Human Endogenous Retrovirus (HERV) Transcriptome Is Dynamically Modulated during SARS-CoV-2 Infection and Allows Discrimination of COVID-19 Clinical Stages.

SARS-CoV-2 infection is known to trigger an important inflammatory response, which has a major role in COVID-19 pathogenesis. In infectious and inflammatory contexts, the modulation of human endogenous retroviruses (HERV) has been broadly reported, being able to further sustain innate immune responses due to the expression of immunogenic viral transcripts, including double-stranded DNA (dsRNA), and eventually, immunogenic proteins. To gain insights on this poorly characterized interplay, we performed a high-throughput expression analysis of ~3,300 specific HERV loci in the peripheral blood mononuclear cells (PBMCs) of 10 healthy controls and 16 individuals being either convalescent after the infection (6) or retesting positive after convalescence (10) (Gene Expression Onmibus [GEO] data set GSE166253). Results showed that the exposure to SARS-CoV-2 infection modulates HERV expression according to the disease stage and reflecting COVID-19 immune signatures. The differential expression analysis between healthy control (HC) and COVID-19 patients allowed us to identify a total of 282 differentially expressed HERV loci (deHERV) in the individuals exposed to SARS-CoV-2 infection, independently from the clinical form. In addition, 278 and 60 deHERV loci that were specifically modulated in individuals convalescent after COVID19 infection (C) and patients that retested positive to SARS-CoV-2 after convalescence (RTP) as individually compared to HC, respectively, as well as 164 deHERV loci between C and RTP patients were identified. The identified HERV loci belonged to 36 different HERV groups, including members of all three classes. The present study provides an exhaustive picture of the HERV transcriptome in PBMCs and its dynamic variation in the presence of COVID-19, revealing specific modulation patterns according to the infection stage that can be relevant to the disease clinical manifestation and outcome. IMPORTANCE We report here the first high-throughput analysis of HERV loci expression along SARS-CoV-2 infection, as performed with peripheral blood mononuclear cells (PBMCs). Such cells are not directly infected by the virus but have a crucial role in the plethora of inflammatory and immune events that constitute a major hallmark of COVID-19 pathogenesis. Results provide a novel and exhaustive picture of HERV expression in PBMCs, revealing specific modulation patterns according to the disease condition and the concomitant immune activation. To our knowledge, this is the first set of deHERVs whose expression is dynamically modulated across COVID-19 stages, confirming a tight interplay between HERV and cellular immunity and revealing specific transcriptional signatures that can have an impact on the disease clinical manifestation and outcome.

Molecular diversity and phenotypic pleiotropy of ancient genomic regulatory loci derived from human endogenous retrovirus type H (HERVH) promoter LTR7 and HERVK promoter LTR5_Hs and their contemporary impacts on pathophysiology of Modern Humans.

Timelines of population-level effects of viruses on humans varied from the evolutionary scale of million years to contemporary spread of viral infections. Correspondingly, these events are exemplified by: (i) emergence of human endogenous retroviruses (HERVs) from ancient germline infections leading to stable integration of viral genomes into human chromosomes; and (ii) wide-spread viral infections reaching a global pandemic state such as the COVID-19 pandemic. Despite significant efforts, understanding of HERV's roles in governance of genomic regulatory networks, their impacts on primate evolution and development of human-specific physiological and pathological phenotypic traits remains limited. Remarkably, present analyses revealed that expression of a dominant majority of genes (1696 of 1944 genes; 87%) constituting high-confidence down-steam regulatory targets of defined HERV loci was significantly altered in cells infected with the SARS-CoV-2 coronavirus, a pathogen causing the global COVID-19 pandemic. This study focused on defined sub-sets of DNA sequences derived from HERVs that are expressed at specific stages of human preimplantation embryogenesis and exert regulatory actions essential for self-renewal and pluripotency. Evolutionary histories of LTR7/HERVH and LTR5_Hs/HERVK were charted based on evidence of the earliest presence and expansion of highly conserved (HC) LTR sequences. Sequence conservation analyses of most recent releases 17 primate species' genomes revealed that LTR7/HERVH have entered germlines of primates in Africa after the separation of the New World Monkey lineage, while LTR5_Hs/HERVK successfully colonized primates' germlines after the segregation of Gibbons' species. Subsequently, both LTR7 and LTR5_Hs undergo a marked ~ fourfold-fivefold expansion in genomes of Great Apes. Timelines of quantitative expansion of both LTR7 and LTR5_Hs loci during evolution of Great Apes appear to replicate the consensus evolutionary sequence of increasing cognitive and behavioral complexities of non-human primates, which seems particularly striking for LTR7 loci and 11 distinct LTR7 subfamilies. Consistent with previous reports, identified in this study, 351 human-specific (HS) insertions of LTR7 (175 loci) and LTR5_Hs (176 loci) regulatory sequences have been linked to genes implicated in establishment and maintenance of naïve and primed pluripotent states and preimplantation embryogenesis phenotypes. Unexpectedly, HS-LTRs manifest regulatory connectivity to genes encoding markers of 12 distinct cells' populations of fetal gonads, as well as genes implicated in physiology and pathology of human spermatogenesis, including Y-linked spermatogenic failure, oligo- and azoospermia. Granular interrogations of genes linked with 11 distinct LTR7 subfamilies revealed that mammalian offspring survival (MOS) genes seem to remain one of consistent regulatory targets throughout ~ 30 MYA of the divergent evolution of LTR7 loci. Differential GSEA of MOS versus non-MOS genes identified clearly discernable dominant enrichment patterns of phenotypic traits affected by MOS genes linked with LTR7 (562 MOS genes) and LTR5_Hs (126 MOS genes) regulatory loci across the large panel of genomics and proteomics databases reflecting a broad spectrum of human physiological and pathological traits. GSEA of LTR7-linked MOS genes identified more than 2200 significantly enriched records of human common and rare diseases and gene signatures of 466 significantly enriched records of Human Phenotype Ontology traits, including Autosomal Dominant (92 genes) and Autosomal Recessive (93 genes) Inheritance. LTR7 regulatory elements appear linked with genes implicated in functional and morphological features of central nervous system, including synaptic transmission and protein-protein interactions at synapses, as well as gene signatures differentially regulated in cells of distinct neurodevelopmental stages and morphologically diverse cell types residing and functioning in human brain. These include Neural Stem/Precursor cells, Radial Glia cells, Bergman Glia cells, Pyramidal cells, Tanycytes, Immature neurons, Interneurons, Trigeminal neurons, GABAergic neurons, and Glutamatergic neurons. GSEA of LTR7-linked genes identified significantly enriched gene sets encoding markers of more than 80 specialized types of neurons and markers of 521 human brain regions, most prominently, subiculum and dentate gyrus. Identification and characterization of 1944 genes comprising high-confidence down-steam regulatory targets of LTR7 and/or LTR5_Hs loci validated and extended these observations by documenting marked enrichments for genes implicated in neoplasm metastasis, intellectual disability, autism, multiple cancer types, Alzheimer's, schizophrenia, and other brain disorders. Overall, genes representing down-stream regulatory targets of ancient retroviral LTRs exert the apparently cooperative and exceedingly broad phenotypic impacts on human physiology and pathology. This is exemplified by altered expression of 93% high-confidence LTR targets in cells infected by contemporary viruses, revealing a convergence of virus-inflicted aberrations on genomic regulatory circuitry governed by ancient retroviral LTR elements and interference with human cells' differentiation programs.

Increased Presence of Antibodies against Type I Interferons and Human Endogenous Retrovirus W in Intensive Care Unit COVID-19 Patients.

In this work, we observed an increased presence of antibodies (Abs) against type I interferon (IFN-I) in coronavirus disease 2019 (COVID-19) patients admitted to the intensive care unit (ICU) compared to non-ICU COVID-19 patients and healthy control (HC) subjects. Human endogenous retrovirus W (HERV-W) can reactivate after viral infection; therefore, we also investigated the presence of antibodies against HERV-W envelope (HERV-W-env)-derived epitopes. A total of 113 subjects (41 female and 72 male subjects) were analyzed. A significant difference in autoantibodies against IFN-α, IFN-ω, and HERV-W was observed between HCs and ICU patients; indeed, the latter have higher levels of autoantibodies against IFN-α, IFN-ω, and HERV-W than subjects with mild COVID-19 and HCs. Neutralizing anti-IFN-I autoantibodies may affect the ability of IFN-I to bind to the type I interferon receptor (IFNAR), blocking the activation of the antiviral response. IMPORTANCE In this work, we report the increased presence of IFN autoantibodies in correlation with HERV-W-env autoantibodies in ICU COVID-19 patients. The novelty of the results is in the association of these IFN autoantibodies with autoantibodies against HERV-W-env, a protein recently discovered to be overexpressed in lymphocytes of COVID-19 patients and correlated with severe disease and pneumonia. Type I IFNs are part of a complex cross-regulatory network; however, in a small percentage of cases, the increase in autoantibodies against these proteins may lead to damage to the host instead of protection against infectious diseases.