www.sciencetranslationalmedicine.org/cgi/content/full/7/296/296ra112/DC1
Supplementary Materials for HLA class II genes modulate vaccine-induced antibody responses to affect HIV-1 acquisition Heather A. Prentice, Georgia D. Tomaras, Daniel E. Geraghty, Richard Apps, Youyi Fong, Philip K. Ehrenberg, Morgane Rolland, Gustavo H. Kijak, Shelly J. Krebs, Wyatt Nelson, Allan DeCamp, Xiaoying Shen, Nicole L. Yates, Susan Zolla-Pazner, Sorachai Nitayaphan, Supachai Rerks-Ngarm, Jaranit Kaewkungwal, Punnee Pitisuttithum, Guido Ferrari, M. Juliana McElrath, David C. Montefiori, Robert T. Bailer, Richard A. Koup, Robert J. O’Connell, Merlin L. Robb, Nelson L. Michael, Peter B. Gilbert, Jerome H. Kim, Rasmi Thomas*
*Corresponding author. E-mail:
[email protected] Published 15 July 2015, Sci. Transl. Med. 7, 296ra112 (2015) DOI: 10.1126/scitranslmed.aab4005
The PDF file includes: Fig. S1. Multiple alignment of different Env (120–204) and partial V2 sequences (160–183). Fig. S2. Cocrystal structure of HIV-1 gp120 (red) binding to CD4 (green) and the Fab of mAb 17b (blue) (23). Table S1. Odds ratios for two-way interaction analysis of HLA class II alleles with Env-specific IgA and Env (120–204)–specific IgG. Table S2. Association between Env-specific IgA or Env (120–204)–specific IgG and HLA class II alleles present in more than 5% of the study population. Table S3. High IgG binding to multiple Env (120–204) antigens correlates with presence of DPB1*13 and is associated with decreased HIV-1 acquisition across multiple subtypes. Table S4. IgG responses to five overlapping peptides spanning Env (120–204) were significantly associated with presence of DPB1*13. Table S5. Comparison of frequency of amino acid (AA) sites in Env-gp70 in RV144 breakthrough infections stratified by DPB1*13. Table S6. Odds ratios for IgA binding to different recombinant Env proteins on HIV-1 acquisition after stratification by absence or presence of HLA-DQB1*06. Table S7. Odds ratios for HIV-1 acquisition in univariate analyses of all HLA class II alleles present in the placebo controls.
Table S8. Odds ratios for HIV-1 acquisition in univariate analyses of all HLA class II alleles present in the vaccinated volunteers.
120 gp70_BCaseA_V1_V2 gp70_A_GN gp70_C_GN AEA244V1V2Tags293F BioRV144_V2_AE BioRV144_V2_C BioRV144_V2_B gp70_BCaseA_V1_V2 gp70_A_GN gp70_C_GN AEA244V1V2Tags293F BioRV144_V2_AE BioRV144_V2_C BioRV144_V2_B
VKLTPLCVTLNCIDLRNATNATSNSNTTNTTSSSGGLMMEQGEIKNCSFNITTSIR VKLTPLCVTLDCNATAS---------------------NVTNEMRNCSFNITTELK VKLTPLCVTLHCTNATFKNNVTND---------------MNKEIRNCSFNTTTEIR VKLTPPCVTLHCTNANLTKANLTNVN--NRTNVSNIIGNITDEVRNCSFNMTTELR -------------------------------------------------KKKTELR -------------------------------------------------KKKTEIR -------------------------------------------------KKKTSIR : .*.:: 204 DKVQKEYALFYKLDIVPIDNPK---NSTNYRLISCNTSVITQA DKKQQVYSLFYKLDVVQINEKN---ETDKYRLINCNTSAITQA DKKQQGYALFYRPDIVLLKENRNNSNNSEYILINCNASTITQA DKKQKVHALFYKLDIVPIEDNN---DSSEYRLINCNTSVIKQP DKKQKVYALFYKLDIVQ-------------------------DKKQKVYALFYRLDIVP-------------------------DKVQKEYALFYKLDVVP-------------------------** *: ::***: *:*
Fig. S1. Multiple alignment of different Env (120–204) and partial V2 sequences (160–183). HIV-1 Env amino acid sequences corresponding to either positions 120–204 or 160–183, relative to the HXB2 sequence reference from different viral subtypes (see table S3) were aligned using Clustal Omega. Sequences matching DPB1*13 specific epitope 120-133 are shown in bold.
Env residue 121 Env residues 124 - 127
Fig. S2. Cocrystal structure of HIV-1 gp120 (red) binding to CD4 (green) and the Fab of mAb 17b (blue) (23). The IgG response identified, which was found to associate with both presence of DPB1*13 and also reduced risk of HIV-1 acquisition, was directed to the Env residues with atoms highlighted in red spheres (residues 124P, 125L, 126C, 127V). IgG binding to this region of Env would be expected to disrupt interaction with CD4. Also highlighted in red is Env residue 121K, binding site of the wellcharacterized neutralizing mAb 17b.
Table S1. Odds ratios for two-way interaction analysis of HLA class II alleles with Env-specific IgA and Env (120–204)–specific IgG.
Infected
Env-Specific
Env (120–204)–Specific
IgA-Allele Interaction*
IgG-Allele Interaction*
Uninfected
N=41
N=202‡
(%)
(%)
OR‼
95% CI
P
q
OR‼
95% CI
P
q
2 (4.9)
25 (12.4)
0.76
0.11-5.36
0.78
0.93
1.13
0.23-5.57
0.88
0.93
DRB1*04
5 (12.2)
34 (16.8)
0.79
0.32-1.97
0.62
0.93
1.15
0.40-3.31
0.80
0.93
DRB1*07
11 (26.8)
31 (15.3)
0.94
0.44-1.99
0.87
0.93
1.89
0.74-4.80
0.18
0.74
8 (19.5)
37 (18.3)
1.17
0.51-2.67
0.71
0.93
1.09
0.44-2.71
0.85
0.93
DRB1*11
3 (7.3)
27 (13.4)
0.60
0.14-2.59
0.50
0.93
0.24
0.02-3.21
0.28
0.88
DRB1*12
12 (29.3)
63 (31.2)
0.66
0.29-1.49
0.32
0.88
1.05
0.47-2.38
0.90
0.93
DRB1*14
8 (19.5)
36 (17.8)
0.65
0.27-1.57
0.34
0.88
1.07
0.42-2.76
0.89
0.93
DRB1*15
15 (36.6)
85 (42.1)
1.77
0.88-3.55
0.11
0.64
0.84
0.38-1.84
0.66
0.93
2 (4.9)
24 (11.9)
0.97
0.24-3.98
0.97
0.97
1.70
0.43-6.65
0.45
0.93
10 (24.4)
31 (15.3)
1.08
0.50-2.31
0.85
0.93
2.48
0.93-6.61
0.07
0.52
12 (29.3)
58 (28.7)
0.70
0.31-1.60
0.40
0.93
1.11
0.49-2.50
0.81
0.93
7 (17.1)
27 (13.4)
4.86
1.26-18.79
0.02
0.32
1.56
0.61-4.02
0.35
0.88
DRB1*15:02
9 (22.0)
60 (29.7)
1.09
0.49-2.42
0.83
0.93
0.49
0.18-1.35
0.17
0.74
DQB1*02
12 (29.3)
45 (22.3)
1.05
0.50-2.21
0.90
0.93
1.52
0.66-3.53
0.33
0.88
DQB1*03
23 (56.1)
114 (56.4)
0.89
0.46-1.72
0.73
0.93
1.03
0.49-2.19
0.93
0.94
DQB1*04
0 (0.0)
21 (10.4)
-
-
-
-
-
-
-
-
DQB1*05
23 (56.1)
122 (60.4)
0.85
0.43-1.67
0.63
0.93
0.78
0.36-1.71
0.53
0.93
DQB1*06
10 (24.4)
39 (19.3)
7.57
2.11-27.20
0.002
0.11
0.93
0.35-2.42
0.88
0.93
Allele DRB1*03
DRB1*09
G grouping† DRB1*03:01:01G
DRB1*09:01:02G
DRB1*04:05 DRB1*07:01
DRB1*07:01:01G
DRB1*12:02 DRB1*15:01
DRB1*15:01:01G
DQB1*03:01
DQB1*03:01:01G
15 (36.6)
72 (35.6)
0.71
0.34-1.46
0.35
0.88
0.94
0.42-2.13
0.89
0.93
DQB1*03:03
DQB1*03:03:02G
9 (22.0)
43 (21.3)
1.09
0.50-2.38
0.83
0.93
1.19
0.49-2.91
0.70
0.93
DQB1*05:01
DQB1*05:01:01G
8 (19.5)
49 (24.3)
0.90
0.39-2.09
0.80
0.93
0.61
0.23-1.63
0.33
0.88
DQB1*05:02
DQB1*05:02:01G
14 (34.1)
73 (36.1)
0.80
0.40-1.60
0.53
0.93
1.32
0.60-2.87
0.49
0.93
DQB1*05:03
DQB1*05:03:01G
5 (12.2)
19 (9.4)
0.45
0.14-1.47
0.19
0.74
1.44
0.48-4.32
0.52
0.93
DQB1*06:01
DQB1*06:01:01G
7 (17.1)
32 (15.8)
6.79
1.53-30.16
0.01
0.26
0.84
0.27-2.61
0.77
0.93
DPB1*02
15 (36.6)
58 (28.9)
0.75
0.37-1.54
0.43
0.93
1.66
0.76-3.66
0.21
0.78
DPB1*04
14 (34.1)
57 (28.4)
1.74
0.85-3.56
0.13
0.72
1.26
0.57-2.82
0.57
0.93
DPB1*05
11 (26.8)
74 (36.8)
0.41
0.18-0.91
0.03
0.32
0.59
0.25-1.39
0.23
0.81
DPB1*13
11 (26.8)
66 (32.8)
0.44
0.20-0.95
0.04
0.32
0.27
0.10-0.76
0.01
0.26
DPB1*02:01
9 (22.0)
33 (16.4)
0.73
0.32-1.68
0.46
0.93
2.09
0.89-4.93
0.09
0.60
DPB1*02:02
7 (17.1)
28 (13.9)
1.10
0.39-3.05
0.86
0.93
0.62
0.18-2.18
0.46
0.93
DPB1*04:01
9 (22.0)
45 (22.4)
2.68
1.09-6.59
0.03
0.32
1.83
0.76-4.40
0.18
0.74
* Previously reported values for Env-specific IgA and Env (120–204)–specific IgG (3). Sex, baseline behavioral risk score, and one significant principal component axis were included as covariates for all models. † Nomenclature used for alleles that were ambiguous for exon 2 by 4-digit HLA typing. ‡ 201 HIV-1 uninfected individuals with complete DPB1 genotyping. ‼ Estimated odds ratios and 95% CIs reflect the results from logistic regression analysis including a two-way interaction term for Env-specific IgA or Env (120–204)–specific IgG and presence of the given allele.
Table S2. Association between Env-specific IgA or Env (120–204)–specific IgG and HLA class II alleles present in more than 5% of the study population. Env-Specific IgA*
Env (120–204)–Specific IgG*
n (%)†
β ± SE
P
q
β ± SE
P
q
DRB1*03
27 (11.1)
-0.28 ± 0.20
0.17
0.52
-0.04 ± 0.20
0.83
0.94
DRB1*04
39 (16.0)
0.03 ± 0.18
0.85
0.94
0.09 ± 0.18
0.60
0.85
DRB1*07
42 (17.3)
-0.10 ± 0.17
0.56
0.85
-0.35 ± 0.17
0.04
0.36
DRB1*09
45 (18.5)
0.34 ± 0.16
0.04
0.36
0.20 ± 0.17
0.23
0.58
DRB1*11
30 (12.3)
0.10 ± 0.20
0.61
0.85
-0.24 ± 0.19
0.22
0.58
DRB1*12
75 (30.9)
-0.28 ± 0.14
0.05
0.36
0.21 ± 0.14
0.13
0.52
DRB1*14
44 (18.1)
-0.08 ± 0.17
0.64
0.85
-0.01 ± 0.17
0.97
0.97
DRB1*15
100 (41.2)
-0.01 ± 0.13
0.96
0.97
0.07 ± 0.13
0.60
0.85
DRB1*04:05
26 (10.7)
0.29 ± 0.21
0.17
0.52
0.35 ± 0.21
0.09
0.50
DRB1*07:01
41 (16.9)
-0.07 ± 0.17
0.68
0.87
-0.31 ± 0.17
0.07
0.48
DRB1*12:02
70 (28.8)
-0.30 ± 0.14
0.04
0.36
0.15 ± 0.14
0.28
0.65
DRB1*15:01
34 (14.0)
0.20 ± 0.19
0.29
0.65
-0.10 ± 0.19
0.59
0.85
DRB1*15:02
69 (28.4)
-0.16 ± 0.14
0.25
0.63
0.20 ± 0.14
0.15
0.52
DQB1*02
57 (23.5)
-0.16 ± 0.15
0.30
0.65
-0.30 ± 0.15
0.05
0.36
DQB1*03
137 (56.4)
0.13 ± 0.13
0.33
0.68
0.03 ± 0.13
0.76
0.89
DQB1*04
21 (8.6)
0.11 ± 0.23
0.63
0.85
0.08 ± 0.23
0.72
0.88
DQB1*05
145 (59.7)
-0.17 ± 0.13
0.19
0.55
-0.02 ± 0.13
0.88
0.94
DQB1*06
49 (20.2)
0.12 ± 0.16
0.46
0.81
-0.14 ± 0.16
0.40
0.77
DQB1*03:01
87 (35.8)
0.08 ± 0.13
0.54
0.85
0.02 ± 0.13
0.88
0.94
DQB1*03:03
52 (21.4)
0.25 ± 0.16
0.10
0.50
0.16 ± 0.16
0.31
0.67
DQB1*05:01
57 (23.5)
-0.02 ± 0.15
0.90
0.95
0.39 ± 0.15
0.01
0.30
DQB1*05:02
87 (35.8)
-0.10 ± 0.13
0.46
0.81
-0.12 ± 0.13
0.38
0.75
DQB1*05:03
24 (9.9)
-0.09 ± 0.22
0.68
0.87
-0.15 ± 0.22
0.50
0.85
DQB1*06:01
39 (16.0)
0.08 ± 0.18
0.64
0.85
0.03 ± 0.18
0.87
0.94
DPB1*02
73 (30.2)
0.08 ± 0.14
0.53
0.85
-0.09 ± 0.14
0.50
0.85
DPB1*04
71 (29.3)
-0.20 ± 0.17
0.17
0.52
-0.30 ± 0.14
0.03
0.36
DPB1*05
85 (35.1)
-0.04 ± 0.14
0.75
0.89
0.05 ± 0.14
0.71
0.88
DPB1*13
77 (31.8)
0.18 ± 0.14
0.20
0.55
0.44 ± 0.14
0.002
0.09
DPB1*02:01
42 (17.4)
0.30 ± 0.17
0.08
0.50
-0.02 ± 0.17
0.92
0.95
DPB1*02:02
35 (14.5)
-0.14 ± 0.18
0.44
0.81
-0.27 ± 0.18
0.14
0.52
DPB1*04:01
54 (22.3)
-0.22 ± 0.15
0.15
0.52
-0.25 ± 0.15
0.10
0.50
Allele
* Previously reported values (3). † 201 HIV-1 uninfected individuals with complete DPB1 genotyping.
Table S3. High IgG binding to multiple Env (120–204) antigens correlates with presence of DPB1*13 and is associated with decreased HIV-1 acquisition across multiple subtypes. Antigen (HIV-1 subtype)*
Alias
DPB1*13 Association β ± SD
P
Antigen-DPB1*13 Interaction†
DPB1*13
Odds Ratio
P
(95% CI) Env 120–204–specific IgG (CRF01_AE)‡
Env 120–204–specific IgG (B)‡
Env 120–204–specific IgG (A)‡
Env 120–204–specific IgG (C)‡
Env 160–183–specific IgG (CRF01_AE)
Env 160–183–specific IgG (B)
AEA244V1V2Tags293F
gp70_BCaseA_V1_V2
gp70_A_GN
gp70_C_GN
BioRV144_V2_AE
BioRV144_V2_B
0.38 ± 0.14
0.45 ± 0.14
0.55 ± 0.13
0.42 ± 0.14
0.35 ± 0.14
0.19 ± 0.14
0.006
0.001
