From the 3997 SHCS patients with both HLA-I data and drug resistance testing data, 5561 potential combinations of HLA-I type and DRMs were examinable, from which only 225 had sufficient power for …
Of the three candidate DRM:HLA type pairs, one pair, RT-E138:HLA-B18, indicates a significant interaction term between the presence of the queried HLA type and the duration of HIV infection in a …
(A) Cox proportional hazard ratios for developing the queried drug-resistant mutation with the queried HLA-I type. (B, C) Cumulative hazard plots of the two pairs from (A) where the hazard ratios …
Overview of general characteristics of SHCS patients and the subsets with sequencing resistance testing data, HLA-I data, and both. IQR: interquartile range; MSM: men who have sex with men; HET: …
All SHCS participants | SHCS patients with resistance testing data | SHCS patients with HLA-I data | SHCS patients with HLA-I and resistance testing data | |
---|---|---|---|---|
Number | 20,741 | 13,116 | 6450 | 3997 |
Median age (IQR) | 56 (48–62) | 54 (47–60) | 55 (49–62) | 54 (47–60) |
Male (%) | 15,064 (72.6%) | 9402 (71.2%) | 4836 (75.0%) | 3027 (75.7%) |
Risk group: MSM | 8100 (39.1%) | 5226 (39.8%) | 2777 (43.1%) | 1784 (44.6%) |
HET | 6841 (33.0%) | 4731 (36.1%) | 2173 (33.7%) | 1439 (36.0%) |
IDU | 4840 (23.3%) | 2568 (19.6%) | 1255 (19.5%) | 620 (15.5%) |
Other | 960 (4.6%) | 591 (4.5%) | 245 (3.8%) | 154 (3.9%) |
White (%) | 14044 (67.7%) | 9993 (76.2%) | 5661 (87.8%) | 3487 (87.2%) |
Ten most common HLA-A, -B, and -C types in study population individuals with both HLA-I and DRM information. Frequency and percentage of individuals with each allele are indicated. DRM, …
HLA-A type | Frequency | Percentage |
---|---|---|
02 | 1838 | 46.0 |
03 | 964 | 24.1 |
01 | 857 | 21.4 |
24 | 668 | 16.7 |
11 | 493 | 12.3 |
68 | 340 | 8.5 |
32 | 302 | 7.6 |
30 | 300 | 7.5 |
26 | 272 | 6.8 |
29 | 261 | 6.5 |
HLA-B type | Frequency | Percentage |
44 | 905 | 22.6 |
07 | 814 | 20.4 |
35 | 729 | 18.2 |
51 | 639 | 16.0 |
15 | 582 | 14.6 |
08 | 500 | 12.5 |
40 | 410 | 10.3 |
18 | 376 | 9.4 |
57 | 328 | 8.2 |
27 | 294 | 7.4 |
HLA-C type | Frequency | Percentage |
07 | 1794 | 44.9 |
04 | 941 | 23.5 |
03 | 812 | 20.3 |
06 | 772 | 19.3 |
12 | 510 | 12.8 |
05 | 485 | 12.1 |
02 | 401 | 10.0 |
16 | 341 | 8.5 |
01 | 328 | 8.2 |
15 | 320 | 8.0 |
Ten most common DRMs from the earliest available resistance testing of the study population, with the frequency and percentage of each among the study population indicated. Specific amino acid …
Gene | Specific DRM | Frequency | Percentage |
---|---|---|---|
RT-E138 | AGKQ | 145 | 3.63 |
RT-T215 | ACDEFILNSVY | 132 | 3.30 |
RT-V106 | AIM | 95 | 2.38 |
RT-V179 | DEF | 82 | 2.05 |
RT-M41 | L | 72 | 1.80 |
PR-M46 | ILV | 47 | 1.18 |
RT-K103 | NS | 46 | 1.15 |
RT-K219 | ENQR | 34 | 0.85 |
RT-D67 | EGN | 34 | 0.85 |
RT-M184 | IV | 30 | 0.75 |
Summary of HLA–drug-resistant mutation pairs in all three approaches. Methods that corroborate the HLA–mutation relationship are indicated by ‘yes.’ DRM, drug-resistant mutation; HLA, human …
DRM:HLA pair | Interaction term in cross-sectional logistic regression | Longitudinal/ survival analysis | Mechanistic plausibility |
---|---|---|---|
RT-E138:HLA-B18 | Yes | Yes | Yes |
RT-E138:HLA-A24 | No | No | No |
RT-V179:HLA-B35 | No | Yes | Yes |
Data files with select anonymized variables necessary for producing main figures.
Overview of Benjamini–Hochberg adjustment of DRM:HLA candidate pairs.
Overview of the Benjamini–Hochberg procedure to correct for multiple testing in selecting HLA–mutation pairs. Pairs were ranked by the p-value of the HLA term in the adjusted logistic regression model predicting for the queried mutation. The numerical rank (I) is divided by the total number of pairs (m = 225) and multiplied by the false discovery rate of 0.2 (Q). With this adjustment, the lowest-ranked pairs where the p-value is lower than (I/m)Q, along with all pairs ranked above, are included after the adjustment (in bold in the table), yielding the three candidate pairs we investigated in-depth (in bold). Only the first 25 rows of the total 225 are shown.
Table of NetMHCpan predictions of top binding peptides for each HLA–DRM candidate pair.
For each HLA–mutation pair, the binding peptides (defined as below a rank of 2% for weakly binding and below 0.5% for strongly binding) are listed ranked in decreasing predicted binding strength according to NetMHCpan. Peptides in bold denote the peptides without the mutation that bind more strongly than all other peptides for that position in the viral amino acid sequence. Peptides in bold and italics denote peptides without the mutation that bind more weakly than a mutated form.