SARS-CoV-2 RNA reverse-transcribed and integrated into the human genome

Abstract

SummaryProlonged SARS-CoV-2 RNA shedding and recurrence of PCR-positive tests have been widely reported in patients after recovery, yet these patients most commonly are non-infectious1–14. Here we investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the human genome and that transcription of the integrated sequences might account for PCR-positive tests. In support of this hypothesis, we found chimeric transcripts consisting of viral fused to cellular sequences in published data sets of SARS-CoV-2 infected cultured cells and primary cells of patients, consistent with the transcription of viral sequences integrated into the genome. To experimentally corroborate the possibility of viral retro-integration, we describe evidence that SARS-CoV-2 RNAs can be reverse transcribed in human cells by reverse transcriptase (RT) from LINE-1 elements or by HIV-1 RT, and that these DNA sequences can be integrated into the cell genome and subsequently be transcribed. Human endogenous LINE-1 expression was induced upon SARS-CoV-2 infection or by cytokine exposure in cultured cells, suggesting a molecular mechanism for SARS-CoV-2 retro-integration in patients. This novel feature of SARS-CoV-2 infection may explain why patients can continue to produce viral RNA after recovery and suggests a new aspect of RNA virus replication.

Host-virus chimeric events in SARS-CoV2 infected cells are infrequent and artifactual

“…We next quantified the reads that partly mapped to the human genome and partly mapped to the SARS-CoV2 genome (see methods ). We found that nearly 0.05-1% of all viral reads are formed of hybrid sequences between host and virus RNAs, a frequency consistent with that recently reported by others 15,16 ( Fig. 1C ).…”

“…RNA-sequencing reads that partly align to the host genome and partly align to the viral genome are the signature of HVC events in RNA-sequencing datasets. Recent reports 15,16 suggesting the presence of HVC events in SARS-CoV2-infected cells have been interpreted as supporting viral integration into the human genome as a mechanism of viral persistence. To gain insights into the authenticity of these events, we re-analyzed the 3 available RNA-seq datasets from patients with COVID-19 (n=57 samples) and in vitro SARS-CoV2 infected cells (n=64 samples).…”

“…In particular, relatively little is known about the processes following viral infection and why some individuals develop little to no symptoms, while others develop life-threatening or persistent (“long”) COVID-19. Recent studies have identified host-virus chimeric (HVC) reads in RNA-sequencing data from SARS-CoV2 infected cells and samples from COVID-19 patients 15,16 . Both studies have suggested that HVC events support potential “human genome invasion” and “integration” by SARS-CoV2.…”

Vaccines against Covid-19: Comparison, Limitations, the Decrease of Pandemic and the Perspective of Viral Respiratory

“…Рекомбинация мРНК ретротранспозонов и РНК экзогенного неретровируса приводит к интеграции комплементарной к ней ДНК в геном [23], поэтому включение информации о mРНКвакцине в геном прививаемого не представляется невозможным. Применительно к SARS-Cov-2 в условиях in vitro уже подтверждено включение его генома в геном человека [30].…”

First Response

“…It is already clear, though mobile and exchangeable, that the human microbiome is part of our functional body (Ogunrinola et al 2020) and that a change in the microbiome, as well as viral gene transfer, is transformative to the body. At the time of writing there exists only a preprint of a yet-to-be-peer-reviewed paper about SARS-CoV-2 RNA fragments in the human genome (Zhang et al 2020) and little can be said about any consequences. However, it points towards the possibility of a deep future of the virus as part of the human genome.…”