Background. Interferon is a marker of host antiviral immunity, which is disordered in COVID-19 patients. ERV can affect the secretion of interferon through the cGAS-STING pathway. In this study, we explored whether IFN-I and HERV-K (HML-2) were activated in COVID-19 patients and whether there was an interaction between them. Methods. We collected blood samples from COVID-19 patients and healthy controls. We first detected the expression of HERV-K (HML-2) gag, env, and pol genes and IFN-I-related genes between patients and healthy people by qPCR, synchronously detected VERO cells infected with SARS-CoV-2. Then, the chromosome distributions of highly expressed HERV-K (HML-2) gag, env, and pol genes were mapped by the next-generation sequencing results, and GO analysis was performed on the related genes. Results. We found that the HERV-K (HML-2) gag, env, and pol genes were highly expressed in COVID-19 patients and VERO cells infected with SARS-CoV-2. The interferon-related genes IFNB1, ISG15, and IFIT1 were also activated in COVID-19 patients, and GO analysis showed that HERV-K (HML-2) can regulate the secretion of interferon. Conclusions. The high expression of HERV-K (HML-2) might activate the increase of interferon in COVID-19 patients, proving that HERV-K does not only play a negative role in the human body.

Background: Human endogenous retroviruses (HERVs) result from ancestral infections caused by exogenous retroviruses that became incorporated into the germline DNA and evolutionarily fixed in the human genome. HERVs can be transmitted vertically in a Mendelian fashion and be stably maintained in the human genome, of which they are estimated to comprise approximately 8%. HERV-K (HML1-10) transcription has been confirmed to be associated with a variety of diseases, such as breast cancer, lung cancer, prostate cancer, melanoma, rheumatoid arthritis, and amyotrophic lateral sclerosis. However, the poor characterization of HML-9 prevents a detailed understanding of the regulation of the expression of this family in humans and its impact on the host genome. In light of this, a precise and updated HERV-K HML-9 genomic map is urgently needed to better evaluate the role of these elements in human health. Results: We report a comprehensive analysis of the presence and distribution of HERV-K HML-9 elements within the human genome, with a detailed characterization of the structural and phylogenetic properties of the group. A total of 23 proviruses and 47 solo LTR elements were characterized, with a detailed description of the provirus structure, integration time, potential regulated genes, transcription factor binding sites (TFBS), and primer binding site (PBS) features. The integration time results showed that the HML-9 elements found in the human genome integrated into the primate lineage between 17.5 and 48.5 million years ago (mya). Conclusion: The results provide a clear characterization of HML-9 and a comprehensive background for subsequent functional studies.

Background: Endogenous retrovirus (ERV) elements can act as proximal regulatory elements in promoting interferon (IFN) responses. Previous relevant studies have mainly focused on IFN-stimulated genes (ISGs). However, the role of ERV elements as cis-regulatory motifs in regulating genes of the JAK–STAT pathway remains poorly understood. In our study, we analyzed the changes in ERV elements and genes under both IFN stimulation and blockade of the signaling pathway. Methods: The effects of interferon on cells under normal conditions and knockout of the receptor were compared based on the THP1_IFNAR1_KO and THP1_IFNAR2_mutant cell lines. The correlation between differentially expressed ERVs (DHERVs) and differentially expressed genes (DEGs) as DEHERV-G pairs was explored with construction of gene regulatory networks related to ERV and induced by proinflammatory cytokines. Results: A total of 430 DEHERV loci and 190 DEGs were identified in 842 DEHERV-G pairs that are common to the three groups. More than 87% of DEHERV-G pairs demonstrated a consistent expression pattern. ISGs such as AIM2, IFIT1, IFIT2, IFIT3, STAT1, and IRF were activated via the JAK–STAT pathway in response to interferon stimulation. Thus, STAT1, STAT2, and IRF1 appear to play core roles in regulatory networks and are closely associated with ERVs. Conclusions: The RNA expression of ISGs and ERV elements is correlated, indicating that ERV elements are closely linked to host innate immune responses.

Post-transcriptional processing and modification of viral RNA, including alternative splicing, polyadenylation, and methylation, play crucial roles in regulating viral gene expression, enhancing genomic stability, and increasing replication efficiency. These processes have significant implications for viral biology and antiviral therapies. In this study, using Oxford Nanopore Technology (ONT) direct RNA sequencing (DRS), we provided a comprehensive analysis of the transcriptome and epitranscriptome features of the HIV-1 B (NL4-3) subtype strain and, for the first time, characterized these features in the CRF01_AE (GX2005002) subtype strain. We identified 11 novel splicing sites among the 61 RNA isoforms in NL4-3 and defined the splicing sites for GX2005002 based on its 63 RNA isoforms. Furthermore, we identified 74 and 79 chemically modified sites in the transcripts of NL4-3 and GX2005002, respectively. Although differences in poly(A) tail length were observed between the two HIV-1 strains, no specific correlation was detected between poly(A) tail length and the number of modification sites. Additionally, three distinct N6-methyladenosine (m⁶A) modification sites were identified in both NL4-3 and GX2005002 transcripts. This study provides a detailed analysis of post-transcriptional processing modifications in HIV-1 and suggests promising avenues for future research that could potentially be applied as new therapeutic targets in HIV treatment.

Hematological malignant tumors (HMTs) are serious diseases that threaten human health and life with high mortality. Therefore, it is necessary to develop novel strategies for diagnosis and treatment. Human endogenous retroviruses (HERVs) have recently attracted increasing attention as potential targets for cancer diagnosis and therapy. In this study, we explored the association between HERV-K expression levels and HMTs development. Clinical data and peripheral blood samples were collected from 236 leukemia, 384 lymphoma patients, and 69 healthy controls. Quantitative polymerase chain reaction was used to detect the expression of HERV-K gag , pol , and env genes in peripheral blood mononuclear cells or different cell subpopulations. Differently expressed HERV-K genes were further tested by using deep sequencing method, and further analyzed with gene ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. B cell- and T cell-related cytokines in patients were also detected by enzyme-linked immunosorbent assay (ELISA). The results showed that the expression levels of the HERV-K gag , pol , and env genes in patients were significantly higher than in healthy controls. There was a correlation between the expression level of HERV-K and the clinicopathological parameters of leukemia patients. HERV-K expression was increased in the B lymphocytes of leukemia and lymphoma patients, but not in the T cells or neutrophils. The GO and KEGG analyses showed that abnormal expression of the HERV-K locus in patients affected immune regulation. The analysis of cytokines proved that the B cell-related cytokines, including interleukin (IL)-1β, IL-2, IL-4, IL-6, IL-10, tumor necrosis factor (TNF)-α, and interferon-gamma, were significantly decreased in patients, while the T cell-related cytokines, including IL-3, IL-12, and TNF-β, were not significantly changed. In conclusion, HERV-K genes might participate in the occurrence and development of leukemia and lymphoma, and might be biomarkers for the detection or evaluation of leukemia and lymphoma.

Endogenous retroviruses (ERVs) are related to long terminal repeat (LTR) retrotransposons, comprising gene sequences of exogenous retroviruses integrated into the host genome and inherited according to Mendelian law. They are considered to have contributed greatly to the evolution of host genome structure and function. We previously characterized HERV-K HML-9 in the human genome. However, the biological function of this type of element in the genome of the chimpanzee, which is the closest living relative of humans, largely remains elusive. Therefore, the current study aims to characterize HML-9 in the chimpanzee genome and to compare the results with those in the human genome. Firstly, we report the distribution and genetic structural characterization of the 26 proviral elements and 38 solo LTR elements of HML-9 in the chimpanzee genome. The results showed that the distribution of these elements displayed a non-random integration pattern, and only six elements maintained a relatively complete structure. Then, we analyze their phylogeny and reveal that the identified elements all cluster together with HML-9 references and with those identified in the human genome. The HML-9 integration time was estimated based on the 2-LTR approach, and the results showed that HML-9 elements were integrated into the chimpanzee genome between 14 and 36 million years ago and into the human genome between 18 and 49 mya. In addition, conserved motifs, cis-regulatory regions, and enriched PBS sequence features in the chimpanzee genome were predicted based on bioinformatics. The results show that pathways significantly enriched for ERV LTR-regulated genes found in the chimpanzee genome are closely associated with disease development, including neurological and neurodevelopmental psychiatric disorders. In summary, the identification, characterization, and genomics of HML-9 presented here not only contribute to our understanding of the role of ERVs in primate evolution but also to our understanding of their biofunctional significance.