei Ronnie R RR Deng Gejing G Louder Mark M Schmidt Stephen D SD Mankoff Zachary Z Wu Lan L Asokan Mangaiarkarasi M Beil Christian C Lange Christian C Leuschner Wulf Dirk WD Kruip Jochen J Sendak Rebecca R Kwon Young Do YD Zhou Tongqing T Chen Xuejun X Bailer Robert T RT Wang Keyun K Choe Misook M Tartaglia Lawrence J LJ Barouch Dan H DH O'Dell Sijy S Todd John-Paul JP Burton Dennis R DR Roederer Mario M Connors Mark M Koup Richard A RA Kwong Peter D PD Yang Zhi-Yong ZY Mascola John R JR Nabel Gary J GJ

Science (New York, N.Y.) 20170920 6359

The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, ...[more]

PMID: 28931639

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Project description:Preventing human immunodeficiency virus (HIV) infection in newborns by vertical transmission remains an important unmet medical need in resource-poor areas where antiretroviral therapy (ART) is not available and mothers and infants cannot be treated prepartum or during the breastfeeding period. In the present study, the protective efficacy of the potent HIV-neutralizing antibodies PGT121 and VRC07-523, both produced in plants, were assessed in a multiple-SHIV (simian-human immunodeficiency virus)-challenge breastfeeding macaque model. Newborn macaques received either six weekly subcutaneous injections with PGT121 alone or as a cocktail of PGT121-LS plus VRC07-523-LS injected three times every 2 weeks. Viral challenge with SHIVSF162P3 was twice weekly over 5.5 weeks using 11 exposures. Despite the transient presence of plasma viral RNA either immediately after the first challenge or as single-point blips, the antibodies prevented a productive infection in all babies with no sustained plasma viremia, compared to viral loads ranging from 103 to 5 × 108 virions/ml in four untreated controls. No virus was detected in peripheral blood mononuclear cells (PBMCs), and only 3 of 159 tissue samples were weakly positive in the treated babies. Newborn macaques proved to be immunocompetent, producing transient anti-Env antibodies and anti-drug antibody (ADA), which were maintained in the circulation after passive broadly neutralizing antibody clearance. ADA responses were directed to the IgG1 Fc CH2-CH3 domains, which has not been observed to date in adult monkeys passively treated with PGT121 or VRC01. In addition, high levels of VRC07-523 anti-idiotypic antibodies in the circulation of one newborn was concomitant with the rapid elimination of VRC07. Plant-expressed antibodies show promise as passive immunoprophylaxis in a breastfeeding model in newborns. IMPORTANCE Plant-produced human neutralizing antibody prophylaxis is highly effective in preventing infection in newborn monkeys during repeated oral exposure, modeling virus in breastmilk, and offers advantages in cost of production and safety. These findings raise the possibility that anti-Env antibodies may contribute to the control of viral replication in this newborn model and that the observed immune responsiveness may be driven by the long-lived presence of immune complexes.

Dataset Information

Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques.

Publications

Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques.

Similar Datasets

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