IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis
Abstract Background Combination antiretroviral treatment (cART) cannot eradicate HIV-1 from the body due to the establishment of persisting viral reservoirs which are not affected by therapy and reinitiate new rounds of HIV-1 replication after treatment interruption. These HIV-1 reservoirs mainly co...
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2021
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oai:doaj.org-article:9d335b9fadb540eeb1f023c64679c30e2021-11-21T12:16:03ZIRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis10.1186/s12916-021-02156-51741-7015https://doaj.org/article/9d335b9fadb540eeb1f023c64679c30e2021-11-01T00:00:00Zhttps://doi.org/10.1186/s12916-021-02156-5https://doaj.org/toc/1741-7015Abstract Background Combination antiretroviral treatment (cART) cannot eradicate HIV-1 from the body due to the establishment of persisting viral reservoirs which are not affected by therapy and reinitiate new rounds of HIV-1 replication after treatment interruption. These HIV-1 reservoirs mainly comprise long-lived resting memory CD4+ T cells and are established early after infection. There is a high variation in the size of these viral reservoirs among virally suppressed individuals. Identification of host factors that contribute to or can explain this observed variation could open avenues for new HIV-1 treatment strategies. Methods In this study, we conducted a genome-wide quantitative trait locus (QTL) analysis to probe functionally relevant genetic variants linked to levels of cell-associated (CA) HIV-1 DNA, CA HIV-1 RNA, and RNA:DNA ratio in CD4+ T cells isolated from blood from a cohort of 207 (Caucasian) people living with HIV-1 (PLHIV) on long-term suppressive antiretroviral treatment (median = 6.6 years). CA HIV-1 DNA and CA HIV-1 RNA levels were measured with corresponding droplet digital PCR (ddPCR) assays, and genotype information of 522,455 single-nucleotide variants was retrieved via the Infinium Global Screening array platform. Results The analysis resulted in one significant association with CA HIV-1 DNA (rs2613996, P < 5 × 10−8) and two suggestive associations with RNA:DNA ratio (rs7113204 and rs7817589, P < 5 × 10−7). Then, we prioritized PTDSS2, IRF7, RNH1, and DEAF1 as potential HIV-1 reservoir modifiers and validated that higher expressions of IRF7 and RNH1 were accompanied by rs7113204-G. Moreover, RNA:DNA ratio, indicating relative HIV-1 transcription activity, was lower in PLHIV carrying this variant. Conclusions The presented data suggests that the amount of CA HIV-1 DNA and RNA:DNA ratio can be influenced through PTDSS2, RNH1, and IRF7 that were anchored by our genome-wide association analysis. Further, these observations reveal potential host genetic factors affecting the size and transcriptional activity of HIV-1 reservoirs and could indicate new targets for HIV-1 therapeutic strategies.Zhenhua ZhangWim TrypsteenMarc BlaauwXiaojing ChuSofie RutsaertLinos VandekerckhoveWouter van der HeijdenJéssica Cristina dos SantosCheng-Jian XuMorris A. SwertzAndre van der VenYang LiBMCarticleHIVCell-associated HIV-1 RNACell-associated HIV-1 DNAGenetic variantsQuantitative trait locusMedicineRENBMC Medicine, Vol 19, Iss 1, Pp 1-17 (2021) |
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| collection |
DOAJ |
| language |
EN |
| topic |
HIV Cell-associated HIV-1 RNA Cell-associated HIV-1 DNA Genetic variants Quantitative trait locus Medicine R |
| spellingShingle |
HIV Cell-associated HIV-1 RNA Cell-associated HIV-1 DNA Genetic variants Quantitative trait locus Medicine R Zhenhua Zhang Wim Trypsteen Marc Blaauw Xiaojing Chu Sofie Rutsaert Linos Vandekerckhove Wouter van der Heijden Jéssica Cristina dos Santos Cheng-Jian Xu Morris A. Swertz Andre van der Ven Yang Li IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis |
| description |
Abstract Background Combination antiretroviral treatment (cART) cannot eradicate HIV-1 from the body due to the establishment of persisting viral reservoirs which are not affected by therapy and reinitiate new rounds of HIV-1 replication after treatment interruption. These HIV-1 reservoirs mainly comprise long-lived resting memory CD4+ T cells and are established early after infection. There is a high variation in the size of these viral reservoirs among virally suppressed individuals. Identification of host factors that contribute to or can explain this observed variation could open avenues for new HIV-1 treatment strategies. Methods In this study, we conducted a genome-wide quantitative trait locus (QTL) analysis to probe functionally relevant genetic variants linked to levels of cell-associated (CA) HIV-1 DNA, CA HIV-1 RNA, and RNA:DNA ratio in CD4+ T cells isolated from blood from a cohort of 207 (Caucasian) people living with HIV-1 (PLHIV) on long-term suppressive antiretroviral treatment (median = 6.6 years). CA HIV-1 DNA and CA HIV-1 RNA levels were measured with corresponding droplet digital PCR (ddPCR) assays, and genotype information of 522,455 single-nucleotide variants was retrieved via the Infinium Global Screening array platform. Results The analysis resulted in one significant association with CA HIV-1 DNA (rs2613996, P < 5 × 10−8) and two suggestive associations with RNA:DNA ratio (rs7113204 and rs7817589, P < 5 × 10−7). Then, we prioritized PTDSS2, IRF7, RNH1, and DEAF1 as potential HIV-1 reservoir modifiers and validated that higher expressions of IRF7 and RNH1 were accompanied by rs7113204-G. Moreover, RNA:DNA ratio, indicating relative HIV-1 transcription activity, was lower in PLHIV carrying this variant. Conclusions The presented data suggests that the amount of CA HIV-1 DNA and RNA:DNA ratio can be influenced through PTDSS2, RNH1, and IRF7 that were anchored by our genome-wide association analysis. Further, these observations reveal potential host genetic factors affecting the size and transcriptional activity of HIV-1 reservoirs and could indicate new targets for HIV-1 therapeutic strategies. |
| format |
article |
| author |
Zhenhua Zhang Wim Trypsteen Marc Blaauw Xiaojing Chu Sofie Rutsaert Linos Vandekerckhove Wouter van der Heijden Jéssica Cristina dos Santos Cheng-Jian Xu Morris A. Swertz Andre van der Ven Yang Li |
| author_facet |
Zhenhua Zhang Wim Trypsteen Marc Blaauw Xiaojing Chu Sofie Rutsaert Linos Vandekerckhove Wouter van der Heijden Jéssica Cristina dos Santos Cheng-Jian Xu Morris A. Swertz Andre van der Ven Yang Li |
| author_sort |
Zhenhua Zhang |
| title |
IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis |
| title_short |
IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis |
| title_full |
IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis |
| title_fullStr |
IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis |
| title_full_unstemmed |
IRF7 and RNH1 are modifying factors of HIV-1 reservoirs: a genome-wide association analysis |
| title_sort |
irf7 and rnh1 are modifying factors of hiv-1 reservoirs: a genome-wide association analysis |
| publisher |
BMC |
| publishDate |
2021 |
| url |
https://doaj.org/article/9d335b9fadb540eeb1f023c64679c30e |
| work_keys_str_mv |
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