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.     

HERVd: database of human endogenous retroviruses

The human endogenous retroviruses database (HERVd) is maintained at the Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, and is accessible via the World Wide Web at http://herv.img.cas.cz. The HERVd provides complex information on and analysis of retroviral elements found in the human genome. It can be used for searches of individual HERV families, identification of HERV parts, graphical output of HERV structures, comparison of HERVs and identification of retrovirus integration sites.     

Interplay between endogenous and exogenous human retroviruses

In humans, retroviruses thrive more as symbionts than as parasites. Apart from the only two modern exogenous human retroviruses (human T-cell lymphotropic and immunodeficiency viruses; HTLV and HIV, respectively), ~8% of the human genome is occupied by ancient retroviral DNA [human endogenous retroviruses (HERVs)]. Here, we review the recent discoveries about the interactions between the two groups, the impact of infection by exogenous retroviruses on the expression of HERVs, the effect of HERVs on the pathogenicity of HIV and HTLV and on the severity of the diseases caused by them, and the antiviral protection that HERVs can allegedly provide to the host. Tracing the crosstalk between contemporary retroviruses and their endogenized ancestors will provide better understanding of the retroviral world.     

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.     

T cell responses to human endogenous retroviruses in HIV-1 infection

Human endogenous retroviruses (HERVs) are remnants of ancient infectious agents that have integrated into the human genome. Under normal circumstances, HERVs are functionally defective or controlled by host factors. In HIV-1-infected individuals, intracellular defense mechanisms are compromised. We hypothesized that HIV-1 infection would remove or alter controls on HERV activity. Expression of HERV could potentially stimulate a T cell response to HERV antigens, and in regions of HIV-1/HERV similarity, these T cells could be cross-reactive. We determined that the levels of HERV production in HIV-1-positive individuals exceed those of HIV-1-negative controls. To investigate the impact of HERV activity on specific immunity, we examined T cell responses to HERV peptides in 29 HIV-1-positive and 13 HIV-1-negative study participants. We report T cell responses to peptides derived from regions of HERV detected by ELISPOT analysis in the HIV-1-positive study participants. We show an inverse correlation between anti-HERV T cell responses and HIV-1 plasma viral load. In HIV-1-positive individuals, we demonstrate that HERV-specific T cells are capable of killing cells presenting their cognate peptide. These data indicate that HIV-1 infection leads to HERV expression and stimulation of a HERV-specific CD8+ T cell response. HERV-specific CD8+ T cells have characteristics consistent with an important role in the response to HIV-1 infection: a phenotype similar to that of T cells responding to an effectively controlled virus (cytomegalovirus), an inverse correlation with HIV-1 plasma viral load, and the ability to lyse cells presenting their target peptide. These characteristics suggest that elicitation of anti-HERV-specific immune responses is a novel approach to immunotherapeutic vaccination. As endogenous retroviral sequences are fixed in the human genome, they provide a stable target, and HERV-specific T cells could recognize a cell infected by any HIV-1 viral variant. HERV-specific immunity is an important new avenue for investigation in HIV-1 pathogenesis and vaccine design.     

Rate of recombinational deletion among human endogenous retroviruses

The fate of most human endogenous retroviruses (HERVs) has been to undergo recombinational deletion. This process involves homologous recombination between the flanking long terminal repeats (LTRs) of a full-length element, leaving a relic structure in the genome termed a solo LTR. We examined loci in one family, HERV-K(HML2), and found that the deletion rate decreased markedly with age: the rate among recently integrated loci was almost 200-fold higher than that among loci whose insertion predated the divergence of humans and chimpanzees (8 x 10(-5) and 4 x 10(-7) recombinational deletion events per locus per generation, respectively). One hypothesis for this finding is that increasing mutational divergence between the flanking LTRs reduces the probability of homologous recombination and thus the rate of solo LTR formation. Consistent with this idea, we were able to replicate the observed rates by a simulation in which the probability of recombinational deletion was reduced 10-fold by a single mutation and 100-fold by any additional mutations. We also discuss the evidence for other factors that may influence the relationship between locus age and the rate of deletion, for example, host recombination rates and selection, and highlight the consequences of recombinational deletion for dating recent HERV integrations.     

Expression of human endogenous retroviruses in pemphigus vulgaris patients

Molecular Biology Reports - Pemphigus is a severe, potentially life-threatening autoimmune blistering mucocutaneous disease which establishes with autoreactive IgG antibodies that target cellular...     

Human endogenous retroviruses, hormones and APOBEC3G: A connection to explore in schizophrenia

Human endogenous retroviruses (HERVs) represent the footprints of previous retroviral infections. They are integrated within the human germ line and constitute approximately 7% of our genome. They have the potential to harm, given their capacity to alter the cellular metabolism, and could be involved in various pathological processes such as systemic lupus erythematosus or multiple sclerosis. In this respect it has been found that the stimulation of HERVs genome expression was observed after a steroid hormone treatment, stating the first evidence that an enhanced expression of the HERVs genome by hormones may be involved in the etiology of breast cancer. There is now increasing evidence that HERVs may in fact be involved in the etiology of schizophrenia, a disorder characterized by heterogeneous presence of positive, negative and cognitive symptoms that affect all aspects of mental activity, with a first peak incidence for males and females in the decade 15-24 and a second peak at age 55-64 for females, both periods characterized by two moments of significant hormonal changes. In connection with genetic aspects, several studies suggest a linkage between chromosome 22 (22q) and schizophrenia, being different genes of this chromosomal region reported as candidate genes for association with the disorder. Likewise, in a closely region of these genes, on 22q13, is located a gene named APOBEC3G, a potent intrinsic inhibitor of retroviral replication that also includes some HERVs. We propose that hormonal changes that coincide with two peak incidences in schizophrenia produce an enhancement in the expression of some HERV families implicated in the etiopathology of the disorder. The expression of HERVs is followed by a defective action of APOBEC3G that avoids carry out its function, that is, the inhibition of retroviral replication. This altered process might play a critical role in the etiopathogenesis of schizophrenia.     

A large number of the human microRNAs target lentiviruses, retroviruses, and endogenous retroviruses

Retroelements (including transposons, retrotransposons, retroviruses, and lentiviruses) make up a significant portion of eukaryotic genomes. Given their ability to mutate genes these mobile elements always present a threat to the integrity of the host genomes. Recent studies have revealed complex molecular mechanisms that silence the mutagenic ability of these RE as well strategically express the pieces of the incorporated RE that are utilized to silence human endogenous retroviruses (HERVs) or invading exogenous retroviruses (IERV). We have hypothesized that small endogenous RNA originally evolved to quell “foreign” IERV-genes and subsequently emerged into elaborate silencing systems that include RNA interference, miRNA-based gene regulation and other gene silencing mechanisms. Here, we present evidence that the replication of complex RE are most likely silenced or regulated by homologous miRNA that are found as a part of the cellular repertoire. We analyzed Homo sapiens miRNAs for possible target genetic sequences in selected HERVs and IERV found in humans and other large primates. We identified several miRNAs that have >80% sequence homology with human HERVs; -L, -W, and -K, and IERV like SIVcpz, HTLV-1, and HTLV-2. We found an inverse correlation between the numbers and relative degree of homology of miRNAs to the relative replication capacity of a specific RE. Therefore, larger numbers of miRNAs with greater degree of homology are found against the least active RE and the least numbers of miRNAs with smaller degree of homology are found against the most active RE (i.e. HERV-K). Implications of these observations in RE disease and therapy are discussed.     

Identification of a functional envelope protein from the HERV-K family of human endogenous retroviruses

Genome-wide screening of sequence databases for human endogenous retroviruses (HERVs) has led to the identification of 18 coding env genes, among which two-the syncytin genes-encode fusogenic ENV proteins possibly involved in placenta physiology. Here we show that a third ENV, originating from the most "recent" HERV-K(HML2) family, is functional. Immunofluorescence analysis of env-transduced cells demonstrates expression of the protein at the cell surface, and we show that the protein confers infectivity to simian immunodeficiency virus pseudotypes. Western blot analysis of the pseudotyped virions further discloses the expected specific cleavage of the ENV precursor protein. This functional ENV could play a role in the amplification--via infection of the germ line--of the HERV-K genomic copies, all the more as coding HERV-K gag and pol genes can similarly be found in the human genome, which could therefore generate infectious virions of a fully endogenous origin.