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1 doi:.8/nature79 Methods Samples. Human samples were collected after signed informed consent in accordance with Institutional Review Board (IRB)-reviewed protocols of all participating institutions. Patients, and 5 were selected from a group of 8 elite controllers that were screened against a standard panel of HIV isolates (Supplementary Table ). Out of 8 screened patients % showed broad neutralization of the Tier panel with a majority of IC5 titers above. Ig gene sequence analysis. Aliquots of the V H, V and V" chain second PCR products were sequenced and analyzed by Ig BLAST as described previously 9. Recombinant antibody production and purification. Monoclonal antibodies were produced by transient transfection of suspension cultured 9T cells with 9 fectin according to the manufacturer s suggestion (Invitrogen). Supernatants from transfected cells were collected after days of culture. Recombinant protein was purified with Protein G beads (GE Healthcare) according to the manufacturer s instructions, dialysed against PBS in Slide-A-Lyzer Dialysis Cassettes (Pierce) and stored at C. Deglycosylation of gp. For deglycosylation 5µg of GP was treated with PNGase F (New England Biolabs) and O-glycosidase (QA Bio) in 5 mm sodium phosphate without denaturing agents and incubated overnight at 7 C to ensure maximal deglycosylation. For lectin blotting µg of protein was resolved on an SDS-PAGE gel under non-reducing conditions, transferred to polyvinylidene difluoride membranes,

2 doi:.8/nature79 blocked with Western Blocking Reagent (Roche), and incubated with biotinylated Lens culinaris agglutinin (LCA, 5µg/ml, Vector Laboratories) to detect N-linked glycans or Datura stramonium lectin (DSA, 5µg/ml, Vector Laboratories) to detect N- and O-linked glycans. The membrane was next incubated with alkaline phosphatase-conjugated goat anti-biotin antibody, and visualized with -nitro blue tetrazolium chloride/5-bromo-- chloro--indolyl phosphate (Roche). Absorption of gp binding IgG from patient serum. IgG absorption was performed as previously described. In brief, IgG was isolated from patient serum with Protein G beads (GE Healthcare) according to the manufacturer s instructions. µg of IgG was absorbed on magnetic beads (Dynabeads M-8, Invitrogen) coupled to µg of gp by incubating for minutes at room temperature. IgG concentrations were measured by IgG specific ELISA. Surface Plasmon Resonance. All experiments were performed with a Biacore T instrument (Biacore, Inc) in HBS-EP+ running buffer (Biacore, Inc) at 5ºC. Samples were analyzed in kinetic experiments performed in duplicates. Antibodies were immobilized to the surface of CM5 chips (Biacore, Inc.) by standard amine coupling with final immobilization levels of 5 to 5 RU. For kinetic measurement gp, gp and gp core were injected through flow cells in 5 different concentrations (57- nm for gp, 8.-nM for gp and.6-.8nm for gp core ) in HBS-EP+ running buffer (Biacore, Inc.) at flow rates of 5 µl/min (gp and gp) and µl/min (gp core ), with min association and 5 min dissociation. Off rate (k d (/s)), on

3 doi:.8/nature79 rate (k a (/Ms)) and binding constant (K D (M)) values were calculated after subtraction of background binding to a control flow cell using Biacore T Evaluation software using the kinetic analysis and the : binding model. The sensor surface was regenerated between each experiment with a second injection of mm glycine-hcl ph.5 at a flow rate of 5 µl/min.. Kaneko, Y., Nimmerjahn, F. & Ravetch, J.V. Anti-inflammatory activity of immunoglobulin G resulting from Fc sialylation. Science, (6).

4 doi:.8/nature79 Neutralizing activity of patient serum in TZM-bl assays. a CLADE B SF6.LS TIER BAL.6 TIER SS96. TIER 655. TIER QH69. TIER SC66.8 TIER PVO. TIER TRO. TIER CAAN.A TIER TRJO.58 TIER THRO.8 TIER pt pt < pt pt pt pt b 9RW. Q68.a CLADES A/C CLADE A TIER CLADE A TIER Q769.d DU56. CLADE A CLADE C TIER TIER DU. CLADE C TIER c IC5 CLADE pt pt pt pt pt5 pt pt pt pt pt pt5 pt6 PVO. TRO. TRJO.58 THRO.8 9RWOO. Q68.a Q769.d DU56. DU. B A C Supplementary Figure. Neutralizing activity of patient serum in TZM-bl assays. a, Table shows serum dilution IC5s for all six patients on selected clade-b tier- and tier- viruses. b, Table shows serum dilution IC5s for all six patients on selected clade A and C tier- viruses. c, The graph summarizes each patients tier- serologic activity. The Y axis shows the serum dilution IC5, each virus is represented by a different colored symbol (right), and the X axis indicates the source of the serum. indicates not determined values.

5 doi:.8/nature79 Serum absorption by YU-gp trimer and binding to control antibodies a GP whole IgG GP whole IgG GP whole IgG. depleted IgG. depleted IgG. depleted IgG OD5... µg/ml b OD5 GP. b g 7-5d f5 e µg/ml Supplementary Figure. Serum absorption by YU-gp trimer and binding to control monoclonal antibodies. a, ELISA results of serum IgG tested for binding to gp, gp and gp before and after absorption with YU gp trimer. Patients - are represented in red, green, brown and blue respectively. b, binding of b, G, 7-5d, F5, and E to trimerized gp. 5

6 doi:.8/nature79 a b c gp+.5% pt 5 pt - 9 gp- % pt 6.8% 6 gp+ gp- pt - gp % hc.% CD9 gp hc.% CD9 Supplementary Figure. Anti-gp antibody cloning. a, Dot plots show gp-biotin and anti-cd9 staining of blood mononuclear cells pre-gated for IgG and CD9 expression from patients 5 and 6 (pt 5 and 6) and healthy controls (hc and ). See Supplementary Table for participant profiles. Healthy controls (hc and ) were healthy HIV negative men with no known medical problems and normal blood counts. b, Pie charts show the distribution of gp binders and non-binders among all antibodies cloned. The number in the center indicates total number of antibodies analyzed, each pie slice represents a clonal family and the size of the slice is proportional to the number of clonal relatives. Each clonal family is represented by the same color throughout and unique antibodies that are not members of clones are not colored. c, Dot plots show gp and CD9 staining of blood mononuclear cells from patient and as in Fig.. Gated non-gp-binding cells were sorted as negative control (See also Supplementary Table ). 6

7 doi:.8/nature79 Clonal Relationships between gp binding antibodies pt pt pt Core CDbs V CDi GL GL GL GL MW965. <. <. <. <. >5 > DJ > > 5 >5 >5 SF6.LS <.. <..7.8 SS > BaL >5 >5 >5 >5 >5 >5 Supplementary Figure. Sample mutational trees showing clonal relationships between gp binding antibodies. Clones showed identical IgH and IgL chain rearrangements with variations in somatic mutations as indicated by individual circles. Each clone is represented in a separate color. The size of the circle is proportional to the number of clone members with identical somatic mutation patterns. The name of the clone members that are part of a given branch is indicated in the center of each circle. Blank circles represent theoretical intermediates that were not cloned. 7

8 doi:.8/nature79 Anti-gp antibody repertoire a b IgH repertoire IgH CDR pt gp+ pt pt gp+ gp- gp+ gp- pt gp+ All All gp+ gp- IgGm p=.7 p=. p=. p=. p=.79 p=.6 p=.85 p=.8 p=.5 p= p=. p=.6 p=.88 p=.5 p=.6 p=.95 p=. p<. p=. p=.965 JH JH JH JH JH5 JH >+ Supplementary Figure 5. Anti-gp antibody repertoire. Top line indicates patient number and whether the antibodies bind to gp. IgGm are previously published IgG memory antibody controls. Each clone is represented once irrespective of clone size, and somatic variants are not considered. a, IgH repertoire analysis comparing JH gene usage. Each slice is colored to represent a JH as indicated at right. b, IgH CDR positive charges. Each pie slice is shaded to indicate number of positive charges as indicated. P values were calculated with x5 Fisher s Exact and Chi-Square Tests by comparison to the pool of gp non-reactive antibodies except those below the lines, which refer to the paired samples. Somatic hypermutation VH mut VK mut VH mut number of mutations All+ All- IgG p<. p< All+ All- IgG p<. p< CDbs Core VL CDi gp total+ total- IgGmem Supplementary Figure 6. Somatic hypermutation. Graphs show numbers of mutations per antibody for VH (left) grouped by patient, Vκ (middle) grouped by patient, and VH (right) for all antibodies to a specific epitope as indicated. Red stars indicate P values <.. P values were calculated by comparison to the pool of gp non-reactive antibodies except those below the lines, which refer to the paired samples. Each antibody clone is represented once by a single randomly selected clone member. Statistical analyses for mutation numbers were performed using non-paired two tailed Student s t test. 8

9 doi:.8/nature b Time (s) Supplementary Figure 7. Surface plasmon resonance measurements for interaction between selected antibodies and gp. Graphs show antibody dissociation curves over time. The starting concentration of gp was 5-5µg/ml and the different curves represent : dilutions of the starting material. The X-axis shows time in seconds and the Y-axis shows the response rate. The antibodies are indicated above each graph. Red squares indicate anti-cdbs, blue circles anti-gp core, green triangle anti-cdi and yellow triangle anti-vl antibodies. Response units 9

10 doi:.8/nature79 Binding of anti-gp CORE and anti-cdbs antibodies to gp core and stabilized core a CD BS abs-wt CORE CORE abs-wt CORE b OD5. CD BS abs-8b CORE.. CORE abs-8b CORE. µg/ml Supplementary Figure 8. Binding of anti-gp core anti-cdbs antibodies to gp core and stabilized core. Graphs show the ELISAs for binding to YU gp core (a), and the 8b mutant YU gp core that was stabilized in the CD bound state (b). AntiCDbs and anti-core antibodies from patients -6 were tested for binding to both forms of gp at a starting concentration of µg/ml. Control antibody b is shown in red, negative control antibody mgo5 in green. Supplementary Fig. 9 Binding of anti-gp CORE antibodies to gp, gp D68R and gp D68A/E7A OD5.5. b pt pt pt pt pt6 Supplementary Figure 9. Binding of anti-gp core antibodies to gp, gp D68R and gp D68A/E7A. Anti-Core antibodies from patients - and 6 were tested in ELISA for their binding to YU gp, gp D68R and gp D68A/E7A. Red lines indicate binding to gp, blue to gp D68R and green to gp D68A/E7A. B is shown as a control.

11 doi:.8/nature79 Effect of deglycosylation on BAL gp binding a MW (kda) MW standard gp aglyco-gp gp aglyco-gp gp aglyco-gp b.5 G. c 6 5 Coomassie blue-staining LCA lectin DCA lectin Western blot Anti-gp core OD µg/ml Anti-CDi OD5 OD5 pt pt pt pt Anti-CDbs pt pt pt pt OD5 pt pt pt pt OD5 Anti-VL pt pt pt pt Supplementary Figure. Effect of deglycosylation on BAL gp binding. a, Gel electrophoresis and Coomassie blue staining or Western blot with LCA and DCA lectin of BAL gp and aglyco-bal-gp. b, Representative ELISA results comparing binding to gp and aglyco-gp for control antibody g. The red line indicates gp binding and green line indicates aglyco-gp reactivity. Antibody concentration is shown on the X axis and OD5 on the Y axis. c, Binding to gp (red) or aglyco-gp (green) as measured by ELISA under saturation conditions for all neutralizing antibodies from patients -. Epitopes, patient source, antibody number and relative (see above) OD5 are indicated. Stars show antibodies sensitive to deglycosylation. Supplementary Table Clinical information of patients and healthy controls gender date of birth diagnosis cd+ Tcells/µl virus copies/ml clinical status pt pt pt pt pt5 pt6 HC HC male male male male male male male male 7-Jul Aug-956 -Jul- -Jan-965 -Jun Feb-966 -Jan / 98 / / / non progressor elite controller elite controller / elite controller slow progressor HIV neg HIV neg Supplementary Table. Clinical information of patients and healthy controls.

12 doi:.8/nature79 Supplementary Table. Neutralization screen of plasma samples against standard virus panel. () TZM.bl Neutralization Assay: Plasma ID5 Titer Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Neg. Control Sample ID Date Internal Ref SF6.LS BaL.6 SS QH69. SC66.8 PVO. TRO. AC..9 RHPA59.7 THRO56.8 REJO5.67 TRJO55.58 WITO6. CAAN5.A SIVmac5.WY5 BWH- 9/8/ WD 6 < < < < 77 < 9 7 < BWH-7 /6/ WD 5 9 < < < 7 65 < 95 < 587j 5// WD, < 69 7 < 6I (GAP) /6/ WD < CR6r // WD < 5 6 < CRO559 // WD6, , < EH 56C // WD7 < < 968 AG // WD8 7, ,55 7,5 97 5, 75, < PMA 766 /5/ WD < 76 7 < 87 // WD 8,5, < 89 // WD < 87 // WD, < < 5 59 < 85 /7/ WD, < 5 6 < 867 // WD, < 5 67 < 888 /5/ WD < < 89 9// WD6, < 8 // WD7 6,7, < FW 9// WD8, 98 < < < 7 5 < 6 < FW // WD9 9,, < FW 9/7/ WD < FW56 // WD, < 6 69 < FW57 /8/ WD, < CTR 5 // WD 9 5 < < 9 55 < 5 < CTR 9 /7/ WD < < CTR JL /9/ WD5, < < 76 < < CTR 5 9// WD < < < < < < CTR 9 /5/6 WD7, < < < < 6 66 < < CTR // WD8 6 7 < 8 89 < < < < 6 < 5 < CTR 9/8/ WD < < CTR 9/8/ WD, < < < CTR 9// WD < < CTR 6 DS 9/5/ WD, < 9 57 < 8 < CTR 7 MS 9/5/ WD, < < 9 < CTR 8 LC 9// WD 8,95, < < CTR JM 9// WD < 5 < < 5 8 < CTR 7 RB 9/8/ WD6 6 9 < 5 < < < < CTR 9/9/ WD < < < CTR HML // WD8, < 7 < CTR JFU // WD < < CTR VS // WD 5, < CTR WG // WD < < CTR 6 ML /8/ WD < CTR 7 RC /8/ WD < < CTR 8 CB /9/ WD, < < 9 7 < CTR 9 TZ /9/ WD5, < CTR 5 HAG // WD < CTR 57 AF // WD7 9 9 < 65 < < < < 8 6 < CTR 59 KW // WD8, < < 9 < CTR 6 SM // WD < < CTR 6 /8/ WD5, < Supplementary Table. Neutralization screen of plasma samples against standard virus panel. () TZM.bl Neutralization Assay: Plasma ID5 Titer Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Neg. Control Sample ID Date Internal Ref SF6.LS BaL.6 SS QH69. SC66.8 PVO. TRO. AC..9 RHPA59.7 THRO56.8 REJO5.67 TRJO55.58 WITO6. CAAN5.A SIVmac5.WY5 CTR 7 /6/ WD < < 7 < < 7 79 < CTR 7 // WD5 6, < < CTR 8 // WD5, < CTR 8 // WD55 6, < CTR 85 // WD < 6 < < < 5 < 87 < CTR 88 // WD < CTR 9 // WD58 < < < 6 < < CTR 97 // WD59 6, < 9 < CTR 99 // WD6, < 6 < CTR /5/ WD6,56, < CTR /5/ WD6 9, < < CTR 5 // WD < CTR 7 // WD6 7,8 59 9, , < CTR /7/ WD65, < CTR /8/ WD66, < CTR 5 /8/ WD67, < < < < CTR 7 // WD68, < < 8 7 < 59 9 < CTR 8 // WD < 6 5 < < CTR /7/ WD < 5 < < < 76 < CTR /7/ WD7 9 5 < < 66 9 < CTR 5 /7/ WD7, < < CTR 6 // WD < < < CTR 8 // WD7, < 6 < CTR 9 // WD75,6 7 5 < < < < 5 56 < CTR // WD < CTR // WD77,68 8 < < 85 < < < 5 9 < < 57 < CTR 5 /8/ WD78, < 76 < < 75 7 < CTR 7 // WD79 5, < 9 7 < CTR 8 // WD < < CTR 9 // WD8, < CTR // WD8, < < 56 9 < < CTR // WD8, < 9 < < 8 < CTR /6/ WD8 5,9, < < 6 9 < CTR /6/ WD85, < < CTR 7 /7/ WD86, < 68 < < 8 66 < CTR 5 SP /6/ WD < CTR 55 // WD88 5,55 7 < 6 < < < 89 5 < CTR 56 // WD < < 9 75 < CTR 6 /8/ WD < < < 5 9 < CTR 6 /9/ WD9, < < 7 76 < CTR 65 /9/ WD9 8 6 < 6 < < CTR 68 /6/ WD < < CTR 7 // WD9, < 5 < < 7 < 78 6 < CTR 7 // WD95, < 8 < < CTR 76 /9/ WD < 97 < < < CTR 8 /5/ WD97, < CTR 8 /6/ WD98,6 < 9 < < < < < < 8 88 < 8 9 < CTR 9 5// WD < < 6 < CTR 9 5/8/ WD < < CTR 95 5/9/ WD < Naïve Serum Neg. Control < < < < < < < < < < < < < < < <

13 doi:.8/nature79 Supplementary Table. Neutralization screen of plasma samples against standard virus panel. () TZM.bl Neutralization Assay: Plasma ID5 Titer Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Neg. Control Sample ID Date Internal Ref SF6.LS BaL.6 SS QH69. SC66.8 PVO. TRO. AC..9 RHPA59.7 THRO56.8 REJO5.67 TRJO55.58 WITO6. CAAN5.A MuLV 88 //9 WD 7,5 9 < < CTR VB HRES //9 WD 9,8,9 7 9 < < CTR // WD, < < < 6 < CTR KH /5/ WD < < < < 9 BWH--BZ // WD7 6 8 < < < 6 9 < CTR DM /5/ WD8, < < 9 8 < < < 58 < < < < < CTR 5-LD // WD < < < 75 < MC CRQ // WD < < < < CTR 8 NM /9/ WD,8, < 85 < 97 CTR 5-DR /7/ WD 5,59, 5 5 < 6 < < 5 5 CTR 5-HS // WD 6, < 7 55 CTR 5-AA // WD 6,7, < < 79 CTR 55-BW // WD5, < < 7 < 56 CTR 6 RR 5/5/ WD6,6 9 7 < < < < 8 9 CTR 6-JO 5/6/ WD7 8,655, < CTR 66 RH 5/6/ WD8, < < CTR 76 WM 6// WD9 >, < 5 < 7 CTR 8 CC 7// WD 6, < CTR 9 8// WD 8 < < < CTR 98 MI 8// WD < < // WD,5 8 6 < CTR 6 KP 8// WD5, 9 < < 67 7 < 6 7 < CTR 9 9// WD6 6, < < 6 < < 5 8 < < < < CTR 9/9/ WD7,6 6 < < CTR (UCLA ) // WD8, < < 7 9 CTR 99 5/5/ WD9 7, CTR 5/7/ WD, < CTR 5/7/ WD 557 < < < < < 9 < < 7 < 8 6 < CTR 5// WD 65 6 < 7 < < 85 5 < GS 96G 5/8/ WD 5 < 85 < 8 < < 69 7 CTR 5// WD5 6, < CTR 5// WD6,97 < < < CTR 6 5// WD7, < CTR 6// WD, CTR 5 6/5/ WD 5, < 7 85 CTR 6 6/9/ WD, < < CTR5 6/6/ WD < < < < < < < < 5 < < 9 < CTR 6// WD 6, < 5 7 < 6 < CTR 6// WD5, CTR 6// WD6, CTR 7 7/8/ WD8 5 < 57 < < < 8 < 6 < < < CTR 8 7/9/ WD9 587 < < 99 7 < 6 57 CTR 5 8// WD5 7, < CTR 5 8// WD5 68 < 6 < < 59 5 Supplementary Table. Neutralization screen of plasma samples against standard virus panel. () TZM.bl Neutralization Assay: Plasma ID5 Titer Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Tier Neg. Control SF6.LS BaL.6 SS QH69. SC66.8 PVO. TRO. AC..9 RHPA59.7 THRO56.8 REJO5.67 TRJO55.58 WITO6. CAAN5.A MuLV Sample ID Date Internal Ref CTR 5 8// WD5, < 5 9 < 6 5 < CTR 5 8// WD5, < < 7 < 69 6 CTR 56 8// WD5 8, < CTR 6 8/8/ WD55, < 7 5 CTR 65 8/7/ WD56,7 < 9 < < < < < < < < < 5 6 < CTR 69 8// WD57 < < < 5 < < < < < 6 9 CTR 68 8// WD < < CTR 7 8/8/ WD59, < 5 < 56 8 < 9 < 7 7 < MEF 7V77 8// WD6, < 8 5 < 79 7 < 5 6 CTR 7 8/9/ WD6, < < CTR 76 8// WD < < 8 6 CTR 77 8// WD6 6, < < < CTR 79 9/5/ WD6 < < < < < < 56 9 < CTR 86 9// WD < 5 < < 89 9 < 6 5 < CTR 9 9// WD66 7, < < 68 7 CTR 9 9// WD67,5, < CTR 95 9// WD68, < < < < FCH--FW57 // WD7 8, < < CTR 5 // WD7 5, < CTR 9 // WD7 9, < < < < 7 < 8 < CTR // WD7, < CTR /6/ WD7 6 < < < < < < 58 < CR559M ESR /8/ WD75 9,9, < 97, CTR 6 /6/ WD76 6, < < 7 9 < CTR 7 /7/ WD77, < < CTR 8 /8/ WD78, < < < 7 9 < CTR // WD < 6 7 < < CTR // WD8 7,5 9 9 < 5 < 5 < < 6 87 < CTR /5/ WD < < < CTR // WD < < < 5 75 < CTR 6 // WD8 >,7, < CTR 8 /7/ WD < < BWH- SP /9/ WD85 7,6 < < 6 < < 7 9 < CTR 6 // WD86, < < < 6 8 CTR 7 // WD87 < 9 < 9 5 < < 7 < < CTR 9 /7/ WD88 77 < 6 < < CTR /9/ WD89 96 < 9 < < 7 < Supplementary Table. Screen of 8 plasma samples from a cohort of HIV- infected elite controllers against a standard panel of HIV isolates. Shown are the reciprocal dilutions needed to achieve a 5 % inhibition in the TZM.bl neutralization assay. Samples were tested primary at a : dilution and then titrated -fold seven times in duplicate wells. HIVIG was used as positive control at a starting concentration of 5ug/ml. Negative controls were normal naive human plasma and Murine Leukemia Virus pseudovirus. Patients, and 5 correspond to CTR8, CTR and CTR7 respectively. Patients with broad activity against tier- viruses are marked in red.

14 doi:.8/nature79 Supplementary Table a. Repertoire and reactivity of gp binding antibodies, patient pt Ab name VH D JH (-) CDR (aa) (+) Length /" V/" J/" (-) CDR (aa) (+) Length Binding Peptide Library NEUT # of relatives /5-8 6 HEAPRYSYAFRRYYHYGLDV 5 " - ASWDDSLSGWV CDbs NEG /5-8 6 HEAPRYSYAFRNYYHYGLDV " - AAWDDSLNGWV CDbs NEG /-9 6 DRRRFLEWSLYGMDV 5 - QQYGSSPEYT CDbs NEG /-9 AGLDYNFWNGKGRKGAFDV 9-5 QQYDS 5 CDbs NEG /-6 GTLWFGESGLRLDH -6 QQYNSFPPT 9 CDbs NEG /-6 / GSLWFGESGLRLDH -6 QQYNSFPPT 9 CDbs NEG /-7 -/- 6 NRRVAMPEAMILSFYMDV 8 -/D- QQYGRSP 7 CDbs NEG /-9 6 GIQEDYDFWREYRELDY 7 -/- MQGTHWPRT 9 CDbs NEG /-9 VVPMFSIFGVVKANYFDY 8 " -5 GTWDSSLSAVL Core NEG /-9 6 VISGRITIFYYNYIDV 6 " 576 ASWDNSLSGPV Core NEG /-9 6 VLSGRITIFYYYYMDV 6 " 576 ASWDNSLSGPV Core NEG /-6/-8 GFRGSPFSSGSLYFDS 6 - HQYAYSPRT 9 Core NEG /-5/7-7 GFRGSPFSSGSLYFDS 6 - / HQYASSPRT 9 Core NEG /-/- GFRGNVFSTGWFYLDF 6 - / QQYSSSPRT 9 Core NEG /-/- GFRGSPLSSGSLYFDS 6 - / HQYASSPRT 9 Core NEG /7-7 GFRGSPFSSGSMYFDS 6 - HQYASSPRT 9 Core NEG /-9 6 DFPRFHRLVGNYDFWRGTLDRFSYMD 5 7 D-9/-9 MQSIQ 5 Core NEG /-66-6/- 6 STPLVWPPANGLDV -/D- QEYGRSPPFP Core NEG /6-/5-5 DNRDQWLVLRSWFDP 5 D-9/-9 / QQSYTTPVT 9 Core NEG /-7/- 6 5 SVITDLHTFGDYESGDPSYYYMDV -5 / QQYNSYSGT 9 CDi NEG / AVITDLHTFADYELGDPSYFYMDV -5 / QQYKSYSGT 9 CDi NEG / AVITDLHTFGDYELEDPSYYYMDV -5 QQYKSYSGT 9 CDi NEG /-6/- RGRRQIGDY 9 D-9 QQSFGIPPWT CDi NEG /-/- RGRRQIGDY 9 D-9 QHSFGSPPWT CDi NEG /- SYYDFSIGDGAFDV 6 " -7 AAWDDSFDYV V V /-9 SYYDFQTDSGAFDV 6 " -7 /6 AAWDDSLDYV V V /-9 SYYDFRSDSGAFDI 6 " -7 /6 AAWDDSLDYV V V GGGYPRGNMDV -5 QQYTNYPWT 9 gp NEG /5-5 5 DTTTFTTFGGGPNMGGFDP 9-9 QQLRT 5 gp IMMUNODOM /-5 5 DTTTFSSFGSPPHMGGLDP 9-9 QQLRT 5 gp IMMUNODOM /-6 5 DTTTFTSFGSPPRMGGLDP 9-9 QQLRT 5 gp IMMUNODOM /-6 5 DTTTFGAFGGGANMGGLDP 9-9 QQLRT 5 gp IMMUNODOM /- 5 DTTTFSSFGSPPNMGGLDP 9-9 QQLRT 5 gp IMMUNODOM /-6 5 DTTTFGAFGGSPNMGGLDP 9-9 QQLRT 5 gp IMMUNODOM PYVQTVATTTFDF " - / CSYAGGRTVV gp NEG PVVNTILPYCDV - QQYGRSPYT 9 gp NEG /5-8/5- RGHSFTSPFDS - QQYGSSLR 8 gp NEG /-6 5/ EFQTSGVVREG -5 5 QQYYSDSIT 9 gp IMMUNODOM /6-/-9 RRRSAWSPFDS -9/- QLLQSN 6 gp NEG - Supplementary Table b. Repertoire and reactivity of gp binding antibodies, patient pt Ab name VH D JH (-) CDR (aa) (+) Length /" V/" J/" (-) CDR (aa) (+) Length Binding Peptide Library NEUT # of relatives /5 DRMFWQQLAKYDS -6 LQTHSYPRT 9 CDbs NEG /5 DRMFWQQLAKYDS -6 LQNHNYPRT 9 CDbs NEG /-6 6 GPLGDYDF 8-5 QQYTAYPWT 9 CDbs NEG /-/-59 -/-9 GRDYNFWSGGGRYYFDF 7 " - QSYDSSLSGSWV CDbs NEG /-/-59 -/- /5 GRDYNFWGGGGKINFP 7 " - QSYDSSLSGSWV CDbs NEG /-9 SRGDYNFWSGYPEYHFDR 8-8 MQPLQTPYT 9 Core NEG /-9/-6 /5 EYRFDDWGPLDH -8 MKSQHSPRT 9 Core NEG /-6 6 LDWVRGVMNLVENHYAMDV 9 - QQSGTSLLT 9 CDi NEG /6-9/ GDLLGYTDSWYEFDYYYMDV - QQYAGSLT 8 CDi NEG GRLFVQWPPQGGFDT 5 - QEYGRAPPYP VL NEG GRLFMQWPPQGGFDP 5 - QEYGRSPPYP VL NEG GRLFVQWPPQGGFDT 5 - QEYGRAPPYP VL NEG GRLFVQWPPQGGFDT 5 - QEYGRAPPYP VL NEG GRLFVQWPPQGGFDT 5 - QEYGRAPPYP VL NEG GRLFVQWPPQGGFDT 5 - QEFGRAPPYP VL NEG GRLFVQWPPQGGFDP 5 - QEYGRAPPYP VL NEG GRLFMQWPPRGGFDP 5 - QEYGRAPPYP VL NEG GRLLMQWPPRGGFDP 5 - QYYGSSPPST VL NEG GRLLMQWPPRGGFDP 5 - QYYGSSPPST VL NEG GRLLMQWPPRGGFDP 5 - QYYGSSPPST VL NEG GRLLMQWPPRGGFDP 5 - QYYGTSPPST VL NEG /-9/ ERVLVVPDQDADYYYYFFDV -5 LFAGT 5 V V /-8/ ERVLVFPDQDADYYYYFFDV -5 LFAGT 5 V V /5-/- 6 6 ENVLMESDDYYYYYYMDV -5 LFAGT 5 V V /-7/- LPRTTGIRNAFDF " -8 SSYAATNHWV VL NEG /-7/- LPRTTGIRNAFDI " -8 / SSYAGTNHWV VL NEG /- 6 5 DSEDYVDYYYMDV - QQRTSWPLALS VL NEG WVVTAAEEYFDY - 5 QQYRYSVII 9 VL NEG WVVTAAEEYFDY - 5 QQYRYSVII 9 VL NEG WVVTAAEEYFDY - 5 QQYRYSVII 9 VL NEG -6 -/- -/-7/- HYDALDY 7-8 MQALETLG 8 V V /-9/-8 /5 TRNTGNSLPYWFDL - QQRGHWPLT 9 gp NEG /-9/-8 5 TRNTGNSLPYWFDL - QQRGHWPLT 9 gp NEG /-5 / HGASANYGPGSYSAEHFQH 9-5 QEYNNYN 7 gp IMMUNODOM /-6 / HGASENYGPGSYSAEHFQH 9-5 QEYNTYT 7 gp IMMUNODOM /-6 / HGASANYGPGSYSAEHFQH 9-5 QEYNTYT 7 gp IMMUNODOM /-6 RGHSFSLPFDS - QKYGSSLT 8 gp NEG /-6 RGHSFSLPFDS - QKYGSSLT 8 gp NEG /6-5/6-9 RGHSFSLPFDS - QKYGSSLT 8 gp NEG -75-6/-/-59 -/-/- GAINSSPSYFDS - QQRVNWPPN 9 gp NEG /-/-59 6-/-6/6-6 GDITSSPLYFDF - QQR-TWPPI 8 gp NEG -5-6/-/-59 -/-6 GAINSSPLYFDS - QQRVNWPPN 9 gp NEG /7-7/-6 /5 RNWGNFDH 8 - LQCGSSPPYT gp NEG /5-/-7 /5 DRLSFSVQVEQGVLQF 6 - QQRYSWPSLT gp NEG /6-5/6-9 DRLSFSVQVEQGVLDY 6 - QQRYSWPSLT gp NEG MALPSGPLDRSGYYFDD 7-7 QKYNNAPWT 9 gp IMMUNODOM MALASGPYDVSGYYFDY 7-7 QKYNGAPWT 9 gp IMMUNODOM MALASGPYDVSGYYFDY 7-7 QKYNGAPWT 9 gp IMMUNODOM MALTSGPYDVSGYYFDY 7-7 QKYNGAPWT 9 gp IMMUNODOM /6-5/6- HIAVGGREEE - QQRSTTPPEYT gp IMMUNODOM /6-5/6- HIAVGGSEDH - QGRTTRPPDYT gp IMMUNODOM /6-5/6- HIAVGGSEEH - QQRTTRPPDYT gp IMMUNODOM /6-5/6- HIAVGGREEE - QQRTTRPPEYT gp IMMUNODOM /-5/- PAQAGVGPRFDY " - CSYAGSYTYV gp NEG -

15 doi:.8/nature79 Supplementary Table c. Repertoire and reactivity of gp binding antibodies, patient pt Ab name VH D JH (-) CDR (aa) (+) Length /" V/" J/" (-) CDR (aa) (+) Length Binding Peptide Library NEUT # of relatives / /5-/-6 EKGQWLTVPPYYFDS 5 D-9 5 QQSHSPS 7 CDbs NEG /-59-6/6-9/5- EKGQWVTLPPYYFDS 5 D-9 5 QQSHSPS 7 CDbs NEG /- HKSVLLWFRELDY - QQYGSSPFT 9 CDbs NEG /- VGGTVWSGYSNYLDY 5-5 QQRSNWAIT 9 Core NEG /-/- DYTASGRHFFDY D-9 QQSSSKP 7 Core NEG /-6 DYTASGRHFFDY D-9 QQSAGTP 7 Core NEG DYTARGRHFFDY D-9 QQSSSTP 7 Core NEG /6-5/6-6 DYSAAGRHLFDS D-9 NEG DYTARGRHFFDY D-9 NEG /- 6 TRCFGANCFNFMDV - QQYYISP 7 VL NEG /-9/-6 6 TGGLLRFPEV " - SSYSSTNTYV VL NEG /6-9/- SGPGLLRGFDY " - / SSYTSSSTLGVV VL NEG /-/- VPRTTATRNAFDI " -8 / SSYAGINN 8 VL NEG DYTARGRHFFDY D-9 QQSSSTPFT 9 CDi NEG /-9 GPDDFWSGYPKY - QQYGSSWT 8 CDi NEG /6-9/5-6 5 GEFDSSGFDYESWYPYYMDV - QQYASSPFT 9 CDi NEG /- DNPVLQLGELSSSLDY 6-5 QQRGIWPLQIT CDi NEG /5-/-5 AQGDILTEGYFDY " -/-7 AAWDDSLHV 9 CDi NEG /5-/-5 AQGDILTEGYFDY - /5 QKATT 5 NEG PEPSSIVAPLYY - QQYGTLHPRT gp NEG PEPSSIVGALYY - QWYGTLHPRT gp NEG /5- DPQVEVRGNAFDI D-9 5 QQTYTSPIT 9 gp NEG /5- DPQIEIRGNAFDI D-9 5 QQTFTDPVT 9 gp NEG /- /5 DPQVNRRGNCFDH D-9 QQTYRSVT 8 gp NEG /-/- /5 DPQVNRRGNCFDH D-9 QQTYSSVT 8 gp NEG /-5/- GRREGLNFLLDY -6 5 QQYNYYPIT 9 gp NEG /-6-6/-9 5 ADYDNIWDSRGGFDL QKYDTDPMT 9 gp NEG /-9 6 AHHDFWRAPVDV - QQYATSSLYT gp NEG /-7/- PQYNLGRDPLDV - QQYGLSPWT 9 gp NEG /-7/- PQYNLGREPLNV - HQYALSPWT 9 gp NEG /5-/- RRGQRLLAYFDY -5 QQYNNWPPA 9 gp NEG /-8/- RSPGGGYAFDI - HQYGSSQR 8 gp NEG /-9 ADYDLLTSSYHFDS " 7- LLLPYYGGPWI gp NEG /- GDYDILTSSYQFDY " 7- LLLLYYGGPWI gp NEG /-7 LDGEAFRYYLDL " - / SSFTPTNTLV gp NEG /-6 LDGEAFRYYFDS " - / GSFTTSLTLV gp NEG /-/-7 6 DLRPMRGNWAMHV " -8 SSYAGSNNFV gp NEG - - -/-8 -/-9/- 5 TFITASWFDS " -/-8 CSYAGTYSYV gp NEG /-/-6 PHSPTNIPSRPLDY " - CSYAGSYIWV gp NEG - Supplementary Table d. Repertoire and reactivity of gp binding antibodies, patient pt Ab name VH D JH (-) CDR (aa) (+) Length /" V/" J/" (-) CDR (aa) (+) Length Binding Peptide Library NEUT # of relatives -8 -/- -/5-5/5-8 5 EGGSLWFGGANWLDP 5 - QHYGNSPRVT CDbs NEG /5-8 5 EGGSLWFGGANWLDP 5 - / QHYGNSPRVT CDbs NEG /5-/- GYDNSGPDY 9 - QQRANWPPGGT CDbs NEG /5-8/- /5 DQVGRYSFGFATGQQRVSAISD -9 QQTYTFPYS 9 CDbs NEG /-6 ERSTKYSFWSAVMRPDAFDL -7 QQYDSAPVT 9 CDbs NEG /-9 5 GGSALITIFGVDPKFDP 7 " -/-7 AAWDDSLDGFWV CDbs NEG /-6 6 RVKFPLWFGETTYYYYGMDV " -5 / GTWDSSLSAVV CDbs NEG /- KYPAYYDILTGYYRNYYFDY " - / CSHTSSDTLV Core NEG /-9 KYPAYYDILTANYRSYYFDY " - / CSYTSSATVV Core NEG /5-/- LRATIAGFDY -7 LQYNAYPLT 9 Core NEG /5-/- LRATIPGFDY -7 LQYNAYPLT 9 Core NEG /-5/5- LRATTPGFDY -7 LQYSTYPLT 9 Core NEG /-9 6 DGKGKAYYDFWSGYRNQKYYGLDV -5 QQYWPA 8 Core NEG /- LRRGYFDSGGDH -7 LQHNNYPWT 9 Core NEG /-/- LRRGYYDSGEDY -7 LQHNRYPWT 9 Core NEG /-5 6 ELSGEYHFWSGTYRYGVDV 9 - QQYGSSPRT 9 Core NEG /-9 6 DRVSDYDFWSGKRGYGMDV 9-5 Core NEG - - -/-9 6 EQKDYDFWNGLYKYGMDV 8-5 QQYWPRT 9 Core NEG /- GQRNVLHFLERKAFDI 8-9 QQSFGTPRT 9 Core NEG /6-9/- / GPRVFFESSGYYFRN 5 - QQYGSSPL 8 Core NEG /-8 -/- /5 GPRVLFESSGHYLRD 5 - / QQYGRSPL 8 Core NEG /- /5 GPRVFFESSGYYFRD 5-7 HLYVSRPV 8 Core NEG /-9 GTRYDFWSGFSNRDGRALAGYFDY -5 QQYNSDYT 8 Core NEG /- ARPRSPWDSTGWSVGY 6 - QQYGGSPPDT Core NEG /- -/-8 /5 DFVSIYGVAYFTGGGPSSPDI " -7 / AAWDDSLGGVV Core NEG B/-9 -/-9 KRVTIFGVVDTPRGYFDY 8 - QYYGSSPYT 9 Core NEG /5-8/5- / DQLGRYSFGFVTGQNKVSAISD -9 QQSYTFPYI 9 Core NEG /5-8/- /5 DQRGRYSFGFVTGQTKVSAISD -9 QQTFTFPYT 9 Core NEG -69 -/-8 -/- 5 GALWFGQLRGLDP -5 5 QQYWPIT 9 Core NEG /-6 6 GPGSMVRGLIVTSYGMDV 8-7 LQHNSYPLT 9 VL NEG /-/- RGRLNIPSPSAILTAFDV 8-9 QQSYNTRPLT VL NEG /5-/- GPKSVASLSYFDK - 5 QQRSNWPPKIT VL NEG /- REIRFGELSFYFDY -5 QQYKSYSPLT VL NEG /- REIKFGELSFYFDS -5 QQYKSYSPLT VL NEG DAFVSSAMDV -9 QHLNSYPRMYT VL NEG - Supplementary Table d. Repertoire and reactivity of gp binding antibodies, patient (continued) Ab name VH D JH (-) CDR (aa) (+) Length /" V/" J/" (-) CDR (aa) (+) Length Binding Peptide Library NEUT # of relatives /6-/-6 ENYSDGWYEVGHFDL 5-9 QQTYASVT 8 CDi NEG /5-/- ENYSDGWNEVGHFDF 5-9 / QQSHTSVT 8 CDi NEG /5-/6-5 ENYSDGWEEVGHFDS 5-9 / QQTYSSVT 8 CDi NEG /5-/6-5 ENYSDGWEEVGHFDY 5-9 / QQSYSSVT 8 CDi NEG /5-6 7 DEGSWVEAADEWDEHLFREMAV - HQYGSSPQS 9 CDi NEG /5-6 7 DEVSWVEAADEWDEHLFREMAV - HQYGSSPQS 9 CDi NEG /-5/ DEASWVEAADEWDEHLFREMAV - HQYGSSPQT 9 CDi NEG /-8/- 6 HLVVAVAAGPDYFSYGMDV 9 - QQFGSSPGT 9 CDi NEG /5-/-6 5 SRGYAYDSGGHYFPTWFDP 9-9 QQSYDTPRT 9 CDi NEG /6-5/6- LDSSSGWEEVGYFDR 5-9 QQSNSSPWT 9 CDi NEG /- /5 SLTGRLHLGELSSGIGP 7 - QQRSIWPPSLT CDi NEG /- 6 5 CSIVGNGDFLEEDSHYPAMDV - QQCTLPLT 8 CDi NEG /5-/- 6 5 NYLIESRYDEKDYYYAMDV 9-5 QQYDILPLT 9 CDi NEG /-7/-8 6 DSGFDLDYYDTNELYFGFDY " -5 / GTWDSSLRAAL CDi NEG /-7/-8 6 DSGFDLDYYDTNELYFGFDY " -5 / ATWDSSLRTAL CDi NEG /- 6 QNIAARTAERLYEYYFYGMDV - QQYDNLPT 8 CDi NEG /6-5/6-6 QNIAARAAEKLYEYYFYGMDV - / QQYDNLPT 8 CDi NEG /-6/6-9 CYSGRSRYFFDS -9 QQSQRTPHT 9 CDi NEG /- DLARYGVTSIVPEFGFDF 8-5 QQYPST 6 gp NEG /-/- 6 DRWVRPQFPSMDFQYNGLDV -9 QQLGT 5 gp NEG /-8 -/-/-9 / GFHFWSGTGTRPRNWYFDL 9 - QQYGSSPST 9 gp NEG /5- VAISYAGLIVVPGPFDV 7-7 QKYDTAP 7 gp IMMUNODOM /- VSITYAGLIVVPGAFDV 7-7 / QKYDTAP 7 gp IMMUNODOM VLTDLDQGNPRMDV -5 QQYETYPWT 9 gp NEG VLTDLDQGNPRMDV -5 / QQYETYPWT 9 gp NEG /5-8/5-6 GRGSTFPSAQFSYFGLDV 8-9 QQLGT 5 gp IMMUNODOM /-/5-5 6 GRGSFTGFDQYHYYGMDV 8-9 / QQLGT 5 gp IMMUNODOM /5-8/5-6 GRGYSHGFQQYNYYGMDV 8-9/-7 / QQLGT 5 gp IMMUNODOM /5-8 6 GRGSFQGFQQYEYYGMDV 8 -/-5 gp IMMUNODOM /5-8 6 GRGSFQGFQQYEYYGMDV 8 -/-5 gp IMMUNODOM -6 -/-59 5-/-7/6-5 6 GGGYAVVGPKYGLDV 5 " -8 GAYTTTSTLV gp NEG /-59 5-/5-6 GGGYAVVGPKYGLDV 5 " -8 GAYTTTSTLV gp NEG /- QVRAPTLRFRHGGYFET 7 " - QSYDTSLSDTGV gp NEG /5-8/- QLRAPTTRFRHGGYFEN 7 " - QSYDTSLTDTGV gp NEG -5-6-/'-/- /5 SDPAIAAAGSLDL -9 HQLDS 5 gp IMMUNODOM /6-9/6- /5 SDPAIAAAGSLDL -9 HQLDS 5 gp IMMUNODOM /6-5/6-9 /5 SDPAIAAAGSLDL -9 HQLDS 5 gp IMMUNODOM /6-5/6-9 /5 SDPAIAAAGSLDL -9 HQLDT 5 gp IMMUNODOM /-/- /5 RDKYQYIDSSGDYPFDR 7 - QQYDNLPRVT gp NEG /- HIGAGGPYSEY - QQRTTWPPEYT gp IMMUNODOM /-/- RTTLVNFGVFDL - QHYGNSRWT 9 gp NEG /5-8/-6 /5 DKDASIYGYRILNH - 5 QYYDHRPAIA gp NEG /5-/-8 5 DQGGYPVSPVGPKWFDP 7 " - CSYAGSYT 7 gp NEG - 5

16 doi:.8/nature79 Supplementary Table e. Repertoire and reactivity of gp binding antibodies, patients 5 and 6 pt 5 Ab name VH D JH (-) CDR (aa) (+) Length /" V/" J/" (-) CDR (aa) (+) Length Binding Peptide Library NEUT # of relatives /5 DVRLVAVPGAD - SSYTSSLTLV CDi NEG EHRLPPPTGRRTRNWFDP / QSYDSSVSVV CDi NEG - " DRVGRRLGELSAGFDY 6 - QQRSIWPPSLT CDi NEG GSLYDYRDNADLKPSYYYAMDV - SSYSATGVA 9 CDi NEG - " YEGKRSGMDV - QQYDNLPLA 9 CDi SVITDLHTFGDYESGDPSYYYMDV -7 QRYNRDPYI 9 CDi NEG DWIGYDYDGSGSHLRDESFDI - MQATHWPPG VL NEG RYKYLPGDQHMPWDY 5 - QQYDNLPPRVT gp NEG RYKYLPGDQHMPWDN 5 - gp NEG pt 6 Ab name VH D JH (-) CDR (aa) (+) Length /" V/" J/" (-) CDR (aa) (+) Length Binding Peptide Library NEUT # of relatives HRANYDFWGGSNLRGYFDP 7 - QQYGTSPTT 9 CDbs NEG HRADYDFWNGSNLRGYFDP 9 - QQYGSSPTT 9 CDbs NEG HRANYDFWGGSNLRGYFDP 9 - QQYGTSPGT 9 CDbs NEG DRYEAAWFGADKVYGMDV 8 D-7 LQHHSYPWT 9 Core NEG /-8 6 DQRDCSTNRCFGVFGYYMDV - QHRSSWPLT 9 gp NEG b/-9 6- RGIAAAGFYFQN -5 HHYKSDCQT 9 gp NEG b/-9 6- RGIAAAAFYFQT -5 HHYSSSSHT 9 gp NEG 6-6 -b/-9 6- RGIAAAGFYFQH -5 HHYMSDLQT 9 gp NEG /- 5/ EIGVAEH 7 -NL 5 QQYFTSVIT 9 gp Supplementary Table f. Repertoire and reactivity of gp non binding antibodies, patient pt- Ab name VH D JH (-) CDR (aa) (+) Length /" V/" J/" (-) CDR (aa) (+) Length Binding N - -6 DEIVGALLGAFDI -6 QQYNTYPLT 9 N SAYYRNWFDS - QQFNSYPPLT gp- N GVWEAPDGSSYYYYMAD 7 D-9 QQGFSAPFT 9 gp- N DSRPQALVAALDV - MQGTYWLWT 9 N /-5 VRRGSSYPDY -5 QQYHNWPPS 9 gp- N /-6 6 LFGAKRLGVAPSGYYMDV 8 D-9 5 QQSYTTPL 8 gp- N /-6 RGSLLIKYFDY - QQRSNWPPGLT N TYYNFWSDQSQGLDFDY 7-5 QQYNSYFRT 9 gp- N HLIAPTAGNYFYP " - CSYAGRDTSWV gp- N / KVYSDGWSPPTGFVY 5 - QQYGSSRRWT N GGSMIRGVPSPFYYGMDV 8 - HQCGSSPRT 9 gp- N FGRTPWFDP 9 - MQGTHWPWT 9 gp- N /5-/- GDSGPTGFDY -5 QQYNWPPFT 9 gp- N DKPAYDEYAEETIAPHNYHAMDL - QQYYSTPVT 9 N DVIVGALLGAFDI -6 QQYKTYPVT 9 gp- N SFYDNGGYYLGLDY -5 HQYNKWDT 8 N /-6/7-7 SIYSTGPAPVY " - YSTDNSGKQHWV gp- N /5 DLID D-9 QQSYSTPYT 9 N /-8 IKGPPRGNFGVAFYF 5 D- QQHDTFPFT 9 gp- N /-6 5 GTQSYSAVAPGWFDP 5 - QQYYSSPLT 9 gp- N GGYDYGDHYYYYMDV 5-5 QQYGSSIT 8 N DVVERPGFGDFRYDYYGMDV D-9 MQSLHLPYT 9 gp- N /5 DRLSSFWSGGIDQ -7 5 QSYNGDPPVT gp- N APYISSSHLDYW " -5 LSADSSSTYQV gp- N QRWETIDY 8 " -5 GSWDGSLNAGV N AREGRWFSDNYYAMDV 6 - QQYGFSLPVT gp- N-55 -b/-9-9/-6/- GVGTRYYVYFDS " - QSYDSSLSGWV N DRGSSGWYGWLDP -5 QQYDVWPLT 9 N EMAATSDAFDI -5 QQYKKWPPWT N SIAADDYYYYYMDV - 5 QQYGSSPIT 9 N /- LEGTDY 6 D- 5 QQYDRLPIT 9 gp- N AQFHNSGYYYSGLDY 5 - QHHGSSPTWT gp- N /- APPPGSTEWAYYFDY 5-5 QHYNNWPYT 9 N-68 -h/ REGSQGAFDI " - QAWDSSTAV 9 gp- N AAIPIGDSKYSYFDS 5 - QQYYTVPS 8 N GVRSIVGAHFDY D-8 MQALQTSLT 9 N GHSSSWTKFNWFGP -5 QQYSGPLT 8 gp- N-77 -/ RDRYNWKYYYLDV -9 QQLNSDPPWT N GLTVATLYDAFDV D-9 MQSIQLPLT 9 gp- N HSRPGAPPHYFDY - QQYGSSAPYT N LYYNFGSGYDTGIGDH 6-7 QNYNKPPRT 9 N VKQFLEWLYLDY D-9 QQSYSIAGT 9 N PSYGGYDDQGWYFEY 5 " - QVWDSGRDSWV N-9-5-5/-8/-9 5 KGRGYGYWFDS -5 5 QQYYKWPPIT N AFQASMVRGVIVDPYGMDV 9 - QQYYSTPHT 9 Supplementary Table g. Repertoire and reactivity of gp non binding antibodies, patient pt- Ab name VH D JH (-) CDR (aa) (+) Length /" V/" J/" (-) CDR (aa) (+) Length Binding N EGGYSDFWSGYSGFDY 7 " - SSYTISSPRV gp- N ANYYDSSGYGLDI " - / QSYDSSLSG 9 gp- N HYYGSGLTKDYYEYIDV 7 " - QSYDSSLGVEV N DRFNWGGYFFDS -5 QQYNSYPLT 9 N RMATLTGGYYYYYMDV 6 D-8 5 MQSLQTPIT 9 gp- N /- 6 RISSSSWYMVDNSHTLHFYYMDV " -7 AAWDDSLSGLNWV gp- N /- 6 AARRAFYYYYMDV -5 QQFNTYSQT 9 gp- N GATYYYDSSGHQSRRAFDI 9-5 MQGTYWPPSIT gp- N ASGSYILGTMDV - QQRTSWPQT 9 gp- N- - -5/- 6 MNPPWFRGGSNNPYSYYYMDV -9 /5 gp- N QTTDEGRQWLVGFQH 5-5 QQYENWLT 8 gp- N IYDGRGYYSYFFDL -7 QLYNSVPQT 9 gp- N-8 -b/-59-5 /5 LGCSGGSCYEDS - QQYSTTPRT 9 N- -6 -/-6 LTKNPSQDFWGSYLYYFED 9 D-9 QQGYSTPWT 9 gp- N AGREGWFDP 9 D-9 5 HQSYSTPPT 9 gp- N /- QVSSYSSSGYRREFDY 6 - QQYYSIPPWTF gp- N SGVHYMDV 8 D-9 QQSFSTLWT 9 gp- N FTQRQGGFDY " - QSYDNSLSGWV N HGRTVFGVVRNYYYMDV 7 D-9 5 N NGHSALGGEYFQH D- HQCDNLIAR 9 N DHGIKPDNYYDISGYNLDYFDY - QQYGSSPPT 9 gp- N NGHSSLGGGYFPH D- QQYDNLLAH 9 N AGHCSSTSSVYCPFDM 6 - QEYYILPCS 9 gp- N-5 - -/-9 TNWAFVTGYYRFDF 6 " -5 GTWDGSLTTGV N GLYDSSGYYFGY " - / YSYAGNSLGV gp- N TLDGNFHWDF " - CSFTYVNPTYL N DRAPYGAFEPFDF -5 QQYNRYSYT 9 gp- N RYCSSTTCYRGHFDY 5 " -8 SSYADTFGV N LTGPSGYCDSSGCYWFDP 8 " - N-8 -h/-8-7/- 6 DRDYDEDFDF " - CSYAGSYSYV N /-/-7 5 DLVSVSPPYGNYGPDNNWFDF -5 QQYNNLPVT 9 gp- N DFGRAYAIGYFEY -5 QQYDSFSWT 9 gp- N LIPVSGAFDV - QQRSTWPPT 9 gp- N GGSPEH 6 D-9 N DGRYSGDDQYYYHYYYMDV 9 - QYYGMSVT 8 gp- N /5-5/- 6 ESWLYSNGDYYYMDV 5-5 QQYHNWPRT 9 gp- N-56 -/-6 - EAGSVTATGPFDS -5 QQYSHYRT 8 gp- N LYFDWAPHAFDI D- 5 N QEWELQPFDY - QQYGSSLLYT gp- N /-6 EEPRDAFDL 9 " -7P 6 STWDYSLSAHEDV N /-8 SQGNTAIDY 9 - MQGTYWPPLT gp- N /6-6 DLLPDYPVSSAPEDF 5 - QQRHNWPIS 9 gp- N LPKSRMVGGDHLPFYPDF 8 " - AAWDDSLNGHGV N-9 - -/-6 6 DLNFGVVTPYYYYYLDV 7-5 QSKT gp- N DNTISGVVPRWFDY -5 QQYNNWPPFT gp- N PGYCNNNICTHWFDT 5 " -8 N LSSDRIVVVGPDY - QQRSNWPRLT Supplementary Table. IgH and IgL chain gene sequence information and antibody reactivity and neutralization assay results of cloned antibodies. indicates not determined. The number of clone members with % IgH and IgL chain gene sequence homology is indicated and clonal relatives with various degrees of somatic mutations are shown in the same color. a-e, Antibodies from gp-reactive IgG B cells from patients -6. f, g, Antibodies from gp non-reactive IgG B cells from patients and 6

17 doi:.8/nature79 Supplementary Table Affinity measurements by surface plasmon resonance antibody epitope ka (/Ms) kd (/s) KD (M) b gp CDBS.E+ 8.E-7.E- CDBS.E+.5E-.7E-8 CDBS.7E+ 5.E-.E-8 CDBS 9.8E+.E-.E-8 Core.9E+7.E-5.8E- Core.7E+.5E-5.E-9 Core 5.E+.E- 6.9E-9 Core 5.E+ 9.8E-.E-8 Core.E+.E-5.E- Core.E+.9E- 5.E-9 CDi.E+ 5.7E+5.E-9 VL.E+.E-5.E-9 VL 7.7E+.E-5 5.E- CDBS.E+.9E-.E-8 gp gp core ka (/Ms) kd (/s) KD (M) ka (/Ms) kd (/s) KD (M) 6.7E+.E-5.E-.E+5 5.E-5.5E- 5.5E+.E- 5.9E-9.8E+5.9E-.E-9.9E+.E-.E-8.E+ 8.E-.9E-8.7E+.E-5 5.8E-9 5.8E+ 7.E-5.E-9 5.E+.E-.E-9 8.E+.E-5 5.E-.E+.E-.E-8.E+5.E- 9.7E-.E+5.5E-.7E-8.5E+5.E-6 7.E-.7E+5 7.5E-5.E-.E+5 5.7E-5.E-.6E+5 9.E-5.5E-.7E+5 7.8E-.6E-9 Supplementary Table. Affinity measurements of b and selected patient antibodies by surface plasmon resonance. Stars indicate cases in which the sensorgrams are virtually flat during the dissociation phase. Off-rates might therefore be even slower than the ones listed. Epitopes against which the affinities were measured are indicated above.(m=mol/liter; s=seconds) 7

18 doi:.8/nature79 a Supplementary Table 5 Competition ELISA experiments Competing Gp Core Antibodies (non-biotinylated) biotinylated antibodies Gp Core CDbs B > CDi V-Loop >. >. >. > > > >. >. >. 6.6 >. b biotinylated antibodies Competing CDbs Antibodies (non-biotinylated) B Gp Core CDbs B >. > >.. 5. CDi V-Loop >. > >. >. >. >. >. 8.6 >. > >. >. >. c biotinylated antibodies Competing CDi Antibodies (non-biotinylated) Gp Core >. >. >. >. >. >. >. >. >. > CDbs >. > > >..6 >. >.. >. >. B >. >. >. >. >. >. >. >. >. >. >. >. >. CDi 9. >. >..7 > >. > >. V-Loop >. >. 9.5 >. >. >. > >. >. d biotinylated antibodies Competing VL antibodies (non-biotinylated) D Gp Core >. >. >. >. >. >. >. CDbs >. >. 86. >. >. >.. B >. >. >. >. >. >. >. CDi >. >. >. > >. V-Loop > Supplementary Table 5. Summary of gp competition ELISA experiments. Numbers indicate IC5s for the specific antibody in ELISA assays measuring the blocking of the binding of the indicated biotinylated antibody (indicated at left) to gp. a, anti-gp core antibodies. b, anti-cdbs antibodies. c, anti-cdi antibodies. d, anti-vl antibodies. Biotinylated antibodies are: b, -6 anti-cdbs, -9 anti-core, -8 anti-cdi, and -79 anti-vl. 8

19 doi:.8/nature79 Supplementary Table 6 In vitro Tzm-bl neutralization assay. a CDBS CORE CDi VL TIER CLADE STRAIN C MW965. >5 >5 >5 >5 >5 >5 >5 >5 9.8 <. <. <. <. >5 >5 >5 >5 >5.8 A DJ6.8. > > > >5.7 >5 >5 >5 B SF6.LS >5 > >5.9. >5 <. B SS96. >5 >5 >5 >5 >5 8. > >5 >5 >5 5. >5 B BaL > > >5 >5. >5.8 B 655. >5 >5 >5 >5 >5 >5. > >5 >5 >5 >5 >5 B RHPA59.7 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 B TRO. >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 B SC66.8 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 B PVO. >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 gp pt TIER CLADE STRAIN IGG POOL C MW965. >5 >8 >5 >5 >5 >5 8. A DJ6.8 >5 >8 >5 >5 >5 >5 5.5 B SF6.LS >5 >8 >5 >5 >5 >5 5.5 B SS96. >5 > B BaL.6 >5 >8 >5 >5 >5 >5 8.5 B 655. >5 >5 88 B RHPA59.7 >5 >5 8 B TRO. > > > >5 > B SC66.8 > >5 > B PVO. >5 >5 89 controls b g F5 E. >5 >5. >5.9 > >5 6.9 >5. > >5. > D.5.5 < >5 >5 >5 b CDBS CORE CDi VL TIER CLADE STRAIN C MW965.. <. 6.8 <. >.5.9 > >5 > >5 > >5 A DJ > >5 >5 >5 6.5 >5 5. >5 > >5 > >5 B SF6.LS..98 >5.6 >..9 >5 <. <.. >5 > >5 >. B SS96. >5 6 >5. > >5.6.8 >5 > >5 >.86 B BaL.6 >5.9 >5 8. >.7 7. > >5 > >5.5 B >5.6 >5 >5 >5 >5X >5 >5X >5 > >5 >.9 B RHPA59.7 > >5X >5 >5 >5 >5 >5 >5X >5 >5X >5 > >5 > 5 B CAAN5.A > >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 > >5 > >5 B THRO56.8 >5X >5 >5 >5X >5X >5X >5 >5 >5 >5 >5 > >5 > >5 B SC >5X >5 79. >5X >5 >5 >5X >5X >5X >5 > >5 >5 gp pt TIER CLADE STRAIN IGG POOL C MW965. >5 >5 > >5 > > > > >.7 A DJ6.8 >5 >5 > >5 > > > > > B SF6.LS >5 >5 > >5 > > > > > 6. B SS96. >5 >5 > >5 > > > > > 8.8 B BaL.6 >5 >5 > >5 > > > > >.5 B 655. >5 >5 > >5 > > > > > 5 55 B RHPA59.7 >5 >5 > >5 > > > > > 59 >5 B CAAN5.A >5 >5 > >5 > > > > > 6 >5 B THRO56.8 >5 >5 > >5 > > > > > 58 >5 B SC66.8 >5 >5 > >5 > > > > > 95 >5 9

20 doi:.8/nature79 c Supplementary Table 6 CDBS CORE CDi VL TIER CLADE STRAIN C MW965. >5 >5 >5 >5. >5.5 >5 >5 > >5 >5 >5 A DJ >5X >5 >5 >5 >5 >5 >5 >5 > >5 >5 >5 B SF6.LS 5.7. >5. >5 >5 >5 > >5 >5 >5 B SS96. >5 >5 >5 >5.7 5 >5 >5 8. >5 >5 >5 B BaL >5 > >5 >5.9 >5 >5 >5 B 655. >5 >5 >5 >5 >5 >5 > B RHPA59.7 >5 >5 >5 >5 >5 >5 > B TRO. >5 >5 >5 >5 >5 >5 > B SC66.8 >5 >5 >5 >5 >5 >5 > B PVO. >5 >5 >5 >5 >5 >5 > TIER CLADE STRAIN C MW965. > > >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 A DJ6.8 > > >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 B SF6.LS > > >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 B SS96. > > >5 >5 >5 >5 >5 >5 >5 >5 >5 >5X >5 >5 B BaL.6 > > >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 >5 B 655. >5 >5 >5 >5 >5 B RHPA59.7 >5 >5 >5 >5 >5 B TRO. >5 >5 >5 >5 >5 B SC66.8 >5 >5 >5 >5 >5 B PVO. >5 >5 >5 >5 >5 gp IGG pt POOL >5 7 >5 7 >5 65 >5 9 >5 d CDBS TIER CLADE STRAIN C MW >5 5. >5 >5.9 A DJ6.8 >5 >5.6 >5.9 >5 B SF6.LS > >5 B SS96. >5 >5 >5 >5 >5X >5 B BaL.6 >5 8. > B 655. > >X B RHPA59.7 > > > > >5 >5 >5 B TRO. > > > > >5 >5 >5X B SC66.8 > >X > > >5 >5 B PVO. > > > > >5 >5 CORE TIER CLADE STRAIN C MW965. >5 >5 >5..6 >. > >5. >5 >5.5 >5X A DJ > > B SF6.LS >5 B SS96. >5 >5X >5 >5 > > >5 > >5 75. >5X >5 >5 >5 B BaL.6 >5X. >5X > >5X.6 >5X >5 B 655. >5X >5X >5X.9 > > >5.5.5 >5X >5X >5 B RHPA59.7 >5 >5 >5 > > > >5 > >5 > >5 >5 >5 >5 B TRO. >5 >5 >5 > > > >5 > >5 > >5 >5 >5 >5 B SC66.8 >5X >5 >5X > > > >5X >X >5 > >5 >5 >5 >5 B PVO. >5 >5 >5 > > > >5 > >5 > >5 >5 >5 >5 VL TIER CLADE STRAIN C MW >5X. >5.5.. >.8.7 >5 > > >5 9. >5 A DJ >5X. >5 5. >5X >5X > > >5 >5X > > >5 >5 >5 B SF6.LS 6. > >5 5. > >.5 >5 6.5 >5 B SS96. >5 > >5 >5 > > >.5 >5 > > >5 >5X >5 B BaL.6..7 >5X > > > 6. >5 > > >5 >5 >5 B 655. >5 >X >5 >5 >5 >5 >5 > >5 >5 >5 > >5 B RHPA59.7 >5 > >5 >5 >5 >5X >5X > > >5 >5 > >5 B TRO. >5 > >5 >5 >5 >5X >5X >5 > > >5 >5 > >5 B SC66.8 >5 > >5 >5 >5 >5 >5 > > >5 >5X > >5 B PVO. >5 > >5 >5 >5 >5X >5X > > >5 >5 > >5 TIER CLADE STRAIN C MW965. >5 >5 > > > > >5 >5 > >5 >5 >5 >5 >5 A DJ6.8 >5 >5 > > > > >5 >5 > >5 >5 >5 >5 >5 B SF6.LS >5 >5 > > > > >5 >5 > >5 >5 >5 >5 >5 B SS96. >5 >5 > > > > >5 >5 > >5 >5 >5 >5 >5 B BaL.6 >5 >5 > > > > >5 >5 > >5 >5 >5 >5 >5 gp CDi IGG pt POOL 9 < > B 655. >5 >5 B RHPA59.7 >5 >5 B TRO. >5 >5 B SC66.8 >5 >5 B PVO. >5 >5 > 7 6 > >

21 doi:.8/nature79 Supplementary Table 6 e CDi VL gp CDBS CORE gp TIER CLADE STRAIN TIER CLADE STRAIN C MW965. >5 >5 >5. >5 >5 C MW >5 >5 A DJ6.8 >5 >5 >5 >5 >5 5. >5 A DJ6.8.. >5 >5 B SF6.LS >5 8. >5. >5 <. >5 B SF6.LS >5 B SS96..9 >5 >5 5. >5 B SS96. >5 >5 >5 B BaL.6 >5 >5 >5 >5 >5 >5 >5 B BaL.6 6. >5 >5 B 655. >5 >5 >5 >5 >5 B >5 B RHPA59.7 >5 >5 >5 >5 >5 B RHPA59.7 >5 >5 >5 >5 B TRO. >5 >5 >5 >5 >5 B TRO. >5 >5 >5 >5 B SC66.8 >5 >5 >5 >5 >5 B SC66.8 >5 >5 >5 B PVO. >5 >5 >5 >5 >5 B PVO. >5 >5 >5 >5 Supplementary Table 6. In vitro Tzm-bl neutralization assay. Numbers indicate IC5s for the specific monoclonal antibody, serum IgG, or pooled antibodies in the Tzm-bl assay measuring inhibition of infection by the indicated viral strains. X indicates activity that did not reach IC5 values at the concentration tested. a-d, patients - and previously described control antibodies; e, patients 5, 6.