Identification of Copper Transporter 1 as a Receptor for Feline Endogenous Retrovirus ERV-DC14.

Vertebrates harbor hundreds of endogenous retroviral (ERV) sequences in their genomes, which are considered signs of past infections that occurred during evolution. On rare occasions, ERV genes like env are maintained and coopted by hosts for physiological functions, but they also participate in recombination events with exogenous retroviruses to generate rearranged viruses with novel tropisms. In domestic cats, feline leukemia virus type D (FeLV-D) has been described as a recombinant virus between the infectious FeLV-A and likely the ERV-DC14 env gene that resulted in an extended tropism due to the usage of a new uncharacterized retroviral receptor. Here, we report the identification of SLC31A1 encoding the copper transporter 1 (CTR1) as a susceptibility gene for ERV-DC14 infection. Expression of human CTR1 into nonpermissive cells was sufficient to confer sensitivity to ERV-DC14 pseudotype infection and to increase the binding of an ERV-DC14 Env ligand. Moreover, inactivation of CTR1 by genome editing or cell surface downmodulation of CTR1 by a high dose of copper dramatically decreased ERV-DC14 infection and binding, while magnesium treatment had no effect. We also investigated the role of CTR1 in the nonpermissivity of feline and hamster cells. While feline CTR1 was fully functional for ERV-DC14, we found that binding was strongly reduced upon treatment with conditioned medium of feline cells, suggesting that the observed resistance to infection was a consequence of CTR1 saturation. In contrast, hamster CTR1 was inactive due to the presence of a N-linked glycosylation site at position 27, which is absent in the human ortholog. These results provide evidence that CTR1 is a receptor for ERV-DC14. Along with chimpanzee endogenous retrovirus type 2, ERV-DC14 is the second family of endogenous retrovirus known to have used CTR1 during past infections of vertebrates. IMPORTANCE Receptor usage is an important determinant of diseases induced by pathogenic retroviruses. In the case of feline leukemia viruses, three subgroups (A, B, and C) based on their ability to recognize different cell host receptors, respectively, the thiamine transporter THTR1, the phosphate transporter PiT1, and the heme exporter FLVCR1, are associated with distinct feline diseases. FeLV-A is horizontally transmitted and found in all naturally infected cats, while FeLV-B and FeLV-C have emerged from FeLV-A, respectively, by recombination with endogenous retroviral env sequences or by mutations in the FeLV-A env gene, both leading to a switch in receptor usage and in subsequent in vivo tropism. Here, we set up a genetic screen to identify the retroviral receptor of ERV-DC14, a feline endogenous provirus whose env gene has been captured by infectious FeLV-A to give rise to FeLV-D in a process similar to FeLV-B. Our results reveal that the copper transporter CTR1 was such a receptor and provide new insights into the acquisition of an expanded tropism by FeLV-D.

Species-specific KRAB-ZFPs function as repressors of retroviruses by targeting PBS regions.

SignificanceHosts often target the relatively conserved regions in rapidly mutating retroviruses to inhibit their replication. One of these regions is called a primer binding site (PBS), which has to be complementary to the host tRNA to initiate reverse transcription. By analyzing endogenous retroviral elements, we found that host cells use this sequence as a target in efforts to block the expression of viral elements. A specific type of zinc finger protein targets the PBS in a host genome, which not only inhibits the transcription of endogenous viruses but also inhibits the replication of exogenous retroviruses with the same PBS. Thus, our study sheds light on a strategy for searching for host restriction factors targeting retroviruses.

A spontaneous genetically induced epiallele at a retrotransposon shapes host genome function.

Intracisternal A-particles (IAPs) are endogenous retroviruses (ERVs) responsible for most insertional mutations in the mouse. Full-length IAPs harbour genes flanked by long terminal repeats (LTRs). Here, we identify a solo LTR IAP variant (Iap5-1solo) recently formed in the inbred C57BL/6J mouse strain. In contrast to the C57BL/6J full-length IAP at this locus (Iap5-1full), Iap5-1solo lacks DNA methylation and H3K9 trimethylation. The distinct DNA methylation levels between the two alleles are established during preimplantation development, likely due to loss of KRAB zinc finger protein binding at the Iap5-1solo variant. Iap5-1solo methylation increases and becomes more variable in a hybrid genetic background yet is unresponsive to maternal dietary methyl supplementation. Differential epigenetic modification of the two variants is associated with metabolic differences and tissue-specific changes in adjacent gene expression. Our characterisation of Iap5-1 as a genetically induced epiallele with functional consequences establishes a new model to study transposable element repression and host-element co-evolution.

Our genome provides a complete set of genetic instructions for life. It begins by directing the growth and development of the embryo, and subsequently supports all the cells of the adult body in their daily routines. Yet approximately 10% of the DNA in mammalian genomes is made up of sequences originating from past retroviral infections, leaving a calling card in our genetic code. While these segments of retroviral DNA can no longer produce new infectious viruses, some of them retain the ability to copy themselves and jump into new parts of the genome. This can be problematic if they jump into and disrupt an important piece of genetic code. To protect against this, our bodies have evolved the ability to chemically strap down retroviral sequences by adding methyl groups to them and by modifying the proteins they are wrapped around. However, some of these endogenous retroviruses can dodge such so-called epigenetic modifications and disrupt genome function as a result. Studying a population of widely used inbred laboratory mice, Bertozzi et al. have identified a retroviral element that evades these epigenetic restraints. They discovered that some mice carry a full-length retroviral sequence while others have a shortened version of the same element. The shorter sequence lacked the repressive epigenetic marks found on the longer version, and this affected the expression of nearby genes. Moreover, the repressive marks could be partially restored by breeding the short-version mice with a distantly related mouse strain. Bertozzi et al. highlight an important issue for research using mouse models. Inbred laboratory mouse strains are assumed to have a fixed genetic code which allows scientists to conclude that any observed differences in their experiments are not a product of background genetic variation. However, this study emphasizes that this assumption is not guaranteed, and that hidden genetic diversity may be present in ostensibly genetically identical mice, with important implications for experimental outcomes. In addition, Bertozzi et al. provide a new mouse model for researchers to study the evolution and regulation of retroviral sequences and the impact of these processes on cell function.

The paradigm of immunosenescence in atherosclerosis-cardiovascular disease (ASCVD).

The new immunosenescence paradigm (2015) was an attempt to explain a mechanism by which macrophages could be immunosuppressed and dysfunctional, yet paradoxically release proinflammatory factors in an unregulated manner. This mechanism was linked to the loss of dehydroepiandrosterone (DHEA) with aging and thus explained how immunosenescence could be causally related to the risk of stress and/or age-associated chronic diseases. At the center of this paradigm was lipid body negative (LB-) foamy macrophage (CD14+CD16+) which produced human endogenous retrovirus K102 (HERV-K102) particles. HERV-K102 may be a protector foamy virus of humans, and its induction may generate trained innate immunity, a special type of autoimmunity, in response to intracellular pathogens, their constituents, toxins, and/or tumors. Overwhelming evidence now suggests that the proinflammatory foamy macrophages driving ASCVD are LB-. Moreover, the monocyte/macrophage phenotype implicated in atherosclerosis-cardiovascular disease (ASCVD) appears to be the CD14+CD16+ intermediate phenotype. These and other observations directly challenge the cholesterol hypothesis. For the prevention and treatment of ASCVD, it is important to address the putative cause of ASCVD -- immunosenescence, rather than the signs or symptoms such as inflammation or elevated cholesterol. Therefore, strategies to reverse or prevent immunosenescence, which improve or maintain an optimal cortisol/DHEA ratio such as isoflavonoids, would be expected to alleviate not only ASCVD but the risk of many other age-associated chronic diseases. Here, the new immunosenescence paradigm will be appraised for its suitability to explain ASCVD risks.

Template Activating Factor-I α Regulates Retroviral Silencing during Reprogramming.

Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) is accompanied by dramatic changes in epigenetic programs, including silencing of endogenous and exogenous retroviruses. Here, we utilized replication-defective and persistent Sendai virus (SeVdp)-based vectors to monitor retroviral silencing during reprogramming. We observed that retroviral silencing occurred at an early reprogramming stage without a requirement for KLF4 or the YY1-binding site in the retroviral genome. Insertional chromatin immunoprecipitation (iChIP) enabled us to isolate factors assembled on the silenced provirus, including components of inhibitor of histone acetyltransferase (INHAT), which includes the SET/TAF-I oncoprotein. Knockdown of SET/TAF-I in mouse embryonic fibroblasts (MEFs) diminished retroviral silencing during reprogramming, and overexpression of template activating factor-I α (TAF-Iα), a SET/TAF-I isoform predominant in embryonic stem cells (ESCs), reinforced retroviral silencing by an SeVdp-based vector that is otherwise defective in retroviral silencing. Our results indicate an important role for TAF-Iα in retroviral silencing during reprogramming.

The effects of nutrient restriction on mRNA expression of endogenous retroviruses, interferon-tau, and pregnancy-specific protein-B during the establishment of pregnancy in beef heifers.

We hypothesize that syncytin-Rum1, bovine endogenous retrovirus-K1 (BERV-K1), pregnancy-specific protein-B (PSP-B), and interferon-τ (IFN-τ) will be influenced by maternal nutrient restriction and be differentially expressed during key stages (day 16, 34, and 50) of the establishment of gestation when fed to meet industry standards. Commercial crossbred heifers (n = 49) were maintained on a total mixed ration and supplemented with dried distillers grains with solubles. All heifers were subjected to 5-d CO-Synch + CIDR estrus synchronization protocol. Non-pregnant, non-bred control (NP-NB) heifers (n = 6) were ovariohysterectomized on day 16, and the remaining heifers were AI to a single Angus sire (day of breeding = day 0). On the day of breeding, heifers were randomly assigned to dietary treatments. One half were assigned to control treatment (CON) targeted to gain 0.45 kg/d, and the remaining half were assigned to restricted treatment (RES), which received 60% of control diets. Heifers were subjected to ovariohysterectomy on day 16, 34, or 50 of gestation. Utero-placental tissues were obtained from the uterine horn ipsilateral (P) and contralateral (NP) to the corpus luteum and separated into maternal caruncle (CAR), maternal endometrium, inter-caruncle, (ICAR), and fetal membrane (FM). There were no interactions between stage of gestation and nutritional treatment for syncytin-Rum1 or PSP-B (P > 0.22). Expression of BERV-K1 was influenced by a treatment × stage of gestation interaction (P = 0.03) in NP-CAR. On day 50, heifers fed the CON diet had greater BERV-K1 expression compared with CON heifers on day 16 and 34 and RES heifers at all sampling time points. There was a treatment × stage of gestation interaction (P < 0.01) for IFN-τ in FM tissue. On 16 d, mRNA expression of IFN-τ was greater (P < 0.01) compared with day 34 and 50 for both CON and RES heifers, but RES FM had greater (P < 0.01) IFN-τ expression compared with CON FM. In P-CAR, PSP-B expression increased (P < 0.01) by 18 000-fold on day 50 compared with NP-NB heifers. In P-ICAR, expression of syncytin-Rum1 in P-ICAR was greater (P = 0.01) on day 16 with a 14.14-fold increase compared with relative expression on day 34 and 50; whereas, PSP-B was increased (P < 0.01) on day 34 and 50 compared with day 16. In conclusion, 40% nutrient restriction had limited influence on mRNA of ERVs, PSP-B, and IFN-τ but stage of gestation differences reinforced the importance of these genes during the establishment of pregnancy.

Effects of UVA1 Phototherapy on Expression of Human Endogenous Retroviral Sequence (HERV)-K10 gag in Morphea: A Preliminary Study.

BACKGROUND Morphea, also known as localized scleroderma, is a rare autoimmune connective tissue disease characterized by skin fibrosis. UVA1 phototherapy is an important asset in the reduction of clinical manifestations in morphea. There are studies claiming that UV light modulates the expression of some human endogenous retroviral sequences. The aim of this study was to determine if the expression of HERV-K10 gag element is lowered by UVA1 phototherapy in morphea, a disease in which such irradiation has a soothing effect. MATERIAL AND METHODS The expression levels of the HERV-K10 gag were assessed by real-time PCR (polymerase chain reaction) in peripheral blood mononuclear cells (PBMC) and skin-punch biopsies of healthy volunteers and 9 morphea patients before and after phototherapy. Additionally, correlations between the HERV-K10 gag expression and age, disease duration, the Localized Scleroderma Skin Severity Index (LoSSI), and antinuclear antibody (ANA) titers were assessed. RESULTS In PBMC, HERV-K10 gag mRNA was significantly elevated after UVA1 phototherapy compared to healthy controls. Most of the patients responded with an increased expression level of this sequence. However, we found no statistical evidence at this point that phototherapy indeed has an effect on the HERV-K10 gag expression (there were no statistical differences in PBMC of morphea patients before and after phototherapy). Similarly, there was no statistically relevant effect of the UVA1 on the expression of HERV-K10 gag in skin. CONCLUSIONS At this point, the effect of UVA1 phototherapy on the expression of HERV-K10 gag cannot be statistically confirmed.

RAPID COMMUNICATION: Expression of an endogenous retroviral element, during early gestation in beef heifers.

Endogenous retroviral gene elements have been implicated in development and formation of the feto-maternal interface. A variant of the syncytin endogenous retroviral envelope gene family, , was recently found in ruminants. We hypothesized that mRNA would be differentially expressed in utero-placental tissues and would fluctuate during key time points of early gestation in beef heifers. Commercial Angus crossbred heifers ( = 46; ∼15 mo of age; BW = 362.3 ± 34.7kg) housed in 6-animal pens were fed daily with native grass hay and supplemented with cracked corn to gain 0.3 kg/d. The heifers were estrus synchronized, artificially inseminated, (d of breeding= d 0) and ovariohysterectomized on d 16, 22, 28, 34, 40, and 50 ( = 9, 6, 6, 7, 6, and 5, respectively) of gestation and at d 16 of the estrous cycle for non-bred, non-pregnant controls (NP; = 7). Harvested tissues were separated into maternal caruncle (CAR), intercarunclar endometrium (ICAR), and fetal membranes, (FM; chorioallantois, d 22 and later). All tissues were obtained from the ipsilateral uterine horn to the CL. Statistical analyses were conducted via the GLM procedure of SAS. Maternal CAR expression of was greater ( = 0.003) on d 50 by 81.5-fold compared to NP controls. At d 50 expression of in CAR was 190.3-fold greater than ( < 0.0001) ICAR. Fetal membranes had greater ( < 0.002) expression of from d 22 until d 50 of gestation compared to maternal ICAR (d 16 not analyzed). Expression of in FM was greater ( < 0.004) than in CAR until d 40 of gestation. Therefore, we conclude that is differentially expressed in utero-placental tissues and may be involved in the establishment of pregnancy. The expression of in maternal tissues is completely novel and indicates unique functions of syncytin in ruminant pregnancy.

In Vivo Chromatin Targets of the Transcription Factor Yin Yang 2 in Trophoblast Stem Cells.

BACKGROUND: Yin Yang 2 (YY2) is a zinc finger protein closely related to the well-characterized Yin Yang 1 (YY1). YY1 is a DNA-binding transcription factor, with defined functions in multiple developmental processes, such as implantation, cell differentiation, X inactivation, imprinting and organogenesis. Yy2 has been treated as a largely immaterial duplication of Yy1, as they share high homology in the Zinc Finger-region and similar if not identical in vitro binding sites. In contrast to these similarities, gene expression alterations in HeLa cells with attenuated levels of either Yy1 or Yy2 were to some extent gene-specific. Moreover, the chromatin binding sites for YY2, except for its association with transposable retroviral elements (RE) and Endogenous Retroviral Elements (ERVs), remain to be identified. As a first step towards defining potential Yy2 functions matching or complementary to Yy1, we considered in vivo DNA binding sites of YY2 in trophoblast stem (TS) cells. RESULTS: We report the presence of YY2 protein in mouse-derived embryonic stem (ES) and TS cell lines. Following up on our previous report on ERV binding by YY2 in TS cells, we investigated the tissue-specificity of REX1 and YY2 binding and confirm binding to RE/ERV targets in both ES cells and TS cells. Because of the higher levels of expression, we chose TS cells to understand the role of Yy2 in gene and chromatin regulation. We used in vivo YY2 association as a measure to identify potential target genes. Sequencing of chromatin obtained in chromatin-immunoprecipitation (ChIP) assays carried out with αYY2 serum allowed us to identify a limited number of chromatin targets for YY2. Some putative binding sites were validated in regular ChIP assays and gene expression of genes nearby was altered in the absence of Yy2. CONCLUSIONS: YY2 binding to ERVs is not confined to TS cells. In vivo binding sites share the presence of a consensus binding motif. Selected sites were uniquely bound by YY2 as opposed to YY1, suggesting that YY2 exerts unique contributions to gene regulation. YY2 binding was not generally associated with gene promoters. However, several YY2 binding sites are linked to long noncoding RNA (lncRNA) genes and we show that the expression levels of a few of those are Yy2-dependent.

A new paradigm about HERV-K102 particle production and blocked release to explain cortisol mediated immunosenescence and age-associated risk of chronic disease.

The majority of chronic diseases in the aging adult are thought to relate to immune aging characterized by dominant immunosuppression and paradoxically, concomitant inflammation. This is known collectively as immunosenescence. The main change thought to be controlling immune aging is the age-related decline in dehydroepiandrosterone (DHEA) and corresponding increase in cortisol; the net effect which decreases the DHEA/cortisol ratio. Exactly how this translates to immunosuppression and concomitant inflammation remains unclear. Recently a new component of the human innate immune system has been discovered. Human endogenous retrovirus K102 (HERV-K102) is a replication-competent foamy retrovirus unique to humans which has been implicated in chronic diseases. Accumulating evidence suggests that HERV-K102 may defend the host against viral infections, as well as against breast and other cancers. Particles are produced in activated monocytes and released into vacuoles but do not bud through the cell surface. This renders macrophages foamy, while the release of particles is only through cell lysis. New evidence presented here suggests DHEA but not DHEA-S may specifically bind and inactivate alpha-fetoprotein (AFP). AFP is a well-established immunosuppressive factor which importantly, also blocks cell lysis induction in macrophages through the 67 kilodalton (kD) AFP receptor (AFPr). Here, it is proposed that a decreased DHEA/cortisol ratio may favor the accumulation of foamy macrophages reflecting the cortisol induction of HERV-K102 particle production concomitant with the blocked release of particles by secreted AFP. This is a new paradigm to explain how cortisol-mediated immunosenescence can result in the persistence of foamy macrophages, and how this relates to risk of chronic disease.

Expression of endogenous retroviruses is negatively regulated by the pluripotency marker Rex1/Zfp42.

Rex1/Zfp42 is a Yy1-related zinc-finger protein whose expression is frequently used to identify pluripotent stem cells. We show that depletion of Rex1 levels notably affected self-renewal of mouse embryonic stem (ES) cells in clonal assays, in the absence of evident differences in expression of marker genes for pluripotency or differentiation. By contrast, marked differences in expression of several endogenous retroviral elements (ERVs) were evident upon Rex1 depletion. We demonstrate association of REX1 to specific elements in chromatin-immunoprecipitation assays, most strongly to muERV-L and to a lower extent to IAP and musD elements. Rex1 regulates muERV-L expression in vivo, as we show altered levels upon transient gain-and-loss of Rex1 function in pre-implantation embryos. We also find REX1 can associate with the lysine-demethylase LSD1/KDM1A, suggesting they act in concert. Similar to REX1 binding to retrotransposable elements (REs) in ES cells, we also detected binding of the REX1 related proteins YY1 and YY2 to REs, although the binding preferences of the two proteins were slightly different. Altogether, we show that Rex1 regulates ERV expression in mouse ES cells and during pre-implantation development and suggest that Rex1 and its relatives have evolved as regulators of endogenous retroviral transcription.

Antimutagenicity of Japanese traditional herbs, gennoshoko, yomogi, senburi and iwa-tobacco.

The multistage induction theory is generally regarded as the mechanism of carcinogenesis. In order to prevent the initiation stage of carcinogenesis, it is meaningful to discover the functional components of edible plants. The objective of this research was to test the antimutagenicity of the functional components of several typical traditional herbs used in Japan. The traditional herbs, gennoshoko (Geranium nepalense var. thunbergii), yomogi (Artemisia vulgaris var. indica), senburi (Swertia japonica), iwa-tobacco (Conandron ramondioides), sarunokoshikake (Elfvingia applanata), kanzo (Glycyeehiza uralensis Fisch) and matatabi (Actinidia polygama) were examined by Ames mutagenesis assay test with Salmonella typhimurium TA98 and TA100 against mutagens, Trp-P-1, Trp-P-2 and B(a)P. The water-soluble components or volatile oil of the herbs were extracted in boiling water. The extracts of gennoshoko showed strong antimutagenicity against B(a)P with S. typhimurium TA98 and TA100, as well as Trp-P-1 and Trp-P-2 with S. typhimurium TA98. Yomogi, senburi and iwa-tobacco were also proved to have good antimutagenicity against Trp-P-1 and Trp-P-2 with S. typhimurium TA98, but weaker antimutagenicity against B(a)P. Other herbs did not show any obvious antimutagenicity against these mutagens. In addition, the volatile oil of yomogi also had remarkable antimutagenic effect against the mutagens we used with S. typhimurium TA98.

Corf, the Rev/Rex homologue of HTDV/HERV-K, encodes an arginine-rich nuclear localization signal that exerts a trans-dominant phenotype when mutated.

Regulation of nucleo-cytoplasmic export of viral transcripts by a viral protein (Rev/Rex) is a characteristic feature in the replication cycle of complex retroviruses. We recently reported that the endogenous retrovirus family HTDV/HERV-K encodes a protein, Corf, that is a cellular Counterpart of Rev/Rex function and thus a new component of nucleo-cytoplasmic pathways. In HTDV/HERV-K-expressing cells, Corf is localized within the nucleoli. Here we describe the nuclear localization signal (NLS) of the Corf protein. Mutations in the NLS lead to cytoplasmic accumulation of the mutated protein and abrogate Corf function in a trans-dominant way.

Intergenic splicing between a HERV-H endogenous retrovirus and two adjacent human genes.

We previously reported that a long terminal repeat (LTR) of a human endogenous retrovirus of the HERV-H family promotes expression of a cellular fusion transcript in teratocarcinoma cell lines. This transcript was termed PLA2L due to two regions of similarity to the secreted form of phospholipase A2. In this study, evidence is presented indicating that this transcript appears to be the result of intergenic splicing between the HERV-H element and two independent downstream genes. The 5' gene has been named HHLA1 (HERV-H LTR-associating 1) and is of unknown function but shows sequence conservation in other mammals. The 3' gene is now known to encode human otoconin-90 (OC90) which, in mice, is a major protein expressed in the fetal inner ear. Evidence for intergenic splicing of these two genes includes: (1) the isolation of LTR-driven HHLA1 transcripts, unspliced to otoconin-90 exons, with variable sites of polyadenylation; (2) the cloning of both the putative human intergenic genomic region and the novel 5' terminus of the mouse otoconin-90 gene; (3) the identification of homologous potential signal sequences in the 5' region of mouse otoconin-90 and in the middle of the PLA2L transcript; and (4) the lack of detectable chromosomal rearrangements involving this region in teratocarcinoma cells. The PLA2L transcript therefore represents a rare example of intergenic splicing of two closely linked genes. We hypothesize that human HHLA1 and OC90 are normally expressed independently from different promoters but are expressed from the LTR promoter and spliced together in teratocarcinoma cells. It is tempting to speculate that the high activity of the LTR promoter in this cell type may induce transcriptional fusion between these two genes.

Expression of the human endogenous retrovirus HTDV/HERV-K is enhanced by cellular transcription factor YY1.

The human endogenous retrovirus HTDV/HERV-K, which resides in moderate copy numbers in the human genome, is expressed in a cell-type-specific manner, predominantly in teratocarcinoma cells. We have analyzed the regulatory potential of the 5' enhancer of the HERV-K long terminal repeat. Protein extracts of HERV-K-expressing teratocarcinoma cell lines (GH and Tera2) and nonexpressing HeLa and HepG2 cells form different protein complexes on the enhancer sequence as detected by electrophoretic mobility shift assays (EMSA). Using competition EMSAs, DNase I footprinting, and supershift experiments, we localized the binding site of these complexes to a 20-bp sequence within the enhancer and showed that the transcription factor YY1 is one component of the HERV-K enhancer complex. Replacement of the YY1 binding site with unrelated sequences reduced expression of the luciferase gene as a reporter in transient-transfection assays.

[Long terminal repeat of the human endogenous retrovirus HERV-K in the intron of the ZNF91 gene]. / Dlinnyi kontsevoi povtor éndogennogo retrovirusa cheloveka HERV-K v introne gena ZNF91.

The relative positions of the ZNF91 gene (exon-intron organization) and the HERV-K human endogenous virus long terminal repeat (LTR), which was earlier found to be located in the ZNF91 gene locus, on the EcoRI restriction metric map of the human chromosome 19 were determined with a high resolution. The direction of the ZNF91 gene transcription relative to the chromosome 19 telomeres was determined. The HERV-K LTR was localized to the ZNF91 gene intron 19. The role of retroviral sequences in the evolution of the ZNF91 gene family is discussed.