Host variation in type I interferon signaling genes (MX1),CCR5Δ32, and MHC class I alleles in treated HIV+ non-controllers predict viral reservoir size

Siegel, David; Thanh, Cassandra; Wan, Eunice; Hoh, Rebecca; Hobbs, Kristen; Pan, Tony; Gibson, Erica A.; Kroetz, Deanna L.; Hunt, Peter W.; Marin, Jeffrey; Hecht, Frederick; Pilcher, Christopher D.; Milush, Jeffrey M.; Martin, Maureen P.; Carrington, Mary; Pillai, Satish K.; Busch, Michael P.; Stone, Mars; Huang, Meei‐Li; Roychoudhury, Pavitra; Haworth, Kevin G.; Jerome, Keith R.; Kiem, Hans–Peter; Henrich, Timothy J.; Deeks, Steven G.; Lee, Sulggi

doi:10.1101/2021.10.31.466670

Cited by 3 publications

(1 citation statement)

References 181 publications

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“…Prior host genome wide association studies (GWAS) have focused on predictors of viral control (during untreated HIV disease), identifying key mutations in the C-C chemokine receptor type 5 gene (CCR5Δ32) and the human Major Histocompatibility Complex (MHC) human leukocyte antigen (HLA)-B and -C regions, that influence viral setpoint [21][22][23][24]. Recently our group reported these mutations (CCR5Δ32 and HLA -B*57:01) are associated with smaller HIV reservoir size [25]. However, mRNA expression from DNA variation is complex and not strictly 1:1 DNA to RNA transcription; gene expression is influenced by various factors (alternative splicing, polyadenylation, regulatory enhancers, epigenetic changes, etc.)…”

Section: Introductionmentioning

confidence: 99%

A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size

Dwivedi,

Gornalusse,

Siegel

et al. 2023

PLoS Pathog

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The major barrier to an HIV cure is the HIV reservoir: latently-infected cells that persist despite effective antiretroviral therapy (ART). There have been few cohort-based studies evaluating host genomic or transcriptomic predictors of the HIV reservoir. We performed host RNA sequencing and HIV reservoir quantification (total DNA [tDNA], unspliced RNA [usRNA], intact DNA) from peripheral CD4+ T cells from 191 ART-suppressed people with HIV (PWH). After adjusting for nadir CD4+ count, timing of ART initiation, and genetic ancestry, we identified two host genes for which higher expression was significantly associated with smaller total DNA viral reservoir size, P3H3 and NBL1, both known tumor suppressor genes. We then identified 17 host genes for which lower expression was associated with higher residual transcription (HIV usRNA). These included novel associations with membrane channel (KCNJ2, GJB2), inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10), and innate immunity (TLR7) genes (FDR-adjusted q<0.05). Gene set enrichment analyses further identified significant associations of HIV usRNA with TLR4/microbial translocation (q = 0.006), IL-1/NRLP3 inflammasome (q = 0.008), and IL-10 (q = 0.037) signaling. Protein validation assays using ELISA and multiplex cytokine assays supported these observed inverse host gene correlations, with P3H3, IL-10, and TNF-α protein associations achieving statistical significance (p<0.05). Plasma IL-10 was also significantly inversely associated with HIV DNA (p = 0.016). HIV intact DNA was not associated with differential host gene expression, although this may have been due to a large number of undetectable values in our study. To our knowledge, this is the largest host transcriptomic study of the HIV reservoir. Our findings suggest that host gene expression may vary in response to the transcriptionally active reservoir and that changes in cellular proliferation genes may influence the size of the HIV reservoir. These findings add important data to the limited host genetic HIV reservoir studies to date.

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Section: Introductionmentioning

confidence: 99%

A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size

Dwivedi,

Gornalusse,

Siegel

et al. 2023

PLoS Pathog

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Viral and Host Biomarkers of HIV Remission Post Treatment Interruption

Giron

Abdel‐Mohsen

2022

Curr HIV/AIDS Rep

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Acknowledgments: MA-M is funded by Bill & Melinda Gates Foundation, Campbell Foundation, the Foundation for AIDS Research (amfAR), and the NIH grants (R01AI165079, R01NS117458, R01DK123733, R01AG062383, and P30 AI 045008). MA-M and L.B.G are members of the investigation team of the NIH-funded BEAT-HIV Martin Delaney Collaboratory to cure HIV-1 infection (UM1AI164570). : LBG is funded by AIDS Clinical Trials Group (NWCS 539). Rachel E. Locke, Ph.D., provided critical comments and editing. We would like to thank

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Differences in expression of tumor suppressor, innate immune, inflammasome, and potassium/gap junction channel host genes significantly predict viral reservoir size during treated HIV infection

Dwivedi

Siegel

Thanh

et al. 2023

Preprint

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The major barrier to an HIV cure is the persistence of infected cells that evade host immune surveillance despite effective antiretroviral therapy (ART). Most prior host genetic HIV studies have focused on identifying DNA polymorphisms (e.g., CCR5Δ32, MHC class I alleles) associated with viral load among untreated "elite controllers" (~1% of HIV+ individuals who are able to control virus without ART). However, there have been few studies evaluating host genetic predictors of viral control for the majority of people living with HIV (PLWH) on ART. We performed host RNA sequencing and HIV reservoir quantification (total DNA, unspliced RNA, intact DNA) from peripheral CD4+ T cells from 191 HIV+ ART-suppressed non-controllers. Multivariate models included covariates for timing of ART initiation, nadir CD4+ count, age, sex, and ancestry. Lower HIV total DNA (an estimate of the total reservoir) was associated with upregulation of tumor suppressor genes NBL1 (q=0.012) and P3H3 (q=0.012). Higher HIV unspliced RNA (an estimate of residual HIV transcription) was associated with downregulation of several host genes involving inflammasome (IL1A, CSF3, TNFAIP5, TNFAIP6, TNFAIP9, CXCL3, CXCL10) and innate immune (TLR7) signaling, as well as novel associations with potassium (KCNJ2) and gap junction (GJB2) channels, all q<0.05. Gene set enrichment analyses identified significant associations with TLR4/microbial translocation (q=0.006), IL-1b/NRLP3 inflammasome (q=0.008), and IL-10 (q=0.037) signaling. HIV intact DNA (an estimate of the "replication-competent" reservoir) demonstrated trends with thrombin degradation (PLGLB1) and glucose metabolism (AGL) genes, but data were (HIV intact DNA detected in only 42% of participants). Our findings demonstrate that among treated PLWH, that inflammation, innate immune responses, bacterial translocation, and tumor suppression/cell proliferation host signaling play a key role in the maintenance of the HIV reservoir during ART. Further data are needed to validate these findings, including functional genomic studies, and expanded epidemiologic studies in female, non-European cohorts.

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Host variation in type I interferon signaling genes (MX1),CCR5Δ32, and MHC class I alleles in treated HIV+ non-controllers predict viral reservoir size

Cited by 3 publications

References 181 publications

A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size

A cohort-based study of host gene expression: tumor suppressor and innate immune/inflammatory pathways associated with the HIV reservoir size

Viral and Host Biomarkers of HIV Remission Post Treatment Interruption

Differences in expression of tumor suppressor, innate immune, inflammasome, and potassium/gap junction channel host genes significantly predict viral reservoir size during treated HIV infection

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