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 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.

Figures

Extended Data Figure 1

Treatment of SHIV infected macaques with single anti-HIV 1 neutralizing mAbs. Plasma viral loads and total CD4+ T cell numbers prior to (the initial 84 days of the SHIVAD8EO infection) and during single mAb treatment are shown. MZ6 and MB6 received the 3BNC117 mAb and MB8 and MCN were administered the 10-1074 mAb. Macaques MB7 and MD5 were not treated.

Extended Data Figure 2

SGA analysis of selected SHIVAD8EO gp120 sequences, present in rebound virus following single mAb immunotherapy, and known to confer resistance to 10-1074 or 3BNC117 mAb. SGA was used to amplify plasma viral RNA following mAb treatment from the plasma of animals KZ6 [day 28], MB6 [day 23], MB8 [day 23], and MCN [day 23]. The gp120 sequences at the top are present in the SHIVAD8EO 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 mAbs. Plasma viral loads and total CD4+ T cell numbers prior to (first 1100 to 1140 days) and during the first or second cycle of combination mAb treatment are shown.

Extended Data Figure 4

BAL CD4+ T cells in five chronically SHIV infected macaques treated with two anti-HIV 1 neutralizing mAbs. Plasma viral loads and the % CD4+ T cells in CD3+ gated BAL specimens, prior to (first 1100 to 1140 days) and during the first or second cycle of combination mAb treatment, are shown.

Extended Data Figure 5

SGA analysis of selected SHIVAD8EO gp120 sequences known to confer resistance to 10-1074 or 3BNC117 mAb, prior to and following combination immunotherapy. Plasma from animals (a) DBZ3 [day 49], (b) DC99A [day 57], (c) DBXE [day 28], (d) DCF1 [day 28], and (e) DCM8 [day 28] were evaluated. The gp120 sequences at the top are present in the SHIVAD8EO molecular clone inoculum. Mutations conferring resistance are highlighted in red.

Extended Data Figure 6

CD4+ T cell numbers increase during combination mAb treatment of SHIVAD8EO infected macaques. Levels of viral RNA and total CD4+T cell/CD4+ T cell subsets in symptomatic chronically infected macaques (a) DBX3 and (b) DCF1.

Extended Data Figure 7

Assays to identify 10-1074- or 3BNC117-specific neutralizing activities in the plasma of mAb 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 bNAb (i.e. HIV-1 strain X2088_9 (10-1074 sensitive); HIV-1 strain Q769_d22 (3BNC117 sensitive). (b) Neutralizing activities in plasma prior to antibody administration (preP), but spiked with 0.01, 0.1, 1, 10, and 100 µg/ml of antibodies 10-1074 (blue) or 3BNC117 (green). Neutralizing activities are reported as plasma ID50 titers (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 mono and combination mAb macaque recipients (a) Macaques treated with one neutralizing mAb; (b) Macaques receiving two cycles of combination mAb treatment; (c) Macaques receiving a single cycle of combination mAb treatment. ID50 titers (left columns) and mAb concentrations (right columns) were measured in the indicated macaque plasma samples prior to (Prebleed) and following (Day) mAb administration.

Figure 1

HIV monoclonal antibodies block SHIV acquisition. a. Neutralization of SHIVAD8EO by three anti-HIV 1 mAbs assayed in TZM-bl cells. b. Pre-exposure passive transfer of 10-1074 mAb to macaques followed by SHIVAD8EO IR challenge. c. Pre-exposure passive transfer of 3BNC117 mAb to macaques followed by SHIVAD8EO IR challenge. Macaques ML1 and MAA received 20 mg/kg of control anti-dengue virus NS1 IgG1 mAb.

Figure 2

Suppression of plasma viremia following mono- or combination anti-HIV 1 neutralizing antibody treatment. (a) Plasma viral loads in post-acute set-point SHIV infected rhesus macaques with/without single mAb treatment. Plasma viral loads and total CD4+ T cell numbers in chronically SHIV infected rhesus macaques [DBZ3 (b), DC99A (c), DBXE (d), DCF1 (e) and DCM8 (f)] following combination mAb treatment.

Figure 3

Plasma viremia rebounds in SHIV infected monkeys when neutralizing antibody levels decline. Viral RNA levels and concentrations of 10-1074 or 3BNC117 mAbs in plasma at various times following initiation of single or combination antibody treatment. In panels c, d, and h, the gp120 changes in present in the rebound virus populations and their frequencies are indicated at the bottom.