Just as we study fossils to understand how animals and plants have evolved, we can study ancient viruses to understand how diseases have emerged and changed over long periods. Unlike fossils, viruses do not leave visible traces in the ground but, instead, they leave viral genes known as endogenous viral elements (or EVEs) that become permanently incorporated in their host’s DNA.

HML-2s are the youngest known EVEs in the human genome. They have evolved gradually by accumulating lots of small genetic changes and no longer actively infect humans. But these virus remnants have long been suspected to play a role in prostate cancer, lupus and other human diseases. Rhesus macaques and other monkeys also have HML-2s but these are less well studied than human HML-2s. Monkeys are often used as models of human biology in research studies, therefore, understanding how HML-2s have evolved in rhesus macaques may enable researchers to establish this monkey as a model for investigating the role of HML-2s in humans.

To investigate this possibility, Williams et al. searched for HML-like EVEs in rhesus macaque genomes published in previous studies. The experiments found that, unlike human HML-2s, the macaque HML-2s underwent a sudden genetic transformation millions of years ago. They acquired a new gene from another virus that completely changed how the macaque HML-2s leave a compartment within the cells of their host that contains most of the host’s genome – a key step in the life cycle of viruses.

The data also suggest that HML-2s may still be actively infecting macaques today and that these EVEs jumped from monkeys into gibbons. This is the first known example of HML-2s moving between different types of primates and it indicates there may be a risk that macaque HML-2s could infect humans.

In the future, the findings of Williams et al. may help researchers develop new approaches to treat prostate cancer and other diseases linked with HML-2s in humans.

Retroviruses (Retroviridae) are a major family of animal viruses, including human viruses capable of causing severe immunodeficiency (HIV-1 and HIV-2) or cancer (HTLV-1) (Chermann et al., 1983; Gallo et al., 1984; Guyader et al., 1987; Jern and Coffin, 2008; Poiesz et al., 1980). Uniquely among animal viruses, they must irreversibly integrate their genome into the host genome in order to replicate (Brown, 1997; Hughes et al., 1978). If an infected cell survives, the integrated viral genome, or provirus, will be stably inherited by daughter cells; if a germline cell is infected, the provirus may be inherited by an offspring of the host organism as a heterozygous allele, which may eventually become fixed in the descendant population (Stoye, 2012). Such proviruses and remnants of such proviruses, known as endogenous retroviruses (ERVs), form a major fraction of most eukaryotic genomes; in humans, ~8% of the genome is composed of such sequences (Griffiths, 2001). These sequences serve as a useful ‘fossil record’ of past viral infections, and can also play important roles in genome evolution, host–viral interactions, and disease; in some animals, such as mice and cats, reactivation and recombination of ERVs with exogenous viruses and/or other ERVs can have severe pathogenic consequences (Bamunusinghe et al., 2017; Bolin and Levy, 2011; Johnson, 2019; Young et al., 2012). No replication competent human ERV (HERV) has been identified; however, the betaretrovirus-like HERV-K group contains one subgroup, human MMTV-like-2, or HML-2 (named for its similarity to mouse mammary tumor virus (MMTV)), which includes many proviruses with full-length open reading frames (ORFs) and other intact functional elements, including two proviruses with full-length ORFs for the four core retroviral proteins Gag, Pro, Pol, and Env (Boller et al., 2008; Hanke et al., 2016; Subramanian et al., 2011; Wildschutte et al., 2016). The majority of HML-2 proviruses containing full-length ORFs are within the LTR5Hs subclade, which is the youngest HERV clade and contains many human specific and insertionally polymorphic proviruses that have not yet reached fixation in human populations (Subramanian et al., 2011; Wildschutte et al., 2016). Although none of these proviruses are replication competent, two groups have shown that a synthetic consensus young HML-2 provirus is weakly replication competent, and expression of HML-2 RNA and proteins has been observed in a number of different diseases (Dewannieux et al., 2006; Garcia-Montojo et al., 2018; Goering et al., 2015; Hanke et al., 2016; Magiorkinis et al., 2013; Schmitt et al., 2013; Wang-Johanning et al., 2014; Lee and Bieniasz, 2007).

The oldest known human HML-2 proviruses have orthologous insertions in both apes and Old World monkeys (OWM), indicating that the clade originated in the common ancestor of the catarrhine primates (Bannert and Kurth, 2006). However, much less is known about the evolutionary history and extent of HML-2 activity in non-human primates than in humans. A recent study reported that HML-2 has more recently been actively replicating in gorillas than in humans, though it is still unclear whether that activity has continued to the present day; some chimpanzee-specific insertions have also been identified, although fewer than in humans or gorillas (Holloway et al., 2019; Macfarlane and Badge, 2015). A 2007 study identified 19 HML-2 proviruses in rhesus macaques (designated as ‘RhERV-K’), including three with almost identical long terminal repeats (LTRs), implying relatively recent integration (Romano et al., 2007). More recently, another study identified several HML-2-like proviruses in rhesus macaques, detected expression of env mRNA, and identified one macaque with an Env-specific immune response (Wu et al., 2016). One of the proviruses identified, which the authors named SERV-K1, has full-length ORFs for gag and env, and only two single nucleotide insertions disrupting the pro and pol ORFs. SERV-K1 is not present in the rhesus reference genome, indicating that it is insertionally polymorphic, and its 5′ and 3′ LTRs are identical in sequence. Both of these characteristics indicate that SERV-K1 is a relatively young insertion (less than about 500,000 years old), and suggests that rhesus macaques could possibly harbor currently or recently active HML-2-like retroviruses. Lastly, a recent study identified SERV-K1-like proviruses in a number of OWM species, including multiple macaque species, geladas, and olive baboons; this study also reported that many of these proviruses had very similar LTRs, suggestive of recent integration (van der Kuyl, 2021). Overall, these studies indicate the potential for recent HML-2 activity in multiple catarrhine primate species, including rhesus macaques. Thus, a comprehensive characterization of HML-2 proviruses in the rhesus macaque reference genome would provide a valuable starting point for further investigations of this potential. In order to investigate the possibility that HML-2 viruses were recently or are currently active in rhesus macaques, we searched for HML-2 proviral sequences in the two most recent rhesus genome assemblies and performed an in-depth characterization of their structure, coding capacity, and evolutionary history, with a particular focus on SERV-K1-like proviruses. We have found that SERV-K1 is part of a large clade of rhesus proviruses that show signs of recent activity. Furthermore, this clade originated as an ancient recombinant between an HML-2-like virus and another retrovirus in the HERVK11(HML-8) clade. The recombinant retrovirus has also undergone at least one interspecies transmission event, from OWM to gibbons. Lastly, we have discovered that the region derived from the recombination with HML-8 functions as a novel constitutive RNA transport element, capable of facilitating export of unspliced and partially spliced viral RNA from the nucleus.

We have characterized a clade of HERV-K HML-2-related ERVs in rhesus macaques and other OWMs that include an ~750 bp non-coding region in between env and the 3′ LTR, derived from a recombination with a HERVK11 HML-8 retrovirus. This recombination resulted in the formation of a chimeric env gene, with the SU surface subunit and part of the TM transmembrane subunit derived from HML-2 env and the rest of TM derived from HML-8 env, including the transmembrane alpha helix and the cytoplasmic tail. The non-coding region is derived from the HML-8 LTR, also known as MER11.

We estimate that the recombination event which formed this clade of viruses, which we are calling SERV-K/MER11, occurred approximately 20–25 million years ago, before the split between the colobine and cercopithecine subfamilies of OWM, but after the split between apes and OWM. Consistent with this estimate, orthologs of the oldest insertions are found in species from both subfamilies of OWM, but not in any apes. This timing is supported by estimated integration times of these ancient elements based on sequence divergence of their 5′ and 3′ LTRs. The majority of the 106 recombinant proviruses so far identified in rhesus genomes are much younger, however, including two subclades of rhesus-specific insertions. Many of these young proviruses are insertionally polymorphic and present at low frequencies in macaques, and 36 of them have identical LTRs. Taken together, this evidence suggests infectious activity of HERV-K-like retroviruses in rhesus macaques within the last 500–250,000 years, and the potential for ongoing replication.

We investigated the coding capacity of these proviruses, and identified full-length ORFs for all genes, including 28 gag, 13 pro, 6 pol, and 7 env ORFs; two proviruses have intact ORFs for the full gag-pro-pol region and could thus potentially make functional retroviral cores, although they are lacking env, and so could not make infectious virus without complementation in trans from a provirus encoding a functional env gene. We compared the sequence of the consensus recent SERV-K/MER11 to HERV-Kcon; the overall nucleotide sequence identity of the coding region is 89.2% and amino acid identity of Gag, Pro, Pol, and Env are 78.5, 91, 91, and 82.5%, respectively. Although the sequence of these viruses has diverged, as expected for RNA viruses that have evolved separately for over 20 million years, it is likely that many of the basic features of HML-2 biology are conserved between these two viruses.

Although many of the proviruses characterized have one or more full-length ORFs, the majority of the proviruses also contain large shared deletions in the coding regions. The deletion containing proviruses are presumably not replication competent, and are reminiscent of human Type 1 HML-2s (Löwer et al., 1993), which contain a 292-bp env deletion, and other shared deletions observed in gorilla HML-2s (Holloway et al., 2019). Like those deletions, they are likely propagated via co-packaging with replication competent viral genomes.

In contrast to the coding regions, the LTRs of SERV-K/MER11 have undergone major structural changes, with large deletions in the U3 region. These deletions have accumulated over millions of years, with unique deletions appearing in the viral lineages in different host species, all converging on the same region of U3. Strikingly, the majority of these deletions overlap with the RcRE in human HML-2; it seems plausible that the accumulation of these RcRE deletions is causally related to the ancient recombination with HML-8 which provided the MER11 element of SERV-K/MER11. We have demonstrated that the MER11 element in a consensus young SERV-K/MER11 provirus is capable of functioning as a Rec-independent CTE, thus explaining how these proviruses are capable of functioning without an RcRE. Of the four most well-characterized betaretroviral systems (MMTV, Jaagsiekte sheep retrovirus, MPMV, and HERV-K HML-2), only one, MPMV, has a CTE system. MPMV was isolated from a rhesus macaque, and is the prototype isolate of the simian retroviruses (SRVs) of Asian macaques. Interestingly, the SRV clade is, like SERV-K/MER11, recombinant, with an env gene more closely related to those of gammaretroviruses than betaretroviruses (Sonigo et al., 1986); this raises the possibility that the SRV CTE system is also derived from a recombination event involving env and an adjacent non-coding sequence (the CTE).

Although these viruses appear to have lost their RcRE, they have retained a rec-like transcript that is predicted to produce a chimeric Rec-like protein, with a second exon derived from the recombinant HML-8-like sequence. This sRec protein does not appear to promote unspliced RNA transport, either with the human HML-2 RcRE or with SERV-K/MER11 sequences, but the conservation of this splice form suggests it may have another function in viral replication. This function may have evolved since the recombination event, or alternatively it may be that the Rec protein of human HML-2 has a second, currently unknown function. We cannot completely rule out the possibility that sRec still has some unspliced RNA transport activity, but the RcRE deletions and presence of an Rec-independent CTE in the MER11 element in combination with the lack of any promotion of unspliced RNA transport in our experiments by an sRec plasmid suggests any such activity is likely minimal. It is also as yet unknown whether the original chimeric sRec formed by the recombination event retained RNA transport activity, or whether that activity was lost over time. An immediate loss of RNA transport activity could provide a simple explanation for why these viruses switched from using a Rec–RcRE system to a CTE, if the original recombinant HML-8-derived region already had CTE activity. However, other evolutionary scenarios remain plausible, and the hypotheses that the ancestral recombinant sRec did not have RNA transport activity and that the ancestral MER11 element had CTE activity remain unproven.

The multiple deletions in U3 centered on the RcRE region indicate that the acquisition of the MER11 CTE resulted in relaxed constraint on this region. Whether these deletions are the result of neutral evolution or were in some way adaptive is unclear, however it is worth noting that four separate lineages in three species seem to have independently acquired such deletions, which seems at least suggestive of adaptive evolution. Potential selective forces include altered U3 promoter activity (which could potentially alter viral tropism), escape from sequence-specific restriction factors such as KRAB ZNFs, or perhaps some maladaptive effect of having both a CTE and RcRE in the same virus. It is also possible that lengthening the viral genome by ~1 kb had deleterious effects on viral fitness (e.g. constraints on the maximum length of RNA that can be efficiently packaged by the capsid), and the deletions relieved this defect. In this context, it is interesting to note that SERV-K1 is only 117 bp longer than HERV-Kcon, and thus the total length of the post-recombination deletions almost matches the length of the HML-8-derived insertion.

We have tested three different MER11 constructs for CTE activity. The largest one is composed of the HML-8-derived region of env, the MER11 element derived from the HML-8 LTR, the PPT, and the predicted U3R region of the SERV-K/MER11 LTR; from this we made two smaller constructs, one containing the full HML-8-derived sequence, without the PPT or U3R, and one containing only the LTR-derived MER11 region. All three constructs had CTE activity, however the construct containing only the LTR-derived MER11 region had noticeably lower activity as measured by the ratio of GFP to mCherry fluorescence, which may indicate that a portion of the env coding region is required for full CTE function. The MER11U3R construct has somewhat higher apparent activity than the MER11-only construct, however this appears to be driven by lower mCherry expression rather than higher eGFP expression, and may be an artifact resulting from placing U3R (which contains the SERV-K/MER11 polyadenylation signal) upstream of mCherry.

It is as yet unknown whether the full MER11 element is required for CTE function, although it is notable that few deletions of the MER11 region have appeared in the SERV-K/MER11 lineage since the original recombination, which would seem to suggest that the full MER11 is necessary for viral replication, whether or not it is all part of the CTE. Interestingly, the HML-2 env-derived sequence in between the MER11 element and the 3′ LTR is ~240 bp long in the oldest SERV-K/MER11 proviruses, but has been reduced to a short remnant containing the PPT in the rhesus-specific clade, as one might predict since it no longer has a function as part of the env ORF.

The full MER11-derived region is much longer than the canonical MPMV CTE, ~1000 bp as compared to 162 bp, and longer than most other previously characterized CTE-like elements as well. However, there are other examples of CTE-like elements much longer than the MPMV CTE; the MusD transport element (MTE) is 412 bp long (Ribet et al., 2007), and the murine leukemia virus (MLV) post-transcriptional regulatory element (PTE) is over 1400 bp long (Pilkington et al., 2014), while the woodchuck hepatitis virus (WHV) post-transcriptional regulatory element or WPRE (known to enhance both export and translation of RNAs) is 592 bp long (Donello et al., 1998). We were not able to identify any regions in MER11 with clear sequence homology to these elements or any other published RNA export element, nor are there obvious functional motifs (e.g. the NXF1-binding loops in the MPMV CTE). However, it is predicted to have strong secondary structure (data not shown), with a complex series of stem loops extending over the entire sequence. In comparison, the MusD MTE, MLV PTE, and WHV WPRE all also have complex, multi-stem loop secondary structures (Donello et al., 1998; Legiewicz et al., 2010; Pilkington et al., 2014).

The above experiments are all in the context of a lentiviral reporter construct, which do not normally use a CTE, and the assay tests the ability of the element to promote viral gene expression, but does not directly test its ability to promote viral replication. Similar reporters have also previously been shown to be somewhat ‘leaky’, which could possibly lead to increased GFP expression via increased translation of low levels of RNA that enter the cytoplasm even without an RNA export element present (Coyle et al., 2003). In order to test the CTE functionality of the SERV-K/MER11 HML-8-derived region in the context of a replicating, natively CTE-using virus, we cloned this region (including both the HML-8 env-derived region and the MER11 element) into a GFP-tagged MPMV infectious clone in place of the original MPMV CTE, and tested this construct’s ability to generate infectious virus in a single round, VSV-G pseudotyped assay. Remarkably, this chimeric virus generated near wild-type levels of infectious virus, in contrast to an MPMV construct with the wt CTE deleted, which completely abrogated infection.

We do not yet know what RNA trafficking pathway is used by the MER11 CTE, although it could plausibly use either the NXF1/Tap pathway used by MPMV and other retroviruses (Kang and Cullen, 1999; Lindtner et al., 2006; Sakuma et al., 2014), or the CRM1/XPO1 pathway, used by foamy viruses (Bodem et al., 2011), and also by retroviruses that use Rev/RRE-like systems (Bogerd et al., 1998; Yang et al., 1999). Interestingly MLV and WHV appear to use multiple export pathways; MLV uses both NXF1- and CRM1-dependent export (Bartels and Luban, 2014; Mougel et al., 2020; Pessel-Vivares et al., 2014; Pilkington et al., 2014; Sakuma et al., 2014), and the WPRE has both CRM1-dependent and -independent functional elements Popa et al., 2002; the pathway used by MusD is still unknown (Legiewicz et al., 2010). It seems plausible to us that the MER11 transport element mechanism may be similarly complex.

Strikingly, the GFP/mCherry ratio of the NL4-3-derived vector containing a MER11 CTE is more than 35 times higher than that of one containing the MPMV CTE, suggesting that it may have higher RNA transport activity. However, it is important to note that the MER11 element in these reporter assays is in the context of a lentiviral genome rather than its native genomic context, which could alter its phenotype in important ways. Additionally, the readout of this assay, eGFP expression, is not a direct measure of RNA export, but rather can be affected by other factors such as RNA stability and translation efficiency. Thus at this time we cannot determine the ‘true’ RNA export efficiency of the MER11 element relative to the other export elements tested, and we cannot rule out the possibility that it may have other effects such as increasing translation efficiency, as has been seen for other PTEs. It is also interesting to consider whether the presence of elements that strongly promote nuclear export of intron-retaining RNAs throughout the macaque genome might have significant effects on alternative splicing of host genes, and whether HML-8 elements in the human genome might also contain CTEs that promote export of host mRNAs with retained introns. The NXF1 gene itself contains a CTE which has been shown to promote export of an alternate NXF1 isoform, and it seems plausible that ERVs might have contributed similar elements to other genes (Li et al., 2006; Li et al., 2016). The presence of a clade of very similar recombinant proviruses in the white-cheeked gibbon genome that clusters within the diversity of OWM SERV-K/MER11 sequences, as well as the absence of such proviruses from great apes strongly suggests that SERV-K/MER11 has undergone at least one interspecies transmission event. The gibbon-specific clade clusters with a group of proviruses from the GSM, a member of the Colobinae subfamily of OWM; curiously, this gibbon-GSM clade is nested within a larger clade that is otherwise specific to the Cercopithecinae subfamily. This tree structure may indicate an earlier interspecies transmission from a cercopithecine monkey to a colobine lineage ancestral to the GSM, which later crossed into gibbons; however, these deeper nodes in the phylogenies are relatively low confidence, and we cannot rule out alternative evolutionary scenarios. This is, to our knowledge, the first evidence of interspecies transmission of a virus in the HERV-K HML-2 clade, and raises a number of interesting questions, most notably, whether macaques or other OWM species still contain actively replicating SERV-K/MER11 viruses, and whether those viruses are also capable of interspecies transmission. Although the current ranges of GSM and northern white-cheeked gibbons do not overlap, the ranges of other members of their respective genera do, as do the ranges of rhesus and other macaques, consistent with the interspecies transmission or transmissions having taken place in southern Asia.

The oldest gibbon provirus we have been able to estimate an integration time for is ~2.4 million years old, indicating that the interspecies transmission to gibbons took place at least 2.4 million years ago. We were unable to estimate integration times for most of the gibbon proviruses because their 5′ and 3′ LTRs had discordant phylogenies, indicating that they have undergone some type of recombination event; one provirus appears to be derived from a crossover recombination between two separate proviruses, resulting in a reciprocal chromosomal translocation. Similar HML-2-mediated genomic rearrangements have been observed in the human genome, however no reciprocal pairs of recombinants were identified in humans (Hughes and Coffin, 2001). More detailed understanding of the timing and location of this transmission event may be provided by screening the genomes of other Asian primate species for SERV-K/MER11 proviruses.

It is also worth considering whether interspecies transmission has any implications for the biology of these viruses. The evidence for at least one and possibly more such transmission events is strong, and geographic proximity makes contact between the GSM and white-cheeked gibbon lineages plausible; however, both species are herbivorous, removing perhaps the most straightforward route of transmission, predation, from consideration. Additionally, the titres of reconstituted HML-2 viruses in cell culture are relatively low, which would seem to make transmission via incidental contact unlikely (Dewannieux et al., 2006; Lee and Bieniasz, 2007). It is possible that the recombinant CTE and/or LTR deletions may have altered the biology of SERV-K/MER11 compared to HERV-K HML-2 in some way that makes interspecies transmission easier.

In summary, we have characterized a clade of ERVs in rhesus macaques that may serve as a valuable model for investigating viral evolution over deep time, and as a model for HERV-K HML-2 virology and pathogenesis. This clade provides a high resolution record of the evolution of a single viral lineage going back approximately 25 million years, potentially up to the present day, that has undergone multiple significant evolutionary transitions, including recombination with divergent viral lineages and interspecies transmission to divergent host species. Rhesus macaques are a well-characterized model organism for human disease; if these viruses are still actively replicating in macaques or other OWM species, they could provide an opportunity to observe the infection dynamics of an HML-2-like virus in a natural host, which could provide insights on currently incompletely understood aspects of HML-2 biology, such as tropism, pathogenic potential, receptor usage, and mode of transmission. Lastly, we have demonstrated that SERV-K/MER11 contains a novel CTE; this provides a fascinating opportunity to investigate the evolution of a retrovirus as it shifted from using a Rev/RRE-type system to a CTE-type system, and to observe how two closely related viruses that use very different RNA trafficking mechanisms differ in their replication dynamics.

All data generated or analyzed during this study are included in the manuscript and supporting files, or are re-analyses of publically available data; source data files have been provided for Figures 1–5, 7, and 8.

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Author details

1. Zachary H Williams

   Department of Biology, Boston College, Boston, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Supervision, Investigation, Visualization, Methodology, Writing - original draft, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-5091-2089

2. Alvaro Dafonte Imedio

   Department of Biology, Boston College, Boston, United States

   Contribution

   Formal analysis, Investigation, Visualization, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

3. Lea Gaucherand

   Molecular Microbiology Program, Tufts University Graduate School of Biomedical Sciences, Boston, United States

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing - review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4477-1021

4. Derek C Lee

   Department of Biology, Boston College, Boston, United States

   Contribution

   Resources, Investigation, Methodology

   Competing interests

   No competing interests declared

5. Salwa Mohd Mostafa

   Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, United States

   Contribution

   Resources, Investigation

   Competing interests

   No competing interests declared

6. James P Phelan

   Molecular Microbiology Program, Tufts University Graduate School of Biomedical Sciences, Boston, United States

   Contribution

   Investigation

   Competing interests

   No competing interests declared

7. John M Coffin

   1. Molecular Microbiology Program, Tufts University Graduate School of Biomedical Sciences, Boston, United States
   2. Department of Developmental, Molecular and Chemical Biology, Tufts University School of Medicine, Boston, United States

   Contribution

   Supervision, Funding acquisition, Writing - review and editing

   Competing interests

   No competing interests declared

8. Welkin E Johnson

   Department of Biology, Boston College, Boston, United States

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing - review and editing

   For correspondence

   welkin.johnson@bc.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0001-5991-5414

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