The phylogeny of orthoretroviral long terminal repeats (LTRs)

LTRs are sequence elements in retroviruses and retrotransposons which are difficult to align due to their variability. One way of handling such cases is to use Hidden Markov Models (HMMs). In this work HMMs of LTRs were constructed for three groups of orthoretroviruses: the betaretroviruslike human MMTV-like (HML) endogenous retroviruses, the lentiviruses, including HIV, and gammaretroviruslike human endogenous retroviruses (HERVs). The HMM-generated LTR alignments and the phylogenetic trees constructed from them were compared with trees based on alignments of the pol gene at the nucleic acid level. The majority of branches in the LTR and pol based trees had the same order for the three retroviral genera, showing that HMM methods are successful in aligning and constructing phylogenies of LTRs. The HML LTR tree deviated somewhat from the pol tree for the groups HML3, HML7 and HML6. Among the gammaretroviruslike proviruses, the exogenous Mouse Leukemia Virus (MLV) was highly related to HERV-T in the pol based tree, but not in the LTR based tree. Aside from these differences, the similarity between the trees indicates that LTRs and pol coevolved in a largely monophyletic way.     

Expression profiles of human endogenous retrovirus (HERV)-K and HERV-R Env proteins in various cancers

The vertebrate genome contains an endogenous retrovirus that has been inherited from the past millions of years. Although approximately 8% of human chromosomal DNA consists of sequences derived from human endogenous retrovirus (HERV) fragments, most of the HERVs are currently inactive and non-infectious due to recombination, deletions, and mutations after insertion into the host genome. Several studies suggested that Human endogenous retroviruses (HERVs) factors are significantly related to certain cancers. However, only limited studies have been conducted to analyze the expression of HERV derived elements at protein levels in certain cancers. Herein, we analyzed the expression profiles of HERV-K envelope (Env) and HERV-R Env proteins in eleven different kinds of cancer tissues. Furthermore, the expression patterns of both protein and correlation with various clinical data in each tissue were analyzed. The expressions of both HERV-K Env and HERV-R Env protein were identified to be significantly high in most of the tumors compared with normal surrounding tissues. Correlations between HERV Env expressions and clinical investigations varied depending on the HERV types and cancers. Overall expression patterns of HERV-K Env and HERV-R Env proteins were different in every individual but a similar pattern of expressions was observed in the same individual. These results demonstrate the expression profiles of HERV-K and HERV-R Env proteins in various cancer tissues and provide a good reference for the association of endogenous retroviral Env proteins in the progression of various cancers. Furthermore, the results elucidate the relationship between HERV-Env expression and the clinical significance of certain cancers.     

Multiplex degenerate PCR coupled with an oligo sorbent array for human endogenous retrovirus expression profiling

Human endogenous retroviruses (HERVs) can be divided into distinct families of tens to thousands of paralogous loci. The expression of HERV elements has been detected in all tissues tested to date, particularly germ cells, embryonic tissues and neoplastic tissues. Hence, the study of HERV expression could represent added value in cancer diagnosis. We developed a quantitative assay combining a multiplex degenerate PCR (MD-PCR) amplification, based on the relative conservation of the pol genes, and a colorimetric Oligo Sorbent Array (OLISA^®). Nine HERV families were selected and amplification primers and capture probes were designed for each family. The features required to achieve efficient amplification of most of the elements of each HERV family and balanced co-amplification of all HERV families were analyzed. We found that MD-PCR reliability, i.e. equivalence of amplification and dose-effect relationship, relied on the adjustment of three critical parameters: the primer degeneracy, the relative concentration of each primer and the total amount of primers in the amplification mixture. The analysis of tumoral versus normal tissues suggests that this assay could prove useful in tumor phenotyping.     

Retroviruses and primate evolution

Human endogenous retroviruses (HERVs), probably representing footprints of ancient germ-cell retroviral infections, occupy about 1% of the human genome. HERVs can influence genome regulation through expression of retroviral genes, either via genomic rearrangements following HERV integrations or through the involvement of HERV LTRs in the regulation of gene expression. Some HERVs emerged in the genome over 30 MYr ago, while others have appeared rather recently, at about the time of hominid and ape lineages divergence. HERVs might have conferred antiviral resistance on early human ancestors, thus helping them to survive. Furthermore, newly integrated HERVs could have changed the pattern of gene expression and therefore played a significant role in the evolution and divergence of Hominoidea superfamily. Comparative analysis of HERVs, HERV LTRs, neighboring genes, and their regulatory interplay in the human and ape genomes will help us to understand the possible impact of HERVs on evolution and genome regulation in the primates. BioEssays 22:161-171, 2000.     

The distribution and expression of HERV families in the human genome

The families of human endogenous retroviruses (HERVs) are widely distributed in the human genome. Here we examined their distribution and expression. Approximately forty thousand HERV elements including truncated and solitary long terminal repeats (LTRs) were identified. These elements were most dense on chromosomes 4, 20, X, and Y. From an analysis of genomic stability during primate evolution, the 5 cent -LTR of the HERV genome (5 cent LTR - internal HERV - 3 cent LTR) appeared to be more often truncated than the 3 cent -LTR. ESTs derived from normal placenta, skeletal muscle, hypothalamus, and testis gave frequent matches to HERV elements. We present a classification of genes associated with HERV elements according to the hierarchical structure of gene ontology.     

Are human endogenous retroviruses pathogenic? An approach to testing the hypothesis

A number of observations have led researchers to postulate that, despite being replication‐defective, human endogenous retroviruses (HERVs) may have retained the potential to cause or contribute to disease. However, mechanisms of HERV pathogenicity might differ substantially from those of modern infectious retroviruses or of the infectious precursors of HERVs. Therefore, novel pathways of HERV involvement in disease pathogenesis should be investigated. Recent technological advances in sequencing and bioinformatics are making this task increasingly feasible. The accumulating knowledge of HERV biology may also facilitate the definition and general acceptance of criteria that establish HERV pathogenicity. Here, we explore possible mechanisms whereby HERVs may cause disease and examine the evidence that either has been or should be obtained in order to decisively address the pathogenic potential of HERVs.     

Human endogenous retroviruses

Several studies have revealed the presence in human DNA of thousands of endogenous retrovirus genomes, or HERVs. Many HERVs are related to extant retroviruses that infect other vertebrates and some have been present in the germ line of primates for millions of years. Although the HERVs that have been isolated are defective and thus do not encode infectious retroviruses, there may be HERVs that are capable of infection. In addition, because HERVs are so ancient in the human lineage, evolution of the human genome may have included the acquisition of some HERV genes for strictly cellular functions.     

Interactions between human endogenous and exogenous retroviruses

Retrovirus genes have become inserted into the human genome for more than one million years. These retroviruses are now inactivated due to mutation, such as deletions or nonsense mutations. After mutation, retroviruses eventually become fixed in the genome in the endogenous form and exist as traces of ancient viruses. These retroviruses are called human endogenous retroviruses (HERVs). HERVs cannot make fully active viruses, but a number of viral proteins (or even virus particles) are expressed under various conditions. By comparison with ERVs, some exogenous retroviruses are still infectious and cause serious diseases threatening human life. Recent studies have shown that some elements of HERVs are closely related to other exogenous retroviruses, including human immunodeficiency virus (HIV). This review will describe the regulation and interaction between HERVs and other active viral infections. In addition, we introduce the development of vaccines and therapeutic agents against these viral infections through the use of HERV elements.