Combination therapy with anti-HIV-1 antibodies maintains viral suppression

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Abstract

HIV-1-infected individuals require lifelong antiretroviral therapy (ART) because treatment interruption leads to rapid rebound viremia. Here we report on a phase 1b clinical trial in which a combination of 3BNC117 and 10-1074, two potent monoclonal anti-HIV-1 broadly neutralizing antibodies that target independent sites on the HIV-1 envelope spike, was administered during analytical treatment interruption. Participants received three infusions of 30 mg/kg of each antibody at 0, 3 and 6 weeks. Infusions of the two antibodies were generally well tolerated. The nine enrolled individuals with antibody-sensitive latent viral reservoirs maintained suppression for 15 to > 30 weeks (median = 21 weeks), and none developed viruses resistant to both antibodies. We conclude that the combination of anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of ART in individuals with antibody-sensitive viral reservoirs.

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Most cited references 26

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Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing.

Jesus Salazar-Gonzalez, Elizabeth Bailes, Kimmy Pham … (2008)

Accurate identification of the transmitted virus and sequences evolving from it could be instrumental in elucidating the transmission of human immunodeficiency virus type 1 (HIV-1) and in developing vaccines, drugs, or microbicides to prevent infection. Here we describe an experimental approach to analyze HIV-1 env genes as intact genetic units amplified from plasma virion RNA by single-genome amplification (SGA), followed by direct sequencing of uncloned DNA amplicons. We show that this strategy precludes in vitro artifacts caused by Taq-induced nucleotide substitutions and template switching, provides an accurate representation of the env quasispecies in vivo, and has an overall error rate (including nucleotide misincorporation, insertion, and deletion) of less than 8 x 10(-5). Applying this method to the analysis of virus in plasma from 12 Zambian subjects from whom samples were obtained within 3 months of seroconversion, we show that transmitted or early founder viruses can be identified and that molecular pathways and rates of early env diversification can be defined. Specifically, we show that 8 of the 12 subjects were each infected by a single virus, while 4 others acquired more than one virus; that the rate of virus evolution in one subject during an 80-day period spanning seroconversion was 1.7 x 10(-5) substitutions per site per day; and that evidence of strong immunologic selection can be seen in Env and overlapping Rev sequences based on nonrandom accumulation of nonsynonymous mutations. We also compared the results of the SGA approach with those of more-conventional bulk PCR amplification methods performed on the same patient samples and found that the latter is associated with excessive rates of Taq-induced recombination, nucleotide misincorporation, template resampling, and cloning bias. These findings indicate that HIV-1 env genes, other viral genes, and even full-length viral genomes responsible for productive clinical infection can be identified by SGA analysis of plasma virus sampled at intervals typical in large-scale vaccine trials and that pathways of viral diversification and immune escape can be determined accurately.

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Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia.

Masashi Shingai, Yoshiaki Nishimura, Florian Klein … (2013)

Neutralizing antibodies can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS. However, earlier studies of anti-human immunodeficiency virus type 1 (HIV-1) neutralizing antibodies administered to infected individuals or humanized mice reported poor control of virus replication and the rapid emergence of resistant variants. A new generation of anti-HIV-1 monoclonal antibodies, possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected individuals. These neutralizing antibodies target different regions of the HIV-1 envelope glycoprotein including the CD4-binding site, glycans located in the V1/V2, V3 and V4 regions, and the membrane proximal external region of gp41 (refs 9-14). Here we have examined two of the new antibodies, directed to the CD4-binding site and the V3 region (3BNC117 and 10-1074, respectively), for their ability to block infection and suppress viraemia in macaques infected with the R5 tropic simian-human immunodeficiency virus (SHIV)-AD8, which emulates many of the pathogenic and immunogenic properties of HIV-1 during infections of rhesus macaques. Either antibody alone can potently block virus acquisition. When administered individually to recently infected macaques, the 10-1074 antibody caused a rapid decline in virus load to undetectable levels for 4-7 days, followed by virus rebound during which neutralization-resistant variants became detectable. When administered together, a single treatment rapidly suppressed plasma viraemia for 3-5 weeks in some long-term chronically SHIV-infected animals with low CD4(+) T-cell levels. A second cycle of anti-HIV-1 monoclonal antibody therapy, administered to two previously treated animals, successfully controlled virus rebound. These results indicate that immunotherapy or a combination of immunotherapy plus conventional antiretroviral drugs might be useful as a treatment for chronically HIV-1-infected individuals experiencing immune dysfunction.

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Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice.

Ariel Halper-Stromberg, Ching-Lan Lu, Florian Klein … (2014)

Latent reservoirs of HIV-1-infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, immunologically invisible, and may undergo homeostatic proliferation, a "shock and kill" approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.

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Author and article information

Journal

Journal ID (nlm-journal-id): 0410462

Journal ID (pubmed-jr-id): 6011

Journal ID (nlm-ta): Nature

Journal ID (iso-abbrev): Nature

Title: Nature

ISSN (Print): 0028-0836

ISSN (Electronic): 1476-4687

Publication date Nihms-submitted: 16 August 2018

Publication date (Electronic): 26 September 2018

Publication date (Print): September 2018

Publication date PMC-release: 26 March 2019

Volume: 561

Issue: 7724

Pages: 479-484

Affiliations

[1 ]Laboratory of Molecular Immunology, The Rockefeller University, New York, New York, USA

[2 ]Laboratory of Experimental Immunology, Institute of Virology, University Hospital Cologne, Cologne, Germany

[3 ]Department I of Internal Medicine, University Hospital Cologne, Cologne, Germany

[4 ]German Center for Infection Research, partner site Bonn–Cologne, Cologne, Germany

[5 ]Center for Molecular Medicine Cologne (CMMC), University of Cologne, Germany

[6 ]Praxis am Ebertplatz, Cologne, Germany

[7 ]Methods in Medical Informatics, Department of Computer Science, University of Tübingen, Tübingen, Germany

[8 ]Duke Human Vaccine Institute, Departments of Surgery, Immunology, and Molecular Genetics and Microbiology, Duke University, Durham, North Carolina, USA

[9 ]Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, California, USA

[10 ]Division of Infectious Diseases, Weill Cornell Medicine, New York, New York, USA

[11 ]Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

[12 ]Howard Hughes Medical Institute, The Rockefeller University, New York, New York, USA

Author notes

Correspondence and requests for materials should be addressed to M.C. ( mcaskey@ 123456rockefeller.edu ), F.K. ( florian.klein@ 123456uk-koeln.de ), or M.C.N. ( nussen@ 123456rockefeller.edu ).

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Article

Manuscript ID: EMS78835

DOI: 10.1038/s41586-018-0531-2

PMC ID: 6166473

PubMed ID: 30258136

SO-VID: 479d8946-bc2f-4c53-bf5c-f820bdf01647

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Combination therapy with anti-HIV-1 antibodies maintains viral suppression

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Most cited references 26

Deciphering human immunodeficiency virus type 1 transmission and early envelope diversification by single-genome amplification and sequencing.

Antibody-mediated immunotherapy of macaques chronically infected with SHIV suppresses viraemia.

Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice.

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