Abstract
BackgroundCombination 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.MethodsIn 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.ResultsThe 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.ConclusionsThe 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.
Highlights
Combination antiretroviral treatment cannot eradicate human immunodeficiency virus (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
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
CD4 nadir is not correlated with RNA:DNA ratio (ρ = − 0.03, False discovery rate (FDR) = 0.68), which indicates that the CD4 nadir correlates with both CA HIV-1 DNA and CA HIV-1 RNA levels in CD4+ T cells
Summary
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. CART does not eradicate HIV-1 from the body while the establishment of persisting viral reservoirs that are not affected by cART, can 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 [2]. Limited work was performed on genetic associations with cell-associated HIV-1 RNA (CA HIV-1 RNA) levels and the ratio of CA HIV-1 RNA to CA HIV-1 DNA (RNA:DNA ratio), the latter indicating (relative) HIV-1 reservoir transcription levels [15]
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