Identification and Characterization of Novel Human Endogenous Retrovirus Families by Phylogenetic Screening of the Human Genome Mapping Project Database

Abstract

Human endogenous retroviruses (HERVs) were first identified almost 20 years ago, and since then numerous families have been described. It has, however, been difficult to obtain a good estimate of both the total number of independently derived families and their relationship to each other as well as to other members of the family Retroviridae. In this study, I used sequence data derived from over 150 novel HERVs, obtained from the Human Genome Mapping Project database, and a variety of recently identified nonhuman retroviruses to classify the HERVs into 22 independently acquired families. Of these, 17 families were loosely assigned to the class I HERVs, 3 to the class II HERVs and 2 to the class III HERVs. Many of these families have been identified previously, but six are described here for the first time and another four, for which only partial sequence information was previously available, were further characterized. Members of each of the 10 families are defective, and calculation of their integration dates suggested that most of them are likely to have been present within the human lineage since it diverged from the Old World monkeys more than 25 million years ago.

Search for active endogenous retroviruses: identification and characterization of a HERV-E gene that is expressed in the pancreas and thyroid

“…More than 50 copies of HERV-E have been estimated to exist in the human genome (Tristem 2000). However, the present study suggests that the only active locus in normal adult tissues may be the ERVE1 locus.…”

Detecting the expression of human endogenous retrovirus E envelope transcripts in human prostate adenocarcinoma

“…The fulllength structure is present in approximately 35-50 copies per human haploid genome. 3 The nucleotide sequence of HERV-E 4-1 reveals a 449 base pair (bp) 3Ј LTR and a 495-bp 5Ј LTR, and the genomic DNA is organized into gag, pol, and env genes interspersed between the 2 LTRs. 6 HERV-E 4-1 gag-pol sequences exhibit approximately 40% homology to Moloney murine leukemia virus DNA.…”

The human endogenous retrovirus K Rev response element coincides with a predicted RNA folding region

“…All retroviruses must express both unspliced and spliced forms of their initial, genome-length RNA transcript during the viral replication cycle (reviewed by Pollard & Malim, 1998;+ Therefore, retroviral replication is dependent on the nuclear export of not only fully spliced viral mRNAs that are comparable to cellular mRNAs, but also of incompletely spliced viral mRNAs that are essentially analogous to cellular premRNAs+ However, eukaryotic cells have evolved mechanisms to block the access of such pre-mRNAs to cellular mRNA export factors until processing is complete+ Retroviruses have therefore had to evolve mechanisms for the nuclear export of their incompletely spliced transcripts that are at least in part distinct from the canonical cellular mRNA export pathway+ At least two different mechanisms utilized by retroviruses for the nuclear export of their unspliced transcripts have been identified+ Several simple retroviruses, including simian type D viruses and avian leukemia viruses, contain a structured RNA element, termed a constitutive transport element (CTE), that directly recruits a cellular RNA export factor (Bray et al+, 1994)+ In the case of the simian type D viruses, this cellular cofactor has been identified as Tap, a protein that is also believed to play a critical role in the final stages of cellular mRNA export (Grüter et al+, 1998;Kang & Cullen, 1999;Katahira et al+, 1999)+ Unlike simple retroviruses, several more complex retroviruses utilize a virally encoded adaptor protein, termed Rev in human immunodeficiency virus type 1 (HIV-1) and Rex in human T-cell leukemia virus type I (HTLV-I), to recruit a distinct cellular nuclear export factor, termed Crm1, to incompletely spliced viral transcripts (Fornerod et al+, 1997;Neville et al+, 1997;Stade et al+, 1997)+ Thus, Rev and Rex bind not only to a highly structured viral RNA element termed the Rev response element (RRE) in HIV-1 and the Rex response element (RxRE) in HTLV-I (Hanly et al+, 1989;Malim et al+, 1989), but also, via a short leucine-rich sequence, to the Crm1 nuclear export factor+ Although Crm1 is unrelated to Tap and does not play a direct role in cellular mRNA export, Crm1 and Tap share the ability to target viral RNAs to the cytoplasm by directly binding to components of the nuclear pore complex (Neville et al+, 1997;Katahira et al+, 1999)+ Recently, a third protein functionally analogous to HIV-1 Rev (H-Rev) and HTLV-I Rex has been identified in human endogenous retrovirus K (HERV-K) (Magin et al+, 1999;Yang et al+, 1999)+ The HERV-K are a family of endogenous viruses, estimated to be present at between 50 and 170 copies per haploid human genome, that first entered the human germ line ;30 million years ago (Medstrand & Mager, 1998;Tristem, 2000)+ The HERV-K are not closely related to any currently known exogenous ret...…”