Presence of a Shared 5′-Leader Sequence in Ancestral Human and Mammalian Retroviruses and Its Transduction into Feline Leukemia Virus

Abstract

Recombination events induce significant genetic changes, and this process can result in virus genetic diversity or in the generation of novel pathogenicity. We discovered a new recombinant feline leukemia virus (FeLV) gene harboring an unrelated insertion, termed the X region, which was derived from endogenous gammaretrovirus 4 (FcERV-gamma4). The identified FcERV-gamma4 proviruses have lost their coding capabilities, but some can express their viral RNA in feline tissues. Although the X-region-carrying recombinant FeLVs appeared to be replication-defective viruses, they were detected in 6.4% of tested FeLV-infected cats. All isolated recombinant FeLV clones commonly incorporated a middle part of the FcERV-gamma4 5'-leader region as an X region. Surprisingly, a sequence corresponding to the portion contained in all X regions is also present in at least 13 endogenous retroviruses (ERVs) observed in the cat, human, primate, and pig genomes. We termed this shared genetic feature the commonly shared (CS) sequence. Despite our phylogenetic analysis indicating that all CS-sequence-carrying ERVs are classified as gammaretroviruses, no obvious closeness was revealed among these ERVs. However, the Shannon entropy in the CS sequence was lower than that in other parts of the provirus genome. Notably, the CS sequence of human endogenous retrovirus T had 73.8% similarity with that of FcERV-gamma4, and specific signals were detected in the human genome by Southern blot analysis using a probe for the FcERV-gamma4 CS sequence. Our results provide an interesting evolutionary history for CS-sequence circulation among several distinct ancestral viruses and a novel recombined virus over a prolonged period. Recombination among ERVs or modern viral genomes causes a rapid evolution of retroviruses, and this phenomenon can result in the serious situation of viral disease reemergence. We identified a novel recombinant FeLV gene that contains an unrelated sequence, termed the X region. This region originated from the 5' leader of FcERV-gamma4, a replication-incompetent feline ERV. Surprisingly, a sequence corresponding to the X region is also present in the 5' portion of other ERVs, including human endogenous retroviruses. Scattered copies of the ERVs carrying the unique genetic feature, here named the commonly shared (CS) sequence, were found in each host genome, suggesting that ancestral viruses may have captured and maintained the CS sequence. More recently, a novel recombinant FeLV hijacked the CS sequence from inactivated FcERV-gamma4 as the X region. Therefore, tracing the CS sequences can provide unique models for not only the modern reservoir of new recombinant viruses but also the genetic features shared among ancient retroviruses.

Identification and characterization of ERV-W-like sequences in Platyrrhini species provides new insights into the evolutionary history of ERV-W in primates

“…Such low recombination rate has been already involved in the Y chromosome delayed loss of Alu transposons as compared with the autosomes, in which genomic redistributions of retroelements is greatly facilitated [40]. The presence of a long 5′ leader sequence between the PBS and gag has been reported to be an unique genetic feature of exogenous gammaretroviruses, providing splicing signals and promoting ribosome synthesis of viral proteins independently of the 5′ cap structure through an internal ribosome entry site (IRES) [39]. A similar 5′ leader region has been identified also in some class I mammalian ERV groups, including anthropoids HERV-T, HERV-I, and HERV-3 [39] as well as HERV-H [31].…”

“…The presence of a long 5′ leader sequence between the PBS and gag has been reported to be an unique genetic feature of exogenous gammaretroviruses, providing splicing signals and promoting ribosome synthesis of viral proteins independently of the 5′ cap structure through an internal ribosome entry site (IRES) [39]. A similar 5′ leader region has been identified also in some class I mammalian ERV groups, including anthropoids HERV-T, HERV-I, and HERV-3 [39] as well as HERV-H [31]. We extended the analysis including a total of 14 gammaretroviral HERV groups, which have been compared with class II and III HERV sequences.…”

“…This stable feature shared by ancient and existing gammaretroviruses further corroborates an important role in their replication cycle. Accordingly, MLV, feline leukemia virus, and koala retrovirus all harbor additional ORFs that are translated in the 5′ leader and encode a glycosylated form of Gag, enhancing the infectivity of the viruses [39]. Similarly, HERV-H pre-gag includes an ORF positioned like the N terminus of MLV gag, possibly encoding for a MLV pp12-like protein [31].…”

“…a based on a classification reported in [14]. b Most basal species with orthologous locus and the start codon of the gag gene, and this element regulates central steps of viral replication, including splicing and -in some instancesribosome occupancy [39].…”

Discovery of the First Human Retro-Giant Virus: Description of its morphology, retroviral kinase and ability to induce tumours in mice

“…RT activity matched to the presence of retroviral antigens at EM immunogold. To test the presence of possible retroviral antigens expressed on the giant particles, we used anti-FeLV gag p27 moAb, used for its ability to bind conserved epitopes among different mammalian retroviruses [10][11][12][13][14][15][16] . At EM immunogold, both the large and satellite ~400 -450 nm giant viral particles shared the same retroviral nature, being specifically labelled by anti-FeLV gag p27 mo-Ab, (Figure 5).…”