The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants

Authors

Sara Bohnstedt Mørup, Centre of Excellence for Health, Immunity, and Infections, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Preston Leung, Centre of Excellence for Health, Immunity, and Infections, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Cavan Reilly, Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Brad T. Sherman, Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Weizhong Chang, Laboratory of Human Retrovirology and Immunoinformatics, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
Maja Milojevic, Centre of Excellence for Health, Immunity, and Infections, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Ana Milinkovic, Chelsea and Westminster Hospital NHS Foundation Trust, London, UK.
Angelike Liappis, Washington DC Veterans Affairs Medical Center and The George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
Line Borgwardt, Center for Genomic Medicine, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Kathy Petoumenos, Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia.
Roger Paredes, Department of Infectious Diseases and IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
Shweta S. Mistry, Division of Biostatistics and Health Data Science, School of Public Health, University of Minnesota, Minneapolis, MN, USA.
Cameron R. MacPherson, Centre of Excellence for Health, Immunity, and Infections, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Jens Lundgren, Centre of Excellence for Health, Immunity, and Infections, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Marie Helleberg, Centre of Excellence for Health, Immunity, and Infections, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Joanne Reekie, Centre of Excellence for Health, Immunity, and Infections, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Daniel D. Murray, Centre of Excellence for Health, Immunity, and Infections, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark. daniel.dawson.murray@regionh.dk.

Document Type

Journal Article

Publication Date

5-3-2024

Journal

AIDS research and therapy

Volume

21

Issue

1

DOI

10.1186/s12981-024-00610-x

Keywords

SKAT-O; HIV-1; Host genetics; Pathway analysis; Type 1 interferon; Viral load

Abstract

BACKGROUND: Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL). METHODS: Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025). RESULTS: The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460-45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4 T-cell count, CD4/CD8 T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants. CONCLUSION: Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.

APA Citation

Mørup, Sara Bohnstedt; Leung, Preston; Reilly, Cavan; Sherman, Brad T.; Chang, Weizhong; Milojevic, Maja; Milinkovic, Ana; Liappis, Angelike; Borgwardt, Line; Petoumenos, Kathy; Paredes, Roger; Mistry, Shweta S.; MacPherson, Cameron R.; Lundgren, Jens; Helleberg, Marie; Reekie, Joanne; and Murray, Daniel D., "The association between single-nucleotide polymorphisms within type 1 interferon pathway genes and human immunodeficiency virus type 1 viral load in antiretroviral-naïve participants" (2024). GW Authored Works. Paper 4981.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/4981

Department

Medicine