Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques

Xu, Li; Pegu, Amarendra; Rao, Ercole; Doria‐Rose, Nicole A.; Beninga, Jochen; McKee, Krisha; Lord, Dana M.; Wei, Ronnie R.; Deng, Gejing; Louder, Mark K.; Schmidt, Stephen D.; Mankoff, Zachary; Wu, Lan; Asokan, Mangaiarkarasi; Beil, Christian; Lange, Christian; Leuschner, Wulf Dirk; Kruip, Jochen; Sendak, Rebecca A.; Kwon, Young Do; Zhou, Tongqing; Chen, Xuejun; Bailer, Robert T.; Wang, Keyun; Choe, Misook; Tartaglia, Lawrence J.; Barouch, Dan H.; O’Dell, Sijy; Todd, John-Paul M.; Burton, Dennis R.; Roederer, Mario; Connors, Mark; Koup, Richard A.; Kwong, Peter D.; Yang, Zhiyong; Mascola, John R.; Nabel, Gary J.

doi:10.1126/science.aan8630

Cited by 235 publications

(248 citation statements)

References 46 publications

Supporting

Mentioning

231

Contrasting

Unclassified

Order By: Relevance

“…We note that an improved 10E8 antibody has been described that utilized a bi-specific strategy in combination with self-targeting to achieve exquisite potency (Huang et al, 2016b) and that trispecific antibodies engineered with 10E8v4 show substantial protection against simian HIV (SHIV) in rhesus macaques (Huang et al, 2016b; Xu et al, 2017). It will be interesting to see whether the enhancements in neutralization potency—achieved here through optimization of semi-specific interactions—will prove to be a general means to improve antibodies.…”

Section: Discussionmentioning

confidence: 99%

Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody

et al. 2018

Self Cite

View full text Add to dashboard Cite

SUMMARY Highly effective HIV-1-neutralizing antibodies could have utility in the prevention or treatment of HIV-1 infection. To improve the potency of 10E8, an antibody capable of near pan-HIV-1 neutralization, we engineered 10E8-surface mutants and screened for improved neutralization. Variants with the largest functional enhancements involved the addition of hydrophobic or positively charged residues, which were positioned to interact with viral membrane lipids or viral glycan-sialic acids, respectively. In both cases, the site of improvement was spatially separated from the region of antibody mediating molecular contact with the protein component of the antigen, thereby improving peripheral semi-specific interactions while maintaining unmodified dominant contacts responsible for broad recognition. The optimized 10E8 antibody, with mutations to phenylalanine and arginine, retained the extraordinary breadth of 10E8 but with ~10-fold increased potency. We propose surface-matrix screening as a general method to improve antibodies, with improved semi-specific interactions between antibody and antigen enabling increased potency without compromising breadth.

show abstract

Section: Discussionmentioning

confidence: 99%

Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody

et al. 2018

Self Cite

View full text Add to dashboard Cite

show abstract

“…[8,9] To address these challenges, broadly neutralizing antibodies that target HIV envelope glycoproteins of the circulating HIV virions have received much attention. [10,11] However, as the immunity generated by these antibodies remains low, neutralization against cell free viruses is inefficient and the treatment outcome remains unsatisfactory. [12] Mean-while, enormous efforts have been devoted to developing safe and effective vaccines as preventive strategies against HIV infection.…”

mentioning

confidence: 99%

T‐Cell‐Mimicking Nanoparticles Can Neutralize HIV Infectivity

et al. 2018

View full text Add to dashboard Cite

To improve human immunodeficiency virus (HIV) treatment and prevention, therapeutic strategies that can provide effective and broad-spectrum neutralization against viral infection are highly desirable. Inspired by recent advances of cell-membrane coating technology, herein, plasma membranes of CD4+ T cells are collected and coated onto polymeric cores. The resulting T-cell-membrane-coated nanoparticles (denoted as “TNPs”) inherit T cell surface antigens critical for HIV binding, such as CD4 receptor and CCR5 or CXCR4 coreceptors. The TNPs act as decoys for viral attack and neutralize HIV by diverting the viruses away from their intended host targets. This decoy strategy, which simulates host cell functions for viral neutralization rather than directly suppressing viral replication machinery, has the potential to overcome HIV genetic diversity while not eliciting high selective pressure. In this study, it is demonstrated that TNPs selectively bind with gp120, a key envelope glycoprotein of HIV, and inhibit gp120-induced killing of bystander CD4+ T cells. Furthermore, when added to HIV viruses, TNPs effectively neutralize the viral infection of peripheral mononuclear blood cells and human-monocyte-derived macrophages in a dose-dependent manner. Overall, by leveraging natural T cell functions, TNPs show great potential as a new therapeutic agent against HIV infection.

show abstract

“…Therefore, a cocktail of bNAbs may be required (Mujib et al 2017b). Impressively engineered bispecific or trispecific bNAbs, capable of targeting multiple vulnerable sites in Env, may provide an alternative solution (Asokan et al 2015; Xu et al 2017). Another caveat is that passive immunization is currently the only method of delivering bNAbs to HIV + individuals, and the half-lives of bNAbs, which range from 12–20 days in HIV + individuals, will require sequential infusions for improved reservoir reduction (Caskey et al 2016; Scheid et al 2016).…”

Section: Directing the Immune Response To Effectively Target The Resementioning

confidence: 99%

Targeting the Latent Reservoir for HIV-1

2018

View full text Add to dashboard Cite

Antiretroviral therapy can effectively block HIV-1 viral replication and prevent or reverse immunodeficiency in HIV-1-infected individuals. However, viral replication resumes within weeks of treatment interruption. The major barrier to cure is a small pool of resting memory CD4+ T cells that harbor latent HIV-1 proviruses. This latent reservoir is now the focus of an intense international research effort. We describe how the reservoir is established, challenges involved in eliminating it, and pharmacologic and immunologic strategies for targeting this reservoir. The development of a successful cure strategy will likely require understanding the mechanisms that maintain HIV-1 proviruses in a latent state and pathways that drive the proliferation of infected cells, which slows reservoir decay. In addition, cure will require the development of effective immunologic approaches to eliminating infected cells. There is renewed optimism about the prospect of a cure, and the interventions discussed here may pave the way.

show abstract

Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques

Cited by 235 publications

References 46 publications

Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody

Surface-Matrix Screening Identifies Semi-specific Interactions that Improve Potency of a Near Pan-reactive HIV-1-Neutralizing Antibody

T‐Cell‐Mimicking Nanoparticles Can Neutralize HIV Infectivity

Targeting the Latent Reservoir for HIV-1

Contact Info

Product

Resources

About