Evolutionary history of the human endogenous retrovirus family ERV9

Several distinct families of endogenous retrovirus-like elements (ERVs) exist in the genomes of primates. Despite the important evolutionary consequences that carrying these intragenomic parasites may have for their hosts, our knowledge about their evolution is still scarce. A matter of particular interest is whether evolution of ERVs occurs via a master lineage or through several lineages coexisting over long periods of time. In this work, the paleogenomic approach has been applied to the study of the evolution of ERV9, one of the human endogenous retrovirus families mobilized during primate evolution. By searching the GenBank database with the first 676 bp of the ERV9 long terminal repeat, we identified 156 different element insertions into the human genome. These elements were grouped into 14 subfamilies based on several characteristic nucleotide differences. The age of each subfamily was roughly estimated based on the average sequence divergence of its members from the subfamily consensus sequence. Determination of the sequential order of diagnostic substitutions led to the identification of four distinct lineages, which retained their capacity of transposition over extended periods of evolution. Strong evidence for mosaic evolution of some of these lineages is presented. Taken altogether, the available data indicate that the possibility of ERV9 still being active in the human lineage can not be discarded.     

Chromosomal distribution, localization and expression of the human endogenous retrovirus ERV9

ERV9 is a class I family of human endogenous retroviral sequences. Somatic cell hybrid genomic hybridization experiments using a mono-chromosomal panel indicate the presence of approximately 120 ERV9 loci in the human genome distributed on most chromosomes. Fluorescence in situ hybridization (FISH) using an ERV9 cDNA probe containing gag, pol and env sequences, verified this observation and a consistent signal was found at the chromosome region 11q13.3-->q13.5. By analysis of a panel of radiation hybrids, an ERV9 locus was mapped to within a 300-kbp region at the chromosome site 11q13. The marker cCLGW567 and the locus MAP3K11/D11S546 centromeric and telomeric flanked it, respectively. Northern blot analysis, using an ERV9 LTR probe, indicated that most normal tissues examined expressed low abundant ERV9 LTR driven mRNAs of various sizes. The most prominent expression was found in adrenal glands and testis. However, the level of expression varied in the same tissues among different individuals indicating that ERV9 mRNA expression probably is inducible in certain tissues or at various cell stages.     

Envelope gene of the human endogenous retrovirus HERV-W encodes a functional retrovirus envelope

A member of the human endogenous retrovirus (HERV) family termed HERV-W encodes a highly fusogenic membrane glycoprotein that appears to be expressed specifically in the placenta. It is unclear whether the glycoproteins of the HERVs can serve as functional retrovirus envelope proteins to confer infectivity on retrovirus particles. We found that the HERV-W envelope glycoprotein can form pseudotypes with human immunodeficiency virus type 1 virions and confers tropism for CD4-negative cells. Thus, the HERV-W env gene represents the first HERV env gene demonstrated to encode the functional properties of a retrovirus envelope glycoprotein.     

Ancestry of a human endogenous retrovirus family.

The human endogenous retrovirus type II (HERVII) family of HERV genomes has been found by Southern blot analysis to be characteristic of humans, apes, and Old World monkeys. New World monkeys and prosimians lack HERVII proviral genomes. Cellular DNAs of humans, common chimpanzees, gorillas, and orangutans, but not lesser ape lar gibbons, appear to contain the HERVII-related HLM-2 proviral genome integrated at the same site (HLM-2 maps to human chromosome 1). This suggests that the ancestral HERVII retrovirus(es) entered the genomes of Old World anthropoids by infection after the divergence of New World monkeys (platyrrhines) but before the evolutionary radiation of large hominoids.     

Characterization of the intragenomic spread of the human endogenous retrovirus family HERV-W

This study examines the intragenomic spread of the human endogenous retrovirus family HERV-W from insertions present within the draft sequence of the human genome. Identification of shared diagnostic differences and phylogenetic analyses revealed the existence of three main subfamilies. The average divergence between sequences for each of the subfamilies suggests that most of the HERV-W elements were inserted within the genome during a short period of evolutionary time. Each one of the subfamilies consists of two types of insertions, the expected proviral sequences and other sequences resembling the structure of processed retrogenes. These HERV-W retrosequences extend from the R region of the 5' long-terminal repeat (LTR) to the R region of the 3' LTR (as viral genomic RNAs), end in poly(A) 3' tails, and are flanked by direct repeats longer than the proviral integrations. Furthermore, several of the HERV-W retrosequences are 5'-truncated at different sites. I suggest the involvement of the L1 machinery in these integrations and discuss the characteristic features of the evolutionary history of HERV-W, with emphasis on the putative impact of HERV-W retrosequence integrations on the mammalian genome.     

Transspecies transmission of the endogenous koala retrovirus

The koala retrovirus (KoRV) is a gammaretrovirus closely related to the gibbon ape leukemia virus and induces leukemias and immune deficiencies associated with opportunistic infections, such as chlamydiosis. Here we characterize a KoRV newly isolated from an animal in a German zoo and show infection of human and rat cell lines in vitro and of rats in vivo, using immunological and PCR methods for virus detection. The KoRV transmembrane envelope protein (p15E) was cloned and expressed, and p15E-specific neutralizing antibodies able to prevent virus infection in vitro were developed. Finally, evidence for immunosuppressive properties of the KoRV was obtained.     

The human endogenous retrovirus family HERV-K(HML-3)

A substantial amount of the human genome is composed of human endogenous retroviruses (HERVs). Manifold HERV families have been identified, among them several so-called HERV-K(HML) families. Although the HERV-K(HML-2) family has been studied in detail, other HERV-K families are not as well characterized. We describe here the HERV-K HML-3 family in more detail. We estimate that there are about 140 proviral loci or remains of such per haploid genome. Most loci are severely mutated. Proviruses displaying larger deletions in gag and pol are common. A multiple alignment of 73 HERV-K(HML-3) sequences displays several potentially important differences compared with the HERVK9I sequence in Repbase. A consensus sequence with open reading frames for all retroviral genes was generated, for which intact dUTPase motifs and env gene variants with different coding capacities are observed. Phylogenetic analysis shows near-monophyly with distinction of two closely related subgroups. Proviruses formed about 36 million years ago. However, no continuous activity through primate evolution is indicated.     

A survey of endogenous retrovirus (ERV) sequences in the vicinity of multiple sclerosis (MS)-associated single nucleotide polymorphisms (SNPs)

Although multiple sclerosis (MS) is one of the most common central nervous system diseases in young adults, little is known about its etiology. Several human endogenous retroviruses (ERVs) are considered to play a role in MS. We are interested in which ERVs can be identified in the vicinity of MS associated genetic marker to find potential initiators of MS. We analysed the chromosomal regions surrounding 58 single nucleotide polymorphisms (SNPs) that are associated with MS identified in one of the last major genome wide association studies. We scanned these regions for putative endogenous retrovirus sequences with large open reading frames (ORFs). We observed that more retrovirus-related putative ORFs exist in the relatively close vicinity of SNP marker indices in multiple sclerosis compared to control SNPs. We found very high homologies to HERV-K, HCML-ARV, XMRV, Galidia ERV, HERV-H/env62 and XMRV-like mouse endogenous retrovirus mERV-XL. The associated genes (CYP27B1, CD6, CD58, MPV17L2, IL12RB1, CXCR5, PTGER4, TAGAP, TYK2, ICAM3, CD86, GALC, GPR65 as well as the HLA DRB1*1501) are mainly involved in the immune system, but also in vitamin D regulation. The most frequently detected ERV sequences are related to the multiple sclerosis-associated retrovirus, the human immunodeficiency virus 1, HERV-K, and the Simian foamy virus. Our data shows that there is a relation between MS associated SNPs and the number of retroviral elements compared to control. Our data identifies new ERV sequences that have not been associated with MS, so far.     

Repression of porcine endogenous retrovirus infection by human APOBEC3 proteins

It has been shown that porcine endogenous retrovirus (PERV) can infect human cells, indicating that PERV transmission poses a serious concern in pig-to-human xenotransplantation. A number of recent studies have reported on retrovirus interference by antiviral proteins. The most potent antiviral proteins are members of the APOBEC family of cytidine deaminases, which are involved in defense against retroviral attack. These proteins are present in the cytoplasm of mammalian cells and inhibit retroviral replication. To evaluate the inhibition of PERV transmission by human APOBEC3 proteins, we co-transfected 293T cells with a PERV molecular clone and human APOBEC3F or APOBEC3G expression vectors, and monitored PERV replication competency using a quantitative analysis of PERV pol genes. The replication of PERVs in cells co-expressing human APOBEC3s was reduced by 60–90% compared with PERV-only control. These results suggest that human APOBEC3G and APOBEC3F might serve a potential barrier function against PERV transmission in xenotransplantation.