Deltaretroviruses

The super-rare 'big beasts' of the retrovirus world

Tracing the history of primate deltaretroviruses

April 9th, 2018

Deltaretroviruses are a genus of retroviruses that have so far only been identified in primates and cattle. They include the Human T-lymphotrophic viruses (HTLVs), which are currently estimated to infect 15-20 million people worldwide.

There are four distinct HTLVs that infect humans. HTLV-1 and HTLV-2 are closely related but have very different geographic distributions. HTLV-1 can cause a rare type of lymphoma called adult T-cell leukaemia/lymphoma (ATLL), while HTLV-2 has been associated with sporadic cases of neurological disorders. HTLV-3 and HTLV-4 have only been found in isolated populations in Central Africa, and are not known to be associated with disease.



peruvian mummy HTLV-1 DNA has been recovered from mummified corpses in the Atacama desert.

The global distribution of HTLV-1 and HTLV-2 seems to reflect to historical patterns of human migration (see figure above), indicating that these viruses have an ancestral presence in the human population.

Among the lines of evidence supporting this are HTLV-1 DNA sequences recovered from 'mummies' excavated in the Atamaca desert Due to the extremely arid conditions that occur in this region, the bodies of people buried there over 1,000 years ago have remained relatively well preserved, such that DNA could be recovered (even in the early 2000s, when techniques for doing this were considerably less advanced than those available today).

The evolutionary relationships between (i) HTLV-1 DNA sequences recovered from an Atacamanian mummy, and (ii) HTLV-1 isolates obtained from infected populations in present day Chile and Japan, were observed to be consistent with a scenario in which HTLV-1 spread to South America along with the human populations that migrated from Asia to the Americas over 10,000 years ago (see figure above).

The HTLVs are closely related to viruses found in african primates, called simian T-lymphotrophic viruses (STLVs). Phylogenetic studies indicate that the various HTLVs (1-4) likely originated in separate primate-to-human transfer events. Accordingly, the deltaretroviruses found in human and non-human primates are now collectively referred to as 'primate T-lymphotrophic viruses' (PTLVs).



A recent study of PTLV sequences obtained from orangutans revealed new insights into the evolutionary history of PTLV-1 (the group of PTLVs that contains HTLV-1) in Asia. This analyses used a molecular clock based approach to estimate the timing of PTLV-1 spread, and indicated that the virus was first introduced into Australia between 3,000 and 4,000 years ago.

The study also inferred that HTLV-1 arrived in Melanesia between 2,300 to 2,700 years ago - approximately corresponding to the time when the Lapita peoples are thought to have migrated into the region.

But while it seems clear that deltaretroviruses have an association with primates that dates back thousands of years, their deeper origins have until recently remained a mystery.


Miocene deltaretroviruses in bat genomes


miniopterus

Most retrovirus genera have an extensive genomic 'fossil record' - comprised of endogenous retrovirus (ERV) sequences - which can be used to investigate their long-term evolutionary history. However, until very recently, no ERVs from deltaretroviruses had been identified, meaning that the deeper associations between deltaretroviruses and mammals have remained largely a matter of speculation.

I've been interested in identifying an ERV derived deltaretrovirus since my PhD days. They are a relatively unusual group of retroviruses, and so far at least, they seem to be relatively rare (both as endogenous sequences and exogenous viruses). This makes them intriguing, as well as interesting from an evolutionary standpoint.

In addition, Deltaretrovirus represents one of only two retrovirus genera known to include viruses that circulate in humans - the other being the genus Lentivirus, which includes both HIV-1 and HIV-2. These two genera are superficially similar. Indeed, when HIV-1 was originally identified, it was assumed to be closely related to the HTLVs and was named "HTLV-III"

A characteristic feature of viruses in both genera is the presence of several auxiliary genes (referred to as 'accessory genes') in addition to those typically found in all infectious retroviruses. It would be useful to understand more about how these complex retroviral genomes evolved - i.e the order in which genes were acquired or lost along the way, and how this may have came about. For lentiviruses, the genomic fossil record has provided some insight into this.

Importantly, phylogenetic trees do not indicate that delta- and lentiviruses are especially closely related. And in one respect - the composition of their DNA sequences - they are strikingly different.

Whereas lentivirus genomes have a marked preference for adenine (A), deltaretroviral genomes have a marked preference for cytosine (C).

In 2016 I collaborated with Dr Daniel Elleder's team at the Institute of Molecular Genetics in Prague to describe the first example of an endogenous deltaretrovirus Daniel's team identified this sequence in in the genome of a bent-winged bat (Miniopterus) by screening the short read archives.

Czech Institute of Molecular Genetics The Institute of Molecular Genetics in Prague, Czech.

Only a single copy of (Miniopterus) endogenous retrovirus A (MinERVa) was found to be present in the bent-winged bat germline. Furthermore, large chunks of this single provirus genome were missing. Retroviruses have three major coding domains and two of these (encoding the polymerase and envelope genes) were absent. However most of the gag domain - which encodes the structural proteins of the the virus particle - was present, as were the two long terminal repeat (LTR) sequences that typically flank integrated retroviruses.

Through phylogenetic analysis, we demonstrated that the Gag protein encoded by MinERVa was more similar to those of deltaretroviruses than to those of any other retrovirus. In addition, the nucleotide composition of MinERVa exhibited a marked cytosine bias, which as I described above, is an unusual and characteristic feature of Deltaretrovirus genomes.

We investigated the presence of the MinERVa insertion in a range of bat species using polymerase chain reaction (PCR), demonstrating that MinERVa inserted into the bat germline between 40 and 20 million years ago. This indicates that the deltaretrovirus that gave rise to MinERVa likely circulated during the Miocene Epoch

rhinolophus bat A rhinolophus bat.

It turns out that MinERVa might not be the only trace of these ancient deltaretrovirus infections in bats. In work now published in the journal Viruses, we describe the detection of an LTR sequence in the genome of horseshoe bats (Rhinolophidae) that seems to be derived from a MinERVa-like virus.

This sequence presumably represents a fragment of viral genome derived from a single integration. The time of the integration was estimated as 11-19 million years ago.

This finding, together with the previously identified endogenous deltaretrovirus in long-fingered bats (Miniopteridae), suggests a close association of bats with ancient deltaretroviruses.

Bovine leukemia virus

Deltaretroviruses have also been identified in cattle. Bovine leukemia virus (BLV) - sometimes called 'bovine leukosis virus' - is thought to be relatively prevalent and widespread in domestic cattle. Despite this, BLV is not particularly well-studied, since - as with many chronic viral infections in domestic animals - there appears to be little interest or concern so long as there is no discernible pathogenesis and/or economic impact.


Coos

Recently, BLV has been associated with breast cancer in humans, and this has stimulated some interest in the virus. However, it is worth emphasising that these claims remain controversial.

Any excuse to show a heilan' coo...

References

Hron T, Farkašová H, Gifford RJ, Benda P, Hulva P, Tamás Görföl, Pačes J, and Elleder D. (2018)
Remnants of an ancient deltaretrovirus in the genomes of horshoe bats (Rhinolophidae). Virus Research 10(4), 185; doi:10.3390/v10040185 view

Farkašová H, Hron T, Pačes J, Hulva P, Benda P, Gifford RJ, Elleder D. (2017)
Discovery of an endogenous Deltaretrovirus in the genome of long-fingered bats (Chiroptera: Miniopteridae). Proc Natl Acad Sci U S A. 114(12):3145-3150.
co-corresponding authors view