A*02:01 46.79 B*35:01 11.97 B*42:02 0.85 C*04:01 37.61 3DL3 97.67A*24:02 19.44 B*51:01 10.47 B*51:13 0.85 C*07:02 29.27 3DL2 99.61A*02:11 18.59 B*15:04 9.62 B*14:01 0.64 C*01:02 21.58 3DP1 100.00A*31:01 10.26 B*44:03 9.19 B*15:10 0.64 C*03:04 18.80 2DL4 99.61A*68:01 9.62 B*48:01 9.19 B*15:17 0.64 C*07:01 9.62 2DL1 97.27A*03:01 7.69 B*35:05 8.97 B*35:11 0.64 C*08:02 8.55 2DL3 95.26A*01:01 7.48 B*14:02 7.48 B*35:19 0.64 C*15:02 8.55 3DL1 96.89A*29:02 6.84 B*40:04 7.26 B*37:01 0.64 C*06:02 7.48 2DS4f 78.60A*02:22 6.62 B*39:05 7.05 B*40:08 0.64 C*16:01 6.84 2DS4d 52.34A*30:02 5.34 B*40:02 7.05 B*41:01 0.64 C*05:01 6.62 2DP1 97.67A*11:01 4.91 B*07:02 6.62 B*51:08 0.64 C*08:01 6.20 2DL2 48.82A*33:01 4.70 B*18:01 5.13 B*07:05 0.43 C*12:03 6.20 2DL5 44.14A*23:01 4.06 B*39:06 5.13 B*15:16 0.43 C*08:03 5.13 2DS1 35.94A*26:01 3.85 B*44:02 5.13 B*27:02 0.43 C*02:02 3.21 2DS2 45.67A*68:02 2.78 B*15:01 4.91 B*27:03 0.43 C*03:03 2.78 2DS3 15.56A*32:01 2.56 B*35:09 4.91 B*35:20 0.43 C*17:01 2.35 2DS5 35.41A*02:05 2.35 B*39:09 4.91 B*35:21 0.43 C*14:02 1.92 3DS1 35.94A*30:01 2.35 B*35:43* 4.49 B*39:12 0.43 C*02:10* 1.28A*33:03 2.35 B*08:01 3.63 B*40:06 0.43 C*03:05* 1.07A*02:13 1.71 B*39:01 3.63 B*44:04 0.43 C*12:02 1.07A*68:17 1.71 B*49:01 3.63 B*46:01 0.43 C*16:02 1.07A*24:53* 1.50 B*38:01 2.99 B*48:02 0.43 C*03:02 0.85A*25:01 1.28 B*35:22 2.56 B*48:12* 0.43 C*15:05* 0.85A*24:03 1.07 B*53:01 2.56 B*58:02 0.43 C*07:04 0.64A*02:04 0.85 B*52:01 2.35 B*13:09* 0.21 C*18:01 0.64A*02:07 0.85 B*58:01 2.14 B*15:02 0.21 C*07:06* 0.43A*74:01 0.85 B*13:02 1.92 B*15:08 0.21 C*14:03 0.43A*01:02 0.64 B*39:14 1.92 B*15:18 0.21 C*05:09* 0.21A*02:64 0.64 B*15:03 1.71 B*15:24 0.21 C*08:04 0.21A*24:25* 0.64 B*35:03 1.71 B*18:03 0.21 C*08:09* 0.21A*34:02 0.64 B*35:06 1.71 B*38:02 0.21 C*08:11* 0.21A*66:01 0.64 B*39:03 1.71 B*39:02 0.21 C*15:06* 0.21A*80:01 0.64 B*50:01 1.71 B*39:08 0.21 C*16:04 0.21A*02:02 0.43 B*45:01 1.50 B*39:22* 0.21A*02:03 0.43 B*57:01 1.50 B*40:01 0.21A*29:01 0.43 B*15:39 1.28 B*41:02 0.21A*31:02* 0.43 B*57:03 1.28 B*44:05 0.21A*36:01 0.43 B*35:02 1.07 B*48:06* 0.21A*68:03 0.43 B*35:04 1.07 B*51:07 0.21A*02:39* 0.21 B*35:10 1.07 B*51:31* 0.21

A*02:105* 0.21 B*39:13* 1.07 B*51:34* 0.21A*03:02 0.21 B*42:01 1.07 B*52:02* 0.21A*11:02 0.21 B*55:01 1.07 B*54:01 0.21A*23:02 0.21 B*15:05 0.85 B*56:01 0.21A*24:01 0.21 B*27:05 0.85 B*78:04* 0.21A*26:03 0.21 B*35:08 0.85 B*81:01 0.21A*66:03 0.21A*68:27* 0.21A*69:01 0.21

Population Frequency (%)HLA locus KIR genes

HLA-A HLA-B HLA-C

Supplementary Table 1

Table S1. Population frequency of HLA -A, -B and -C alleles. Rare alleles (frequency < 0.5%) are highlighted by a grey background and alleles not listed in the Alleles Frequency Net Database (www.allelefrequency.com) in any South American population are indicated by *. KIR gene population frequencies are also included. KIR framework genes are highlighted by bold type red letters while genes determining group A haplotype are highlighted by bolded black letters.

Supplementary Table 2

Table S2. KIR genes associated with differences in median viral loads or CD4 counts. Only those genes showing statistical significant differences are shown (p<0.05, Mann-Whitney test). Only KIR2DS4f shows statistically significant association with viral load differences without being limited by low number of negative individuals. IQR: interquartile range, CI: confidence interval.

KIR N

log10 Viral Load Median

log10 Viral Load IQR

log10 Viral Load 95% CI p q

KIR2DL1 - 4 5.580 5.497-5.705 5.393-5.754 0.0036 0.0504+ 165 4.718 4.239-5.101 4.482-4.713

KIR2DP1 - 3 5.596 n.a. 5.437-5.806 0.0093 0.0650+ 166 4.718 4.239-5.115 4.525-4.793

KIR2DS4f - 37 4.517 4.077-4.764 4.236-4.681 0.0437 0.2040+ 132 4.778 4.298-5.219 4.525-4.793

Population 169 4.727 4.256-5.145 4.500-4.731

KIR NCD4 Count

Median CD4 Count

IQRCD4 Count

95% CI p q

KIR2DS1 - 99 365 275-505 374-452 0.0291 0.1472+ 69 419 330-536 411-482

Population 169 380 309-529 400-454

C*01:02

HIV+ (%)

HIV- (%)

0

2

4

6

8

10

B*40:02 B*35:43 A*23:01 B*57:03

HLA Allotype

Pop

ula

tion

Fre

qu

ency

(%

)

0

2

4

6

8

10

B*48:01

C*03:04

A*24:02

B*40:02

A*31:01

C*15:02

A*02:22

B*35:09

B*35:43

HLA 2-locus Haplotypes

0

5

10

15

20

25

30

2DL3B*50:01

2DL1B*50:01

2DP1B*50:01

2DS3A*02:01

2DS2A*02:01

2DS4C*16:01

HLA Alelle - KIR gene combination

Pop

ula

tion

Fre

qu

ency

(%

)

HIV+<HIV- HIV+>HIV-

HIV+<HIV- HIV+>HIV-

HIV+<HIV- HIV+>HIV-

p=0.029

p=0.020

p=0.012

p=0.031

p=0.005

p=0.008

p=0.024p=0.050

p=0.012

p=0.029 p=0.031 p=0.032

p=0.003

p=0.038

p=0.042

Figure S1. HLA alleles and KIR genes association with HIV infection. Cohort frequencies (%) of individual HLA alleles, 2 HLA allele haplotypes and HLA-KIR combinations showing statistically significant differences between HIV infected (HIV+) or HIV uninfected (HIV-) individuals (p-values <0.05, Fisher’s exact test).

300 600 900 1200

A*30:02-B*57:03A*30:02-C*07:01B*57:03-C*07:01A*30:02-B*52:01A*02:11-B*39:14A*02:11-C*08:01A*11:01-B*51:01A*11:01-C*08:01A*31:01-C*03:04A*30:02-C*03:04A*03:01-C*06:02A*24:02-C*16:01A*03:01-C*01:02B*39:14-C*07:02A*02:22-B*35:43A*02:22-C*01:02A*02:11-B*40:04A*02:11-C*03:04B*39:03-C*07:02A*30:02-C*07:02B*15:16-C*14:02B*39:13-C*07:02B*40:04-C*03:04B*39:05-C*07:02A*31:01-C*07:02A*24:02-B*40:04B*48:01-C*04:01A*02:01-B*39:05A*02:11-B*39:09B*35:05-C*04:01A*02:01-C*07:01A*02:01-C*04:01B*35:01-C*04:01A*02:01-B*35:01A*30:02-C*04:01B*35:09-C*04:01A*02:01-B*35:09B*08:01-C*07:01B*40:02-C*04:01A*31:01-B*39:14B*35:01-C*07:02

CD4 Counts

2-l

ocu

s H

aplo

typ

e

1 2 3 4 5 6

log10 Viral Load

0 5 10 15 20 25

Population Frequency (%)

Mann-Whitneyp=0.0044

***

**

**

**

****

A*30:02-B*57:03A*30:02-C*07:01B*57:03-C*07:01A*30:02-B*52:01A*02:11-B*39:14A*02:11-C*08:01A*11:01-B*51:01A*11:01-C*08:01A*31:01-C*03:04A*30:02-C*03:04A*03:01-C*06:02A*24:02-C*16:01A*03:01-C*01:02B*39:14-C*07:02A*02:22-B*35:43A*02:22-C*01:02A*02:11-B*40:04A*02:11-C*03:04B*39:03-C*07:02A*30:02-C*07:02B*15:16-C*14:02B*39:13-C*07:02B*40:04-C*03:04B*39:05-C*07:02A*31:01-C*07:02A*24:02-B*40:04B*48:01-C*04:01A*02:01-B*39:05A*02:11-B*39:09B*35:05-C*04:01A*02:01-C*07:01A*02:01-C*04:01B*35:01-C*04:01A*02:01-B*35:01A*30:02-C*04:01B*35:09-C*04:01A*02:01-B*35:09B*08:01-C*07:01B*40:02-C*04:01A*31:01-B*39:14B*35:01-C*07:02

Figure S2. Viral load and CD4 counts association with HLA haplotypes. Viral load and CD4 counts were compared between HIV positive (HIV+) subjects expressing a particular 2-locus HLA haplotype (2HLA). Only 2HLA combinations showing significant differences (p<0.05 in the Mann-Whitney test) in viral loads or CD4 counts are shown. For each 2HLA, the distribution of CD4 counts is shown in the left panel, viral load in the middle panel and cohort frequency (%) in the right hand panel. 2HLA are ordered by median viral load in individuals carrying both alleles. Alleles with statistically significant (p<0.05) differences are highlighted by red box-plot if they are associated with higher viral loads or lower CD4 counts and with green box-plots if they were associated with either lower viral load or higher CD4 counts. Boxes indicate the median 25th and 75th quartile and whiskers the upper and lower range limits. 2HLA with p-values below 0.01 are indicated by ** and with p-values below 0.001 by ***. HIV+ individuals under treatment (N=11) were excluded from the analysis. The CD4 counts and median viral loads of the entire HIV+ cohort are indicated by the vertical dashed lines in the left and middle panels. Median population frequencies were compared among 2HLA showing higher or lower median viral loads or CD4 counts.