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

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 o...

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Published in:	AIDS research and therapy Vol. 21; no. 1; pp. 27 - 14
Main Authors:	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, Murray, Daniel D
Format:	Journal Article
Language:	English
Published:	England BioMed Central Ltd 03-05-2024 BioMed Central BMC
Subjects:	Adult Analysis Antiretroviral agents Antiretroviral therapy Antiviral agents Biological response modifiers Care and treatment CD4 antigen CD4 Lymphocyte Count CD8 antigen Cohort Studies Cohorts Complications and side effects Cytokines Development and progression Diagnosis Disease Progression Female Genes Genetic aspects Genomes Genotype Genotypes Health aspects Highly active antiretroviral therapy HIV HIV (Viruses) HIV Infections - genetics HIV Infections - immunology HIV Infections - virology HIV-1 HIV-1 - genetics Host genetics Human immunodeficiency virus Humans Immune system Infection Infections Interferon Interferon Type I - genetics Lymphocytes T Male Medical research Medicine, Experimental Middle Aged Nucleotides Pathway analysis Patient outcomes Polymorphism, Single Nucleotide Population structure Quality control Receptor, Interferon alpha-beta - genetics Sensitivity analysis Single nucleotide polymorphisms Single-nucleotide polymorphism SKAT-O Subgroups T cells Type 1 interferon Viral infections Viral Load United States Africa HIV-1 Pathway analysis Host genetics Type 1 interferon SKAT-O Viral load
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Summary:	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). 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). 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. 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1742-6405 1742-6405
DOI:	10.1186/s12981-024-00610-x