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Human endogenous retroviruses are a family of viruses and its sequences found in the human genomes. HERVs are remnants of very old retroviral infection within genome. It is also involved in cancer and autoimmune disorders (Nelson et al, 2003). ERVs are participating in processes, such as speciation, recombination, ontogenesis, and regulation of tissue specificity and gene expression. Human endogenous retroviruses represent both putative susceptibility genes and putative pathogenic viruses in diseases (Christensen et al, 2003). Human ERVs have been studied in greater detail, and naming of HERVs in the scientific literature but it is confusing so nomenclature of HERVs is not still clear.Â (Blomberg et al, 2009).
Figure 1: Structure of retroviral proviruses.Â There are three genes for Infectious retroviruses:Â gag, which encodes the structural proteins of the viral core;Â pol, which encodes the viral enzymes, including reverse transcriptase; andÂ env, which encodes the surface glycoproteins of the viral envelope. Other regulatory elements are also present in the viral genome, including splice donor (SD) and acceptor (SA) sites (forÂ envexpression) and a primer-binding site (PBS) for a specific tRNA molecule used to initiate reverse transcription. The tRNA specificity varies among different retroviruses and has been used to classify endogenous retroviruses in the human genome (Griffiths,2001).
Classification and distribution:
HERV families have been identified which are over twenty. They are classified based on the single letter of amino acid code for the tRNA specificity of the primer binding site used to initiate reverse transcription. HERVs genomic structure is highly closer to exogenous retroviruses. (Singh et al, 2009). There is 5-8% of human genomic DNA is made up of HERVs and its replication inept in spite of expression of individual HERV genes as of different chromosomal loci depending on the specific tissue(Antony et al,2010)
Origin and evolution:
It is approximate that about 8% of human genome DNA is involved HERVs sequences. HERVs integrated into the genome which follow the ancient germline infections by using exogenous retroviruses and are thus transmitted vertically, rather than horizontal transmission characteristic of an infectious virus. Before 25 million years ago, they started in our ancestors and it is also as present in the genomes of chimpanzees and Old World monkeys. They executed or perform a helpful biological function which is unclear whether they were reserved and therefore persevered during evolution. For example, the protein syncytin in HERV-W which has envelope gene on chromosome 7 is consideration to play a key role in placenta formation (Singh et al, 2009).
Endogenous retroviruses are a kind of transposon like "jumping gene", and one expects them to incorporate into new loci in the human genome. The Jack Lenz 'group finds that humans have integral and active HERVs which theoretically are transferable and therefore can have a comparable pathogenic status in mice. There are number of more or less functional endogenous retroviruses or retrovirus-like transposons are mostly in humans or other eukaryotes. There have been many more exogenous retroviruses in the forefathers of humans than the four human exogenous retroviruses known today (HTLV-1 and -2, HIV-1 and -2) which shows in the plenitude of HERVs. Through exogenous retroviruses, in an animal more or less related to humans, or even in humans themselves many of them may have died but some may survive infectious (Blomberg et al, 2010).
Relationship to disease:
Numerous HERV genes have been noticed as transcripts and proteins in the central nervous system, regularly in the context of neuroinflammation. Relations with diverse syndromes like multiple sclerosis (MS) and several psychiatric disorders in family of HERV-W received considerable attention in large part. Like complete and incomplete open reading frames, in the multiple insertion sites of HERV genes are jointly with their contradictory capacity to be expressed and the difficulties of individual HERVs because of both disease markers and bioactive effectors. For understanding neuropathogenic mechanisms and developing new therapeutic strategies HERV biology is an influential (Antony et al, 2011). In humans, immunodeficiency and neurological disease are caused by exogenous retroviruses. HERVs may well be considered as rising pathogens where in other species endogenous retroviruses pathogens are strongly recognized. HERVs also show multifaceted interactions with exogenous retroviruses and herpesviruses. Multiple sclerosis (MS) and schizophrenia are two neurological disorders which are related with HERVs. The circulation and the central nervous system (CNS) both are exclusively activated in HERV-H, HERV-F and HERV-W which is widely held of MS patients, the envelopes like transcription and proteins come into view strongly connected with disease activity. In schizophrenia patients, anti-HERV-W Gag reactive epitopes expression is down-regulated in the brain but up-regulated in the blood. The pathogenic potential of HERVs definitely qualities further studies (Christensen,Â 2010). Contained by rheumatoid arthritis (RA) HERVs molecular remnants draw parallels with present-day exogenous retroviruses and have been linked previously with immunopathology.
In RA the Mechanisms of pathogenesis for HERV-K is molecular imitation were examined. And a role for HERVs in RA is elucidating by possible autoantigens concerned in autoimmunity were scanned for sequence individuality with retroviral epitopes. In RA patients the significant variation is based on both serologically and transcriptionally and it may be sign that RA is an umbrella term for a number of separate disease divisions which are exacting HERV polymorphisms may play a role in improvement (Freimanis et al, 2010).
Role in gene expression:
Long terminal repeats (LTRs) of HERVs might affect transcription regulation of neighboring genes. The LTR functional categorization based on the particular region within the U3 part emerged to be accountable for the enhancer possessions.The recognized enhancer was able to work in an extremely cell type precise manner. The information fined are in line with the hypothesis suggesting that KIAA1245/NBPF. LTR may affect the regulation of the KIAA1245/NBPF subfamily genes transcription (Abrarova et al, 2010).
Over millions of years of chimpanzee evolution by communicable viruses, HERVs result from familial infection. To cause disease there are some transcriptionally active, express proteins which have the impending for it. Cancer and autoimmunity are link with them by contentious efforts. In 100% of the population, HERVs examined to date are present at the same locus which is main difficulty. HERV-K family members have a new class of insertionally polymorphic which is present in an alternative of individuals, therefore insertionally polymorphic HERVs have proposition that it could be narrative genetic risk factors and hence provide a new let out of life for research into HERVs and disease(Moyes et al, 2007).
In the human genome HERVs are analyze the forces directing the accretion by evaluating de novo HERV incorporation targeting with the allocation of fixed HERV elements. During mutation all knowing genomic HERVs are unmoving but it able to study incorporation targeting using a reconstituted agreement HERV-K. So it is establish that HERV-K (Con) incorporated preferentially in transcription components, in gene-rich regions, and near characteristics linked with vigorous transcription units and associated dictatorial regions. Outside transcription units, genomic HERV-K proviruses are also found preferentially in difference. Inside transcription units genomic HERVKs present alternative and in contradictory transcriptional orientation relative to the host gene, evidence disorderly to host mRNA synthesis is orientation expected but no orientation bias showed in de novo HERV-K (Con) integration within transcription units. A distribution intermediary between de novo HERV-K (Con) integration sites and older fixed HERV-Ks is found in the youngest HERV-K elements in the human genome. Incorporation targeting biases direct initial accretion, and then purifying collection leads to loss of proviruses disrupting gene function are two steps process for findings the accumulation of HERVs in the human germline (BradyÂ et al, 2009). There are two evidences like theoretical and laboratory which associated HERV-K in melanomagenesis and an aetiopathogenic role has not yet been established. Epiphenomena which are possible by expression of HERV-K mRNA and proteins, and formation of RVLPs are connected with tumorigenesis. Furthermore, in normal skin, benign naevi and NEHMWork HERV-K transcription have been reported. Primary melanoma and normal skin are required for HERV-K expressions which are focused on melanoma cell lines and metastasis tissue, and further comparative investigations. In adding, humoral anti-HERV-K immune responses are essential for prospective studies examining which is support the present confirmation that serological HERV-K reactivity offers prognostic information additional to that of recognized melanoma markers. It is complicated to allocate a pathological role to the HERVs investigated so far because of their ubiquity in the population. Rather than HERV-K whole family, but possibly the contribution of individual proviral loci should be examined. In this reverence, for melanoma insertionally polymorphic HERVs merit is further investigation because they may correspond to novel genetic risk factors. Significantly, a result of molecular genetic studies representative specific genotype-phenotype relationships which has been a recent drive towards a molecular classification of melanoma. By using array-based comparative genomic hybridization, a important correlation of ultraviolet radiation exposure and melanoma site toÂ BRAF/NRASÂ gene mutations and additional genetic events established.Insertionally polymorphic HERVs with melanoma is a exploration of the relationship and primary melanoma with clinicopathological subtype is association of HERV expression. In melanomagenesis, In vitroÂ and mouse models have provided attractive insights into the impending mechanisms of HERVs. However, through these mechanisms, inducing genetic mutations which are cause cancers by oncogenic viruses or by expressing oncoproteins and there is little direct confirmation that HERVs act on it. Further purposeful analysis of the HERV-K addition proteins Rec and Np9 are required to establish whether they are significant in the causation of melanoma (Singh et al, 2009).The obtainable concepts give details events previous the clinical demonstration of diseases by quite a few years and provide a foundation for the use of currently available vaccines to protect against convinced HERV-induced diseases, particularly melanoma. criterion for founding the causal role of HERVs in a given disease are projected(Krone et al,2010)
Endogenous retroviruses (ERVs) integrated into human genome after cross-species infectious events millions of years ago. Few of the ERVs retain the basic structure of the integrated proviral form of infectious retroviruses. HERVs represent a key molecular link between the host genome and infectious viral particles. They constitute a large reservoir of viral genes that could be activated by various factors such as mutations or carcinogenic chemical exposures and so forth. Endogenous retroviruses are transmitted genetically in a Mendelian fashion through the germline as proviral DNA. Expression pattern of HERVs can influence the outcome of their presence in many forms, which can be either beneficial or detrimental to the host. ERVs have been reported to play a role in both human physiology and human pathology. Along with their expression in many disease conditions, they have also been reported to be expressed on normal peripheral blood lymphocytes, salivary glands and keratinocytes.