Recombinant Origin and Recent Infectious Activity of a HERV-K(HML-2)-related Retrovirus in Old World Monkeys

Kernekoncepter

A clade of HERV-K(HML-2)-related proviruses in Old World monkeys, designated SERV-K/MER11, originated from an ancient recombination between an HML-2-like virus and an HML-8-related retrovirus. This recombinant virus has been actively replicating in macaques and other Old World monkeys within the last 500,000 years, and has also undergone interspecies transmission to gibbons.

Resumé

The content describes the identification and characterization of a clade of HERV-K(HML-2)-related proviruses in the genomes of rhesus macaques and other Old World monkey species, designated as SERV-K/MER11. Key findings include:

1. SERV-K/MER11 proviruses originated from an ancient recombination event between an HML-2-like virus and an HML-8-related retrovirus, resulting in a chimeric env gene and a ~750 bp non-coding region derived from the HML-8 LTR (MER11 element).

2. The oldest SERV-K/MER11 insertions date back to 20-25 million years ago, before the split between colobine and cercopithecine Old World monkeys, but after the divergence of apes and Old World monkeys. Many younger, rhesus-specific SERV-K/MER11 proviruses show signs of recent or ongoing infectious activity.

3. Several SERV-K/MER11 proviruses have intact open reading frames for viral genes, including two with full-length ORFs for all four core retroviral proteins (Gag, Pro, Pol, Env). Many proviruses are also insertionally polymorphic in rhesus macaque populations.

4. Interestingly, the HML-8-derived MER11 region in SERV-K/MER11 functions as a Rec-independent constitutive transport element (CTE), replacing the Rec/Rec Response Element (RcRE) system used by human HML-2 for nuclear export of unspliced viral RNAs.

5. The authors also identified SERV-K/MER11-like proviruses in the genome of the white-cheeked gibbon, suggesting an interspecies transmission event from an Old World monkey to an ancestral gibbon species at least 2.4 million years ago.

Overall, this work provides important insights into the evolutionary history, genomic structure, and potential for recent infectious activity of an HML-2-related retrovirus lineage in Old World monkeys.

Statistik

The oldest SERV-K/MER11 provirus is estimated to have integrated approximately 25 million years ago.
36 of the SERV-K/MER11 proviruses have identical long terminal repeats (LTRs), suggesting they integrated within the last 500,000 years.
Two SERV-K/MER11 proviruses have intact open reading frames for all four core retroviral genes (Gag, Pro, Pol, Env).
6 out of 23 screened SERV-K/MER11 proviruses were found to be insertionally polymorphic in rhesus macaque populations, with allele frequencies ranging from 10.7% to 70.8%.

Citater

"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."
"36 of the recombinant proviruses have identical LTRs, and thus our best estimate is that they are younger than ~500,000 years old, the average time for a single nucleotide difference to occur between two 588 bp LTRs given the assumed neutral mutation rate."
"The HML-8 derived region functions as a Rec-independent constitutive transport element (CTE), indicating the ancestral Rec-RcRE export system was replaced by a CTE mechanism."

Vigtigste indsigter udtrukket fra

Recombinant Origin and Interspecies Transmission of a HERV-K(HML-2)-related Primate Retrovirus With a Novel RNA Transport Element

by Williams,Z. ... kl. www.biorxiv.org 05-11-2022

https://www.biorxiv.org/content/10.1101/2022.05.11.490678v1

Dybere Forespørgsler

What factors may have contributed to the recent or ongoing infectious activity of SERV-K/MER11 proviruses in Old World monkeys, compared to the lack of replication-competent HML-2 proviruses in humans?

The recent or ongoing infectious activity of SERV-K/MER11 proviruses in Old World monkeys, particularly in rhesus macaques, can be attributed to several factors. One key factor is the structural characteristics of the proviruses, including intact open reading frames (ORFs) for essential viral genes such as gag, pro, pol, and env. The presence of intact ORFs indicates that these proviruses have the potential to produce functional viral proteins, which is a crucial requirement for viral replication and infectious activity. In contrast, the lack of replication-competent HML-2 proviruses in humans may be due to the high frequency of mutations, deletions, and insertions in the ORFs of human HML-2 proviruses, rendering them non-functional and incapable of supporting viral replication.
Another contributing factor to the infectious activity of SERV-K/MER11 proviruses in Old World monkeys is the presence of insertionally polymorphic proviruses. The ability of these proviruses to exhibit insertion polymorphism, where they are present at different frequencies in the population and can be either homozygous or heterozygous at the insertion site, suggests recent or ongoing activity and transmission of these proviruses within the monkey population. This insertion polymorphism allows for the maintenance and spread of active proviruses in the population, leading to potential infectious activity.
Furthermore, the evolutionary history and interspecies transmission of SERV-K/MER11 proviruses play a role in their infectious activity. The recombination event that formed the SERV-K/MER11 clade, involving a fusion between an HML-2-like virus and an HML-8-like virus, likely contributed to the creation of a novel viral genome with enhanced infectivity. This recombinant virus may have acquired advantageous traits that promote viral replication and transmission in Old World monkeys. Additionally, the interspecies transmission of SERV-K/MER11-like proviruses from Old World monkeys to gibbons suggests a potential for cross-species transmission and adaptation, further contributing to the infectious activity of these proviruses in non-human primate populations.

How might the replacement of the Rec/RcRE system with a CTE mechanism in SERV-K/MER11 impact the viral life cycle and host interactions compared to human HML-2?

The replacement of the Rec/RcRE system with a constitutive transport element (CTE) mechanism in SERV-K/MER11 proviruses can have significant implications for the viral life cycle and host interactions compared to human HML-2. The Rec/RcRE system, present in human HML-2, relies on the viral accessory protein Rec binding to the Rec Response Element (RcRE) in the viral RNA to facilitate nuclear export of unspliced and partially spliced viral mRNAs. This system is crucial for efficient viral replication and gene expression in human cells.
In contrast, the presence of a CTE mechanism in SERV-K/MER11 proviruses indicates that these viruses have evolved an alternative strategy for RNA transport that does not require the Rec protein. The CTE likely functions as a constitutive element that promotes the export of unspliced viral RNA from the nucleus to the cytoplasm, independent of a viral accessory protein. This adaptation may confer several advantages to SERV-K/MER11 proviruses:

Increased Efficiency: The CTE mechanism may enhance the efficiency of RNA transport, leading to higher levels of viral gene expression and replication in infected cells. By bypassing the need for Rec, the CTE can streamline the viral life cycle and promote rapid viral spread within the host.

Host Adaptation: The utilization of a CTE may represent a host-specific adaptation of SERV-K/MER11 proviruses to Old World monkeys. This mechanism could be optimized for efficient RNA transport in the cellular environment of monkey hosts, potentially enhancing viral fitness and pathogenicity in these species.

Evolutionary Flexibility: The presence of a CTE in SERV-K/MER11 proviruses provides an example of viral evolutionary innovation and adaptation. This mechanism allows the virus to overcome host restrictions and evolve novel strategies for viral replication, highlighting the dynamic nature of host-virus interactions.

Overall, the replacement of the Rec/RcRE system with a CTE mechanism in SERV-K/MER11 proviruses may impact viral RNA transport, gene expression, and replication dynamics, potentially influencing the pathogenicity and evolutionary success of these viruses in Old World monkeys.

Could the interspecies transmission of SERV-K/MER11-like proviruses from Old World monkeys to gibbons have had any significant evolutionary or biological consequences for the gibbon lineage?

The interspecies transmission of SERV-K/MER11-like proviruses from Old World monkeys to gibbons could have significant evolutionary and biological consequences for the gibbon lineage. This transmission event represents a transfer of viral genetic material from one primate species to another, potentially leading to viral adaptation, host-virus coevolution, and changes in the genomic landscape of the recipient species. Several implications of this interspecies transmission include:

Viral Adaptation: The introduction of SERV-K/MER11-like proviruses into the gibbon lineage may drive viral adaptation to a new host environment. The viruses may undergo genetic changes to enhance infectivity, replication efficiency, or immune evasion in gibbons, potentially shaping the evolution of viral populations within the gibbon population.

Host Immune Response: The interspecies transmission of these proviruses could trigger immune responses in gibbons, influencing the host immune system and potentially leading to immune-mediated selection pressures on both the virus and the host. This interaction may impact the evolution of antiviral defense mechanisms in gibbons and contribute to the diversification of immune-related genes.

Genomic Integration: The integration of SERV-K/MER11-like proviruses into the gibbon genome may have genomic consequences for the host species. Viral insertions can lead to genomic rearrangements, gene disruptions, or regulatory changes, potentially influencing gibbon evolution and genetic diversity.

Cross-Species Transmission: The interspecies transmission of these proviruses highlights the potential for cross-species viral spread and zoonotic events between primate species. Understanding the mechanisms and outcomes of such transmissions is essential for assessing the risks of viral emergence and spillover in primate populations.

Overall, the interspecies transmission of SERV-K/MER11-like proviruses from Old World monkeys to gibbons represents a dynamic interaction between viruses and hosts, with the potential to impact viral evolution, host immunity, and genomic stability in the gibbon lineage. Further research is needed to elucidate the long-term consequences of this transmission event on gibbon biology and the evolutionary trajectory of both the viruses and the host species.