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

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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 dysfunction.

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Figure 1: HIV monoclonal antibodies block SHIV acquisition.
Figure 2: Suppression of plasma viraemia after monotherapy or combination anti-HIV-1 neutralizing antibody treatment.
Figure 3: Plasma viraemia rebounds in SHIV-infected macaques when neutralizing antibody levels decline.

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Accessions

GenBank/EMBL/DDBJ

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.

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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.

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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.

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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.

ae, 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.

ac, 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.

Extended Data Table 1 Cell-associated viral RNA/DNA in rhesus macaques receiving combination monoclonal antibody therapy
Extended Data Table 2 Decay rate constants of SHIV-AD8 RNA in plasma after monoclonal antibody treatment

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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

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