Whole genome sequencing of extreme phenotypes identifies variants in CD101 and UBE2V1 associated with increased risk of sexually acquired HIV-1

Abstract

Host genetic variation modifying HIV-1 acquisition risk can inform development of HIV-1 prevention strategies. However, associations between rare or intermediate-frequency variants and HIV-1 acquisition are not well studied. We tested for the association between variation in genic regions and extreme HIV-1 acquisition phenotypes in 100 sub-Saharan Africans with whole genome sequencing data. Missense variants in immunoglobulin-like regions of CD101 and, among women, one missense/5' UTR variant in UBE2V1, were associated with increased HIV-1 acquisition risk (p = 1.9x10-4 and p = 3.7x10-3, respectively, for replication). Both of these genes are known to impact host inflammatory pathways. Effect sizes increased with exposure to HIV-1 after adjusting for the independent effect of increasing exposure on acquisition risk.

Trial registration: ClinicalTrials.gov NCT00194519; NCT00557245.

Conflict of interest statement

The authors have declared that no competing interests exist.

Figures

Fig 1. Genomic structure of CD101 and UBE2V1, by-variant association significance, Primary Replication Variants, and protein features.

Panel A: The Manhattan plot positioned below the chromosomal region map captures by-variant association significance for all single nucleotide variants (SNVs) present in CD101 for both Discovery and Replication stage samples (red dots indicate the–log10(p) value for Discovery stage, and blue dots for Replication stage). rsIDs are shown below exon symbols only for the 5 Ig-like domain variants for CD101 and the single 3’-UTR variant for UBE2V1 that were associated with HIV-1 acquisition in the Replication analysis. The remaining Primary Replication Variants (PRVs) are indicated as “var”. The rsIDs for the CD101 PRVs are: var2 = rs142460852, var7 = rs12097758, var8 = rs12067543, var9 = rs34248572, var10 = rs150494742, var11 = novel, var12 = rs2296448, var13 = novel, and var14 = rs35163967. Panel B: The Discovery and Replication stage SNVs for UBE2V1. rsIDs are shown below the single 3’-UTR variant (rs6095771) that was associated with HIV-1 acquisition risk in the Replication analysis. The remaining Primary Replication Variants (PRVs) are indicated as “var”. The rsIDs for the UBE2V1 PRVs are: var1 = rs186621934, var2 = rs115164526, var3 = rs6095755, var4 = rs41283596, var5 = rs187204768, var6 = rs193169918, var7 = rs372425380, var9 = rs73278517, var10 = novel, var11 = rs185632114.

Fig 2. Time to seroconversion by Protected sex Index (PI) and tertiles of partner HIV-1 viral load distribution.

The protected sex index (PI) is the proportion of visits at which the female partner reported always having protected sexual intercourse with the HIV-1 infected partner (= 1 –proportion of interviews with reported unprotected sex by the female partner.) The figures show time to seroconversion stratified by tertiles of plasma viral load of the HIV-1 infected partners in log10 copies/mL: Low = (0, 3.8], Medium = (3.8, 4.5], and High = (4.5,8]. Panels show this relationship for by PI strata: Panel A: PI = (0, 0.3], Panel B: PI = (0.3 to 0.6], Panel C: PI = (0.6 to 1.0), and Panel D: PI = 1.0. PI shows reasonable accuracy in predicting overall risk of seroconversion, indicating this variable can be used to eliminate individuals with probably little or no exposure from the study samples although a few more highly exposed individuals might also be dropped from the analysis.

Fig 3. Results of Primary Replication Variant group tests for CD101 and UBE2V1.

Panel A: CD101 Primary Replication Variant (PRV) groups—All three PRV groups present in the Replication stage are shown in the Kaplan-Meier plot. The CD101 Ig-like PRV group is significantly associated with a higher rate of seroconversion after adjustment for multiple testing (p = 1.9 x 10−4), while the 3’-UTR and cytoplasmic PRV tests were not significant. Panel B:UBE2V1 PRV groups—Four variants with False Discovery Rates (FDRs) < 0.05 in a by-variant analysis of Replication stage variants were grouped (red) for visual exploration of effect size. Panel C: CD101 PRVs by FDR grouping–CD101 variants grouped by observed FDR in Replication stage. Panel D: UBE2V1 UTR-5’ PRV, Females—The hazard ratio for presence of the minor allele for rs6095771 in females is shown, which is significant after adjustment for four tests (two variant groups and two sexes, HR = 6.4, nominal p = 1.2x10-3, adjusted p = 4.8x10-3).

Fig 4. Estimated hazard ratio by Protective Index (PI) cut-off defining the analysis sample.

Panel A: CD101 Ig-like missense variant group hazard ratio (HR) estimate increases with increased sexual exposure among the individuals from the augmented sample; Panel B: UBE2V1 5’-UTR Primary Replication Variant HR estimate increases with sexual exposure among the individuals from the augment sample. Two variants contribute to this analysis; see S7 Table. Numbers at the top of each plot indicate total sample size (N) included at that level of the plot, and the p-value (P) for the reported HR.