Antibody-mediated immunotherapy of macaques chronically infected with shiv suppresses viraemia

ABSTRACT Neutralizing antibodies can confer immunity to primate lentiviruses by blocking infection in macaque models of AIDS1,2,3,4. 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

variants5,6,7. A new generation of anti-HIV-1 monoclonal antibodies, possessing extraordinary potency and breadth of neutralizing activity, has recently been isolated from infected

individuals8. 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, 10, 11, 12, 13, 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 macaques15,16. 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

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customer support SIMILAR CONTENT BEING VIEWED BY OTHERS COMBINATION ANTI-HIV ANTIBODIES PROVIDE SUSTAINED VIROLOGICAL SUPPRESSION Article 01 June 2022 PROLONGED VIRAL SUPPRESSION WITH

ANTI-HIV-1 ANTIBODY THERAPY Article Open access 13 April 2022 THERAPEUTIC EFFICACY OF COMBINED ACTIVE AND PASSIVE IMMUNIZATION IN ART-SUPPRESSED, SHIV-INFECTED RHESUS MACAQUES Article Open

access 16 June 2022 ACCESSION CODES ACCESSIONS GENBANK/EMBL/DDBJ * KF738375 * KF738446 DATA DEPOSITS The SHIV-AD8 gp120 sequences known to confer resistance to the 10-1074 or 3BNC117

monoclonal antibodies have been deposited in GenBank/EMBL/DDBJ under accession numbers KF738375 to KF738446. REFERENCES * Mascola, J. R. et al. Protection of macaques against pathogenic

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Scholar  Download references ACKNOWLEDGEMENTS We thank K. Tomioka and R. Kruthers for determining plasma viral RNA loads and B. Skopets, W. Magnanelli and R. Petros for diligently assisting

in the maintenance of animals and assisting with procedures. We also thank D. R. Burton, The Scripps Institute, for providing anti-dengue virus neutralizing monoclonal antibody (DEN-3). This

work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH) and, in part, with federal funds from

the National Cancer Institute, NIH, under contract HHSN261200800001E. AUTHOR INFORMATION Author notes * Masashi Shingai and Yoshiaki Nishimura: These authors contributed equally to this

work. AUTHORS AND AFFILIATIONS * Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, 20892, Maryland, USA

Masashi Shingai, Yoshiaki Nishimura, Olivia K. Donau, Ronald Plishka, Alicia Buckler-White & Malcolm A. Martin * Laboratory of Molecular Immunology, The Rockefeller University, New York,

10065, New York, USA Florian Klein & Michel C. Nussenzweig * Department of Immunology, Laboratory of Humoral Response to Pathogens, Institut Pasteur, 75015 Paris, France, Hugo Mouquet *

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, E/CLS-1001 Boston, 02115, Massachusetts, USA Michael Seaman * AIDS

and Cancer Virus Program, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland 21702, USA, Michael Piatak & Jeffrey D. Lifson * Center for Cancer

Research, National Cancer Institute, National Institutes of Health, Bethesda, 20892, Maryland, USA Dimiter Dimitrov & Michel C. Nussenzweig * Howard Hughes Medical Institute, The

Rockefeller University, New York, 10065, New York, USA Michel C. Nussenzweig Authors * Masashi Shingai View author publications You can also search for this author inPubMed Google Scholar *

Yoshiaki Nishimura View author publications You can also search for this author inPubMed Google Scholar * Florian Klein View author publications You can also search for this author inPubMed 

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author inPubMed Google Scholar * Ronald Plishka View author publications You can also search for this author inPubMed Google Scholar * Alicia Buckler-White View author publications You can

also search for this author inPubMed Google Scholar * Michael Seaman View author publications You can also search for this author inPubMed Google Scholar * Michael Piatak View author

publications You can also search for this author inPubMed Google Scholar * Jeffrey D. Lifson View author publications You can also search for this author inPubMed Google Scholar * Dimiter

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Google Scholar * Malcolm A. Martin View author publications You can also search for this author inPubMed Google Scholar CONTRIBUTIONS M.S., Y.N., M.C.N. and M.A.M. designed the experiments;

M.S., Y.N., F.K., H.M., O.K.D., R.P., A.B.-W. and M.P. performed the experiments; M.S., Y.N., F.K., M.P., J.D.L., D.D., M.C.N. and M.A.M. analysed the data; and M.S., Y.N., M.C.N. and M.A.M.

wrote the manuscript. M.S. and Y.N. contributed equally to the work. CORRESPONDING AUTHORS Correspondence to Michel C. Nussenzweig or Malcolm A. Martin. ETHICS DECLARATIONS COMPETING

INTERESTS The authors declare no competing financial interests. EXTENDED DATA FIGURES AND TABLES EXTENDED DATA FIGURE 1 TREATMENT OF SHIV-INFECTED MACAQUES WITH SINGLE ANTI-HIV-1

NEUTRALIZING MONOCLONAL ANTIBODIES. Plasma viral loads and total CD4+ T cell numbers before (the initial 84 days of the SHIV-AD8EO infection) and during single monoclonal antibody treatment

are shown. KZ6 and MB6 received the 3BNC117 monoclonal antibody and MB8 and MCN were administered the 10-1074 monoclonal antibody. Macaques MB7 and MD5 were not treated. EXTENDED DATA FIGURE

2 SGA ANALYSIS OF SELECTED SHIV-AD8EO GP120 SEQUENCES, PRESENT IN REBOUND VIRUS AFTER SINGLE MONOCLONAL ANTIBODY IMMUNOTHERAPY, AND KNOWN TO CONFER RESISTANCE TO 10-1074 OR 3BNC117

MONOCLONAL ANTIBODY. SGA was used to amplify plasma viral RNA after monoclonal antibody treatment from the plasma of animals KZ6 (day 28 (_n_ = 8)), MB6 (day 23 (_n_ = 8)), MB8 (day 23 (_n_

= 9)) and MCN (day 23 (_n_ = 8)). The gp120 sequences at the top are present in the SHIV-AD8EO molecular clone inoculum. Mutations conferring resistance are highlighted in red. EXTENDED DATA

FIGURE 3 CIRCULATING CD4+ T CELLS IN FIVE CHRONICALLY SHIV-INFECTED MACAQUES TREATED WITH TWO ANTI-HIV-1 NEUTRALIZING MONOCLONAL ANTIBODIES. Plasma viral loads and total CD4+ T-cell numbers

before (first 1,100 to 1,140 days) and during the first or second cycle of combination monoclonal antibody treatment are shown. EXTENDED DATA FIGURE 4 BAL CD4+ T CELLS IN FIVE CHRONICALLY

SHIV-INFECTED MACAQUES TREATED WITH TWO ANTI-HIV-1 NEUTRALIZING MONOCLONAL ANTIBODIES. Plasma viral loads and the percentage of CD4+ T cells in CD3+ gated BAL specimens, before (first 1,100

to 1,140 days) and during the first or second cycle of combination monoclonal antibody treatment, are shown. EXTENDED DATA FIGURE 5 SGA ANALYSIS OF SELECTED SHIV-AD8EO GP120 SEQUENCES KNOWN

TO CONFER RESISTANCE TO 10-1074 OR 3BNC117 MONOCLONAL ANTIBODY, BEFORE AND AFTER COMBINATION IMMUNOTHERAPY. A–E, Plasmas from animals DBZ3 (pre (_n_ = 8); day 49 post first treatment (_n_ =

10); day 24 post second treatment (_n_ = 8)) (A), DC99A (pre (_n_ = 10); day 57 post first treatment (_n_ = 6); day 41 post second treatment (_n_ = 7)) (B), DBXE (pre (_n_ = 9), day 28 (_n_

= 8)) (C), DCF1 (pre (_n_ = 14), day 28 (_n_ = 10)) (D) and DCM8 (pre (_n_ = 7), day 28 (_n_ = 11)) (E) were evaluated. The gp120 sequences at the top are present in the SHIV-AD8EO molecular

clone inoculum. Mutations conferring resistance are highlighted in red. EXTENDED DATA FIGURE 6 CD4+ T-CELL NUMBERS INCREASE DURING COMBINATION MONOCLONAL ANTIBODY TREATMENT OF

SHIV-AD8EO-INFECTED MACAQUES. A, B, Levels of viral RNA and total CD4+ T-cell/CD4+ T-cell subsets in symptomatic chronically infected macaques DBXE (A) and DCF1 (B). EXTENDED DATA FIGURE 7

ASSAYS TO IDENTIFY 10-1074- OR 3BNC117-SPECIFIC NEUTRALIZING ACTIVITIES IN THE PLASMA OF MONOCLONAL-ANTIBODY-TREATED MACAQUES. A, ID50 values measured in the TZM-bl neutralization assay of

10-1074 and 3BNC117 against HIV-1 strains that are sensitive to one but not the other broadly neutralizing antibody (that is, HIV-1 strain X2088_9 (10-1074 sensitive); HIV-1 strain Q769_d22

(3BNC117 sensitive)). B, Neutralizing activities in plasma before antibody administration (preP), but spiked with 0.01, 0.1, 1, 10 and 100 μg ml−1 of antibodies 10-1074 (blue) or 3BNC117

(green). Neutralizing activities are reported as plasma ID50 titres (left columns) and converted to antibody concentrations (right columns) based on measured ID50 values in A. EXTENDED DATA

FIGURE 8 MONOCLONAL ANTIBODY LEVELS IN THE PLASMAS OF MONOTHERAPY AND COMBINATION MONOCLONAL ANTIBODY MACAQUE RECIPIENTS. A–C, Macaques treated with one neutralizing monoclonal antibody (A);

macaques receiving two cycles of combination monoclonal antibody treatment (B); macaques receiving a single cycle of combination monoclonal antibody treatment (C). ID50 titres (left

columns) and monoclonal antibody concentrations (right columns) were measured in the indicated macaque plasma samples before (Prebleed) and after (Day) monoclonal antibody administration.

RELATED AUDIO NEWS & VIEWS AUTHOR LOUIS PICKER TALKS TO NATURE ABOUT TREATING HIV WITH SOME UNUSUALLY POTENT ANTIBODIES. POWERPOINT SLIDES POWERPOINT SLIDE FOR FIG. 1 POWERPOINT SLIDE

FOR FIG. 2 POWERPOINT SLIDE FOR FIG. 3 RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Shingai, M., Nishimura, Y., Klein, F. _et al._ Antibody-mediated

immunotherapy of macaques chronically infected with SHIV suppresses viraemia. _Nature_ 503, 277–280 (2013). https://doi.org/10.1038/nature12746 Download citation * Received: 05 August 2013 *

Accepted: 11 October 2013 * Published: 30 October 2013 * Issue Date: 14 November 2013 * DOI: https://doi.org/10.1038/nature12746 SHARE THIS ARTICLE Anyone you share the following link with

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