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

Mackelprang, Romel D.; Bamshad, Michael J.; Chong, Jessica X.; Hou, Xuanlin; Buckingham, Kati J.; Shively, Kathryn M.; deBruyn, Guy; Mugo, Nelly; Mullins, James I.; McElrath, M. Juliana; Baeten, Jared M.; Celum, Connie; Emond, Mary J.; Lingappa, Jairam R.; Study, Hiv Transmission

doi:10.1371/journal.ppat.1006703

Cited by 18 publications

(33 citation statements)

References 68 publications

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“…In order to determine whether less common variation was associated with KSHV and KS status, particularly since using a rather small patient cohort of n=150, we performed an aggregate analysis as in previous studies [43,44] in which we considered whether each participant carried ≥1 or 0 EPHA2 SNVs with MAF < 5%. Aggregate scores were determined for all SNVs across EPHA2 and for missense, synonymous and untranslated region (UTR) variants.…”

Section: Methodsmentioning

confidence: 99%

EPHA2 sequence variants are associated with susceptibility to Kaposi’s sarcoma-associated herpesvirus infection and Kaposi’s sarcoma prevalence in HIV-infected patients

Blumenthal

Schutz

Meintjes

et al. 2018

Cancer Epidemiology

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Section: Methodsmentioning

confidence: 99%

EPHA2 sequence variants are associated with susceptibility to Kaposi’s sarcoma-associated herpesvirus infection and Kaposi’s sarcoma prevalence in HIV-infected patients

Blumenthal

Schutz

Meintjes

et al. 2018

Cancer Epidemiology

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“…Non-HIV––seroconverting controls were selected for genotyping as those determined to have been exposed to HIV based on epidemiological quantification of HIV exposure. 7 , 13 Only women who were HIV negative at enrollment, randomized to the placebo arm (Partners PrEP), had CD101 genotyping data available, and had baseline risk scores were included in the analysis.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we demonstrated that a cluster of missense variants located in the immunoglobulin-like (Ig-like) domains of the CD101 gene are associated with a 4-fold increased risk of heterosexually acquired HIV among HIV-exposed Africans. 7 CD101 is a potential marker for activated mucosal tissue resident memory T cells 8 and is also thought to modulate regulatory T-cell suppression of tissue inflammation. 9 , 10 Given this documented relevance of CD101 for the regulation of mucosal inflammation and the association of CD101 variants with risk of HIV acquisition, we evaluated whether the impact of BV on HIV acquisition in women differs by the presence or absence of candidate CD101 Ig-like variants.…”

Section: Introductionmentioning

confidence: 99%

Brief Report: Bacterial Vaginosis and Risk of HIV Infection in the Context of CD101 Gene Variation

Wanga¹,

Mackelprang²,

Thomas³

et al. 2020

JAIDS Journal of Acquired Immune Deficiency Syndromes

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Background: Whether bacterial vaginosis (BV) and CD101 immunoglobulin-like (Ig-like) variants independently increase HIV risk through mucosal inflammation is not well understood. We evaluated whether the impact of BV on HIV acquisition in women differs by the presence or absence of candidate CD101 Ig-like variants. Methods: We used data from 2 studies of HIV serodiscordant couples in east (Kenya, Tanzania, and Uganda) and southern (Botswana, South Africa, and Zambia) Africa, which longitudinally assessed HIV acquisition (by ELISA) and BV (by Nugent score ≥7). We used previously generated CD101 sequence data for each case and control participant to create a binary variable indicating the presence/absence of any of 5 CD101 Ig-like variants. Results: Confirming previously shown results in this cohort, Ig-like variants increased HIV-infection risk (adjusted hazard ratio [aHR], = 2.63; 95% confidence interval [CI], 1.41 to 4.89). BV was associated with 2.5-fold higher HIV-infection risk only in the absence of Ig-like variants (aHR = 2.47; 95% CI, 0.99 to 6.15; P = 0.052), whereas in the presence of Ig-like variants, BV was not associated with higher HIV-infection risk (aHR = 0.87; 95% CI, 0.35 to 2.15; P = 0.765); however, a test for interaction was nonsignificant ( P = 0.116). Conclusions: We hypothesized that both BV and CD101 Ig-like variants facilitate HIV acquisition by augmenting similar genital inflammation pathways. Our findings indicate that inflammatory mucosal effects of Ig-like variants may influence the impact of BV on HIV risk. Host-defined inflammatory pathways may be useful targets for HIV prevention.

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“…Our study is the first to evaluate the role of rare-variants in susceptibility to HIV-1 and progression to disease in Botswana using a larger sample size (n = 236), comparing to a previous study that had a cohort of 100 participants from Southern and Eastern African combined (at most 10 samples from Botswana) (33). In our study, the cumulative effects of three sets of novel rare variants within the ANKRD39 (8.48 x 10 -8 ), LOC105378523 (7.45 x 10 -7 ) and GTF3C3 (1.36 x 10 -6 ) genes were significantly associated with HIV-1 progression ( Table 2).…”

Section: Discussionmentioning

confidence: 97%

Whole Genome Rare-Variant Association Study of HIV-1 Progression in a Southern African Population

Thami

Choga

Mulisa

et al. 2020

Preprint

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Despite the high burden of HIV-1 in Botswana, the population of Botswana is significantly underrepresentation in host genetics studies of HIV-1. Furthermore, the bulk of previous genomics studies evaluated common human genetic variations, however, there is increasing evidence of the influence of rare variants in the outcome of diseases which may be uncovered by comprehensive complete and deep genome sequencing. This research aimed to evaluate the role of rare-variants in susceptibility to HIV-1 and progression through whole genome sequencing. Whole genome sequences (WGS) of 265 HIV-1 positive and 125 were HIV-1 negative unrelated individuals from Botswana were mapped to the human reference genome GRCh38. Population joint variant calling was performed using Genome Analysis Tool Kit (GATK) and BCFTools. Cumulative effects of rare variant sets on susceptibility to HIV-1 and progression (CD4+ T-cell decline) were determined with optimized Sequence Kernel Association Test (SKAT-O). In silico functional analysis of the prioritized variants was performed through gene-set enrichment using databases in GeneMANIA and Enrichr. Novel rare-variants within the ANKRD39 (8.48 × 10−8), LOC105378523 (7.45 × 10−7) and GTF3C3 (1.36 × 10−6) genes were significantly associated with HIV-1 progression. Functional analysis revealed that these genes are involved in viral translation and transcription. These findings highlight the significance of whole genome sequencing in pinpointing rare-variants of clinical relevance. The research contributes towards a deeper understanding of the host genetics HIV-1 and offers promise of population specific interventions against HIV-1.

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

Cited by 18 publications

References 68 publications

EPHA2 sequence variants are associated with susceptibility to Kaposi’s sarcoma-associated herpesvirus infection and Kaposi’s sarcoma prevalence in HIV-infected patients

EPHA2 sequence variants are associated with susceptibility to Kaposi’s sarcoma-associated herpesvirus infection and Kaposi’s sarcoma prevalence in HIV-infected patients

Brief Report: Bacterial Vaginosis and Risk of HIV Infection in the Context of CD101 Gene Variation

Whole Genome Rare-Variant Association Study of HIV-1 Progression in a Southern African Population

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