Individuals infected with HIV-1 require lifelong antiretroviral therapy, because interruption of treatment leads to rapid rebound viraemia. 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−1 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 between 15 and more than 30 weeks (median of 21 weeks), and none developed viruses that were resistant to both antibodies. We conclude that the combination of the anti-HIV-1 monoclonal antibodies 3BNC117 and 10-1074 can maintain long-term suppression in the absence of antiretroviral therapy in individuals with antibody-sensitive viral reservoirs.
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We thank all study participants who devoted time to our research; members of the Klein and Nussenzweig laboratories for helpful discussions, especially Y. Bar-On, L. Cohn and M. Jankovic; R. Levin for study coordination and the Rockefeller University Hospital Clinical Research Support Office and nursing staff as well as K. Fiddike, C. Golder, S. Margane, M. Platten, E. Voigt and D. Weiland for help with recruitment and study implementation; K. Jain for help with sample processing; S. Kiss for ophthalmologic assessments; T. Keler and the Celldex Therapeutics team for 3BNC117 and 10-1074 manufacturing and regulatory support; C. Conrad for regulatory support; U. Kerkweg, R. Macarthur and A. Johnson for pharmaceutical services; H. Janicki, M. Ercanoglu, P. Schommers and R. Kaiser for help with virus cultures; C. Scheid and U. Holtick for leukaphereses; S. McMillan, S. Mosher, S. Sawant, D. Beaumont, M. Sarzotti-Kelsoe, K. Greene, H. Gao and D. Montefiori for help with PK assay development, validation, reporting, and/or project management; P. Fast and H. Park for clinical monitoring; and S. Schlesinger for input on study design. This work was supported by the Bill and Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery (CAVD) grants OPP1092074, OPP1124068 (M.C.N.), CAVIMC OPP1146996 (G.D.T., M.S.S.); the Heisenberg-Program of the DFG (KL 2389/2-1), the European Research Council (ERC-StG639961), and the German Center for Infection Research (DZIF) (F.K.); the NIH grants 1UM1 AI100663 and R01AI-129795 (M.C.N.); the Einstein-Rockefeller-CUNY Center for AIDS Research (1P30AI124414-01A1); BEAT-HIV Delaney grant UM1 AI126620 (M.C.); and the Robertson fund of the Rockefeller University. M.C.N. is a Howard Hughes Medical Institute Investigator.
Nature thanks G. Silvestri and the other anonymous reviewer(s) for their contribution to the peer review of this work.
Extended data figures and tables
a, Flow diagram indicating the selection of study participants. b, Individual participant demographics and baseline clinical characteristics. Grey-shaded rows indicate participants who were found to have detectable viraemia (HIV-1 viral load of >20 copies ml−1) at week −2 or day 0. These participants were not included in the efficacy analyses given the lack of viral suppression at baseline. Amer Indian, American Indian; Hisp, Hispanic. *3TC, lamivudine; ABC, abacavir; cobi, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RPV, rilpivirine; RTV, ritonavir; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate. **NNRTI-based regimens were switched four weeks before ART interruption due to longer half-lives of NNRTIs. ***Pre-screening of bulk outgrowth virus obtained from PBMC cultures by TZM-bl assay. #All participants harboured clade B viruses. Viral load <20 D, plasma HIV-1 RNA detected but not quantifiable by clinical assay. d0, day 0; Dx, diagnosis; Scr, screening; Wk −2, week −2.
Extended Data Fig. 2 Demographics, CD4+ T cells during study period in participants and pharmacokinetics of 3BNC117 and 10-1074.
a, Baseline participant demographics. b, Absolute CD4+ T cell counts and percentage of CD4+ T cells among CD3+ T cells at screening (n = 15), day 0 (n = 15), at the time of viral rebound (n = 13) and at the end of the study are shown (n = 15) (see also Supplementary Table 2). The last available time point after resuppression was used as end of the study time point for the participants that reinitiated ART. Red lines indicate mean, error bars indicate standard deviation and individual participants are shown as dots. P values were obtained using a two-tailed paired Student’s t-test comparing CD4+ T cell counts between day 0 and the time of viral rebound. c, d, 3BNC117 (red) and 10-1074 (blue) levels in serum (n = 15) as determined by TZM-bl assay (c) and ELISA (d). In cases in which participants only received 2 infusions due to early viral rebound (9245, 9249 and 9253), only antibody concentrations up to the second infusion were included. Half-life of each bNAb is indicated in days. Curves indicate mean serum antibody concentrations and error bars represent standard deviation. Red and blue triangles indicate 3BNC117 and 10-1074 infusions, respectively. c, In the TZM-bl assay, lower limits of quantification were 0.46 μg ml−1 and 0.10 μg ml−1 for 3BNC117 and 10-1074, respectively. d, In the ELISA, lower limits of detection were 0.78 μg ml−1 and 0.41 μg ml−1, respectively. e, f, Half-lives of both antibodies as measured by TZM-bl assay (e) and ELISA (f). Each dot represents a single participant. The half-lives of both antibodies from the 15 participants enrolled in the study are represented. Black lines indicate the mean value and standard deviation (n = 15). P values were obtained using a two-tailed unpaired Student’s t-test comparing the two antibodies.
Maximum likelihood phylogenetic trees of full-length env sequences containing all sequences obtained from Q2VOA cultures and rebound viruses from SGA or rebound outgrowth of the 15 participants enrolled in the study. Participants are indicated by individual colours.
Extended Data Fig. 4 Viral rebound, amino acid variants at 10-1074 contact sites and sensitivities of latent and rebound viruses in the participants with detectable viraemia (>20 copies per ml) two weeks before or at the start of ATI.
a, Plasma HIV-1 RNA levels (black; left y axis) and bNAb serum concentrations (3BNC117, red; 10-1074, blue; right y axis). Red and blue triangles indicate 3BNC117 and 10-1074 infusions, respectively. Serum antibody concentrations were determined by TZM-bl assay. Grey-shaded areas indicate time on ART. Lower limit of detection of HIV-1 RNA was 20 copies per ml. b, Kaplan–Meier plots summarizing time to viral rebound. The y axis shows the percentage of participants that maintained viral suppression. The x axis shows the time in weeks after the start of ATI. Participants receiving the combination of 3BNC117 and 10-1074 are indicated by the blue line (n = 4). The dotted red line indicates a cohort of individuals receiving 3BNC117 alone during ATI9 (n = 13) and the dotted black line indicates a cohort of participants who underwent ATI without any intervention10 (n = 52). c, Colour charts show Env contact sites of 10-1074 at the G(D/N)IR motif (positions 324–327, according to HXB2 numbering) and the glycan at the potential N-linked glycosylation site at position 332 (NxS/T motif at positions 332–334). LR, latent reservoir viruses isolated by Q2VOA (week −2); RB, rebound viruses isolated by SGA (plasma) or viral outgrowth (PBMCs). Each amino acid is represented by a colour and the frequency of each amino acid is indicated by the height of the rectangle. Shaded rectangles indicate the lack of variation between latent reservoir and rebound viruses at the indicated position. Full-colour rectangles represent amino acid residues with changes in distribution between reservoir and rebound viruses. d, Dot plots showing the IC80 (μg ml−1) of 3BNC117 (left) and 10-1074 (right) against latent and rebound viruses determined by TZM-bl neutralization assay. Q2VOA-derived latent viruses from week −2 are shown as black circles. For outgrowth culture-derived rebound viruses, the highest IC80 determined is shown as red circle. For 9250 and 9253, no viruses could be obtained from rebound outgrowth cultures and pseudoviruses were made from env sequences of the latent reservoir (Q2VOA) and rebound viruses (plasma SGA). Note that 9249 and 9253 had pre-existing resistant viruses in the reservoir (IC50 > 2 μg ml−1). 9248 and 9250 had pre-existing viruses that failed to reach an IC100 when tested up to 50 μg ml−1 for 3BNC117 (Extended Data Fig. 5). Rebound viruses of all four participants had an IC80 or IC100 of >50 μg ml−1 for both 3BN117 and 10-1074.
Extended Data Fig. 5 Phylogenetic env trees and TZM-bl neutralization curves for individuals with viral blips.
a, Circulating reservoir and viral rebound in study participants with detectable viraemia at week −2 or day 0. Maximum likelihood phylogenetic trees of full-length env sequences of viruses isolated from week −2 Q2VOA cultures, rebound plasma SGA and rebound outgrowth from the four participants with viral blips. Open black rectangles indicate Q2VOA-derived viruses from week −2. Viruses obtained at the time of rebound are indicated by red rectangles (plasma SGA) and red stars (rebound PBMC outgrowth cultures), respectively. Asterisks indicate nodes with significant bootstrap values (bootstrap support ≥70%). Clones are denoted by coloured lines. Boxes indicate IC80 values (μg ml−1) of 3BNC117 and 10-1074 against individual clones, with asterisks indicating IC100 > 50 μg ml−1. b, Latent reservoir virus TZM-bl neutralization curves for two participants that had a viral load of >20 copies per ml at day 0 (9248 and 9250). Curves show neutralization titres by 3BNC117 (blue), 10-1074 (red) and other bNAbs, when available, for week −2 Q2VOA-derived viruses present in the circulating reservoir. Three representative viruses from 9248 (left) and 9250 (right) are shown. Although these viruses had low 3BNC117 and 10-1074 IC50 or IC80 titres, the IC100 (black dotted line) is reached only at a high concentration or not reached at all. The neutralization titre was measured by TZM-bl neutralization assay using a five-parameter curve fit method.
Extended Data Fig. 6 Amino acid variants at 3BNC117 contact sites of reactivated latent and rebound viruses.
Colour charts show 3BNC117 contact sites in Env according to HXB2 numbering. Diagram shows the 13 participants that experienced viral rebound before week 30. LR, latent reservoir viruses isolated by Q2VOA (on weeks −2 and 12 when available); RB, rebound viruses isolated by SGA (plasma) and viral outgrowth (PBMCs). Each amino acid is represented by a colour and the frequency of each amino acid is indicated by the height of the rectangle. Shaded rectangles indicate the lack of variation and full-colour rectangles represent amino acid residues with changes in the distribution between the reservoir and rebound.
Maximum likelihood phylogenetic trees of full-length env sequences of viruses isolated from Q2VOA, rebound plasma SGA and rebound PBMC outgrowth cultures from participants 9241, 9244, 9246 and 9247, who rebounded before week 30. Open and closed black rectangles indicate Q2VOA-derived viruses from week −2 and week 12, respectively. Viruses obtained at the time of rebound are indicated by red rectangles (plasma SGA) and red stars (rebound PBMC outgrowth cultures). Asterisks indicate nodes with significant bootstrap values (bootstrap support ≥70%). Clones are denoted by coloured lines mirroring the colours of slices in Extended Data Fig. 10a. Boxes indicate IC80 values (μg ml−1) of 3BNC117 and 10-1074 against representative viruses throughout the phylogenetic tree and clones, when possible (Supplementary Table 4). Asterisks in boxes indicate IC100 > 50 μg ml−1.
a, Maximum likelihood phylogenetic trees of full-length env sequences of viruses isolated from Q2VOA cultures and rebound SGA in the four participants for whom rebound viruses showed recombination events. Open and closed black rectangles indicate Q2VOA-derived viruses from week −2 and week 12, respectively. Rebound plasma SGA- or outgrowth-derived viruses are indicated by closed red rectangles. Green stars represent parent sequences that underwent recombination to produce the child sequences (red stars). b, Circos plots indicating the relationship between the parent sequences and the recombinants. Open and closed black rectangles indicate Q2VOA-derived sequences from week −2 and week 12, respectively. Rebound virus sequences are indicated by red rectangles. The thickness of the black outer bars represents the number of sequences obtained from that particular clone.
Maximum likelihood phylogenetic trees of full-length env sequences of viruses isolated from Q2VOA cultures and rebound plasma SGA and rebound outgrowth from the two participants (9245 and 9251) with pre-existing resistance to one of the two antibodies and the two sensitive participants (9254 and 9255) who maintained viral suppression for >30 weeks (end of the study). Open and closed black rectangles indicate Q2VOA-derived viruses from week −2 and week 12, respectively. Rebound plasma SGA viruses are indicated by closed red rectangles. Asterisks indicate nodes with significant bootstrap values (bootstrap support ≥ 70%). Clones are denoted by coloured lines beside the phylogenetic tree. Numbers correspond to 3BNC117 and 10-1074 IC80 neutralization titres.
a, Pie charts depicting the distribution of Q2VOA-derived env sequences obtained at weeks −2 (W−2) and week 12 (W12). Number in the inner circle indicates the total number of analysed env sequences. White represents sequences isolated only once across both time points and coloured slices represent identical sequences that appear more than once (clones). The size of each pie slice is proportional to the size of the clone. Red arrows denote clones that significantly change in size (P ≤ 0.05 (two-sided Fisher’s exact test)) between the two time points. b, Summary of clonal env sequences and IUPM in the nine individuals with an antibody-sensitive reservoir. c, IUPM versus time of viral rebound in the antibody-sensitive individuals (n = 7) who rebounded within the study observation period (30 weeks). P values were obtained using a two-tailed Pearson correlation test comparing the two variables.
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