- SARS-CoV-2 Biology Points to Endogenous Retrovirus Design
SARS-CoV-2 Biology Points to Endogenous Retrovirus Design
by Fazale RanaJuly 28, 2021
“I’ve been dealing with viral outbreaks for the last 40 years. I’ve never seen a single virus—that is, one pathogen—have a range where 20% to 40% of the people have no symptoms.”
—Dr. Anthony Fauci, National Institute of Allergy and Infectious Diseases
Many of the disease characteristics of COVID-19 continue to baffle life scientists and biomedical practitioners. The confusion is not limited to the high rate of asymptomatic infections—other aspects of COVID-19 are puzzling as well. For example, some patients who have recovered from an initial COVID-19 infection will return positive PCR tests for SARS-CoV-2 weeks, even months, after their recovery. (The PCR test detects the presence and levels of SARS-CoV-2 genetic material in the patient.) These patients show no indication that they were reinfected and they pose no threat to spread the virus to others.
Recently, a team of life scientists from MIT offered an explanation for these unexpected observations.1 These investigators discovered that once the SARS-CoV-2 virus gains entrance into human cells, its genetic material (which is made up of a single plus strand of RNA) can be converted into DNA by cellular enzymes called reverse transcriptases. In turn, the SARS-CoV-2 DNA can then become integrated into the infected cell’s genome. Once in the genome, the SARS-CoV-2 DNA sequences can be transcribed, producing viral RNA that is detected by PCR tests.
This important insight adds to our understanding of the biology and replication cycle of SARS-CoV-2. It also holds significance for assessing the performance of antiviral therapies.
This discovery also has unexpected significance for the RTB creation model. It suggests a possible explanation for the presence of sequence elements called endogenous retroviruses (ERVs) in the human genome (and the genomes of other organisms). Many people regard the ERV sequences in the human genome as the most compelling evidence for human evolution. But, instead of baffling those of us who embrace a creation model for biology, the insights from the MIT team now make it possible to view ERVs as intentional features of genomes designed to serve a variety of purposes—including functioning as part of the innate immune system, offering protection from retrovirus invaders.
Before unpacking the impact of this study on the RTB creation model, a discussion of the work of the MIT scientists (which in and of itself is fascinating and important) is in order. And to do this well, we first need to briefly review the biology and replication of SARS-CoV-2.
SARS-CoV-2 Biology and Replication2
Viral invasion begins when SARS-CoV-2 virions attach to the surface of the host cell. Mediating this binding event is the interaction between the spike proteins that decorate the surface of the SARS-CoV-2 viral particles and the ACE-2 proteins which reside on the host cell’s surface. Once binding takes place, a protease in the host cell membrane cleaves the spike proteins. (Proteases are proteins that break apart protein chains.) This cleavage causes the host cell to engulf the attached SARS-CoV-2 virion, forming an endosome (which is a membrane-bound vesicle that arises from an invagination of the cell membrane). Once formed, the endosome migrates to the cell’s cytoplasm. Within the endosome, an unsheathing process takes place releasing the viral RNA from the protein capsid that surrounds it. As a result of the unsheathing process, the viral RNA finds its way into the host cell’s cytoplasm.
Here, the viral RNA makes its way to a ribosome where it is translated into two large polyproteins. Each of these large polyproteins consists of several individual protein sequences catenated together. Two of the individual proteins contained within the polyproteins are proteases. These internal proteases self-catalyze the cleavage of the two polypeptides. In doing so, they cause the other protein molecules harbored in the two polyproteins to be released as free-standing proteins.
Once released from the two polyproteins, some of the newly released proteins interact with one another to form a complex called the viral replication and transcription complex. This complex produces more copies of the viral genetic material through the activity of several enzymes, including one called an RNA-dependent RNA polymerase. The resulting viral RNA molecules are, in turn, translated to form more copies of the viral replication and transcription complex. They are also translated to produce the structural proteins needed to assemble more viral particles.
The viral replication and transcription complex associate with the host cell’s endoplasmic reticulum. This association leads to the formation of convoluted areas in the membrane of the endoplasmic reticulum. These convoluted areas form protected spaces that allow the viral RNA (produced by the viral replication and transcription complex) to be packaged with capsid proteins. Other structural proteins, such as the spike protein, which are found in the lipid envelope surrounding the viral RNA-protein capsid complex incorporate into the convoluted membranes of the endoplasmic reticulum. From here the encapsulated viral RNA and viral membrane proteins can be processed through the Golgi apparatus to be secreted into the extracellular space through the process of exocytosis.
A Bold Hypothesis
Though life scientists possess detailed insight into much of the biology and the replication of SARS-CoV-2, nothing in their understanding immediately sheds light on the positive PCR tests that persist after COVID–19 patients recover from their initial infection. The MIT investigators think that we may have overlooked a significant aspect of the molecular biology of SARS-CoV-2. Along these lines, they speculate that the SARS-CoV-2 genetic material becomes incorporated into the host cell’s genome and then becomes expressed, generating an ongoing source of viral genetic material.
Their hypothesis is a bit daring, because based on our current understanding of the replication of SARS-CoV-2—which relies on an RNA-dependent RNA polymerase to replicate its genetic material—researchers are hard-pressed to identify a mechanism for the SARS-CoV-2 material to make its way into the host genome.
However, retroviruses (which are also RNA viruses) have a well-characterized mechanism for incorporating their genetic material into the genome of the host cell. Before replication takes place, the retroviral RNA becomes converted into DNA. An enzyme called reverse transcriptase carries out this conversion. The genetic instructions needed to make reverse transcriptase are encoded in the retroviral genome. This protein is packaged in the retroviral capsid along with the retroviral RNA.
The newly made retroviral DNA can then use the invaded cell’s biosynthetic pathways to direct the production of new retroviral particles. The DNA copy of the retroviral genetic material can also become incorporated into the host cell’s genome. When this insertion takes place, the retroviral DNA becomes part of the host cell’s genome. This process is called endogenization.
Even though SARS-CoV-2 doesn’t encode a reverse transcriptase in its genome, the MIT scientists postulated that the SARS-CoV-2 RNA may still be reverse transcribed at some point during its replication cycle by endogenous copies of reverse transcriptase, encoded in the host genome. Biologists know that DNA sequences associated with retrotransposons (such as LINE sequences) found in the host cell’s genome encode for proteins with reverse transcriptase activity.
LINE sequences comprise about 20 percent of the human genome. These mobile DNA elements can make copies of themselves, with the copies becoming randomly inserted throughout the genome. Some LINE DNA sequences lie dormant in the human genome. Others can be transcribed into mRNA that, in turn, can be translated into a protein with reverse transcriptase activity. The LINE reverse transcriptase can make a copy of the LINE mRNA, converting it into DNA that can be integrated into the genome at a new location.
The research team speculated that once it has been synthesized by endogenous reverse transcriptase activity, the SARS-CoV-2 DNA can become integrated into the host cell’s genome. Here, the SARS-CoV-2 DNA sequences can be transcribed, producing viral RNAs that are detected by PCR tests.
An Unexpected Discovery
In support of their hypothesis, the MIT team discovered that:
1) Cultured human cells exposed to SARS-CoV-2 in the laboratory and cells taken from patients infected with SARS-CoV-2 both produce mRNA molecules that include those with hybrid sequences made up of host cell genes and viral genes. This observation suggests that viral genetic material has been incorporated in the host cell’s genome.
2) The predominant viral gene sequences that occur in the hybrid RNA molecules encode the capsid proteins. mRNA molecules that encode the capsid proteins are the most abundant of the viral mRNAs in the cell. These mRNA molecules would be readily available to be transcribed by endogenously sourced reverse transcriptase.
3) In the laboratory, when cells belonging to the HEK293 line are forced to overexpress LINE DNA sequences, SARS-CoV-2 RNA becomes reverse transcribed upon exposure of the cells to virions. The resulting SARS-CoV-2 DNA becomes incorporated into the genome of the HEK293 cells.
4) Exposure of cells to SARS-CoV-2 virions induces LINE expression.
Collectively, these findings provide compelling circumstantial evidence that endogenous reverse transcriptase converts SARS-CoV-2 RNA into DNA and this DNA, in turn, becomes integrated into the host cell’s genome. The evidence also indicates that only portions of the SARS-CoV-2 genome become incorporated into the host cell’s genome. As a result, when the host cell’s machinery transcribes these sequences to produce RNA, it can’t produce virions that can be transmitted to other people.
This discovery carries several important scientific and biomedical implications.
• It explains the unusual PCR results returned for patients who have recovered from COVID–19.
• It will help guide the development of antiviral therapies if the presence of SARS-CoV-2 genetic material in the patient is used to monitor the effectiveness of the antiviral treatment.
• It indicates that the reverse transcription of viral genetic material and its incorporation into the host cell genome may not be limited to SARS-CoV-2. It might be a general feature of other RNA viruses.
This discovery also has implications for the RTB creation model. It gives insight as to why ERV sequences are found in genomes. By doing so, it becomes increasingly reasonable to view ERV sequence elements as the intentional handiwork of a Creator, instead of a reflection of our evolutionary history.
Endogenous Retroviruses and the Case for Human Evolution
On becoming incorporated into an organism’s genome, retroviral DNA is called an ERV. If the ERV infects a germline cell (a sperm cell or an egg cell), it can be inherited, transmitted from generation to generation as a permanent feature of the genome.
If the ERV DNA suffers severe mutations, it becomes disabled, remaining in the genome as nonfunctional, junk DNA.
As it turns out, about 8 percent of the human genome consists of ERVs.
Evolutionary biologists consider the endogenous retroviral populations found in the human genome as evidence that humans have an evolutionary history shared with the great apes. Many human ERVs are also found in the genomes of chimpanzees, bonobos, gorillas, and orangutans. Not only do these ERVs share many of the same sequence patterns, but they also appear in corresponding locations in the genomes.
Evolutionary biologists explain this data by assuming that the shared ancestor of humans and chimpanzees, for example, became infected by these specific retroviruses. Later, the endogenized retroviruses experienced mutations that disabled them. These ERV sequences were retained in the genomes of humans and chimpanzees as their separate evolutionary lineages diverged from the common ancestor. According to the model, the ERVs shared by humans and chimpanzees represent the molecular artifacts of infections that occurred millions of years ago and left their imprint on contemporary genomes via this (presumed) shared ancestor.
Many people consider the presence of ERVs in the human genome (and the genomes of other organisms) to be baffling for the RTB creation model.
• Why would the Creator introduce the same nonfunctional sequence elements in the same locations within the genomes of organisms that naturally group together (based on other biological features)?
• And why would he create these shared sequence elements to bear such strong similarity to retroviruses?
Yet, the RTB creation model predicts that the Creator would have intentionally designed and incorporated ERVs into genomes to serve vital roles. The unexpected discovery that SARS-CoV-2 genetic material becomes incorporated into the host cell’s genome bears on this key prediction. Once incorporated into the genome of host cells, the activity and impact of the SARS-CoV-2 sequences suggest at least one reason why a Creator would intentionally incorporate ERV sequences into the human genome (and the genomes of other creatures) and why these sequences share so much similarity to retroviral sequences.
Impact of SARS-CoV-2 Sequences in the Host Cell Genome
The MIT researchers believe that the SARS-CoV-2 genetic material only becomes incorporated into the genomes of a limited number of cells. And of those cells, only a limited number express the viral genes. Still, they argue that this expression could have important consequences. They speculate that viral proteins that result from the expression of the incorporated viral genes could continuously stimulate the immune system. In doing so, the viral proteins provide the patient with ongoing immunity against SARS-CoV-2, serving as part of the repertoire of proteins and cells that imparts immune memory to the infected individual long after they clear the infection. Toward this end, the incorporated SARS-CoV-2 genetic material housed in the genomes of host cells acts as a type of endogenous DNA vaccine.
As it turns out, the MIT team’s discovery is not the first time that life scientists have detected genetic material from nonretroviral RNA viruses becoming incorporated into the genome of host cells during a viral infection. In 1997, a Swiss research team reported that the genetic material from lymphocytic choriomeningitis virus (LCMV)—an RNA virus—also becomes reverse transcribed into DNA by endogenous reverse transcriptase activity. In turn, the viral DNA then becomes incorporated in the genomes of mouse cells. This DNA serves as an ongoing source of viral proteins that also appear to contribute to immune memory in mice.3
A Proposed Function for ERVs
Based on this insight, I propose a similar role for ERVs in the human genome (and genomes of other animals). That is, I predict that one of the roles of ERVs is to function as a type of DNA vaccine designed into the genomes of organisms, with the proteins produced from the expressed ERV proteins stimulating the immune system, helping it ward off retroviral infections.
In 2019, a research team from China discovered that ERVs in the mouse genome produced RNA transcripts at high expression levels during exposure to RNA viruses.4 These ERV transcripts played a role in activating genes that led to interferon production, contributing to innate immunity in mice. While key aspects of this mechanism differ from the one I propose, it does demonstrate that RNA viral infections upregulate the expression of ERV sequences and establishes the link between expression of ERV DNA sequences and innate immunity.
Considering my proposal, it is also worth noting the work of researchers from the United States, Germany, and Australia. These investigators demonstrated that ERVs in the koala genome serve an antiretroviral role by disrupting the endogenization process of the koala endogenous retrovirus (KoRV). (See “Koala Endogenous Retroviruses (ERVs) Protect Against Retroviral Infections.”) This mechanism is also distinct from the one I propose. Yet it highlights the fact that ERV sequences may play an antiviral role through a variety of distinct mechanisms.
ERVs: Common Descent or Common Design?
Many life scientists regard the shared biological features possessed by organisms (that naturally cluster together) as evidence for their shared evolutionary ancestry. Yet, it is possible to advance an alternative explanation for biological similarities. Instead of evincing common descent, they could be interpreted as shared biological designs. In fact, prior to Charles Darwin, Sir Richard Owen produced a theoretical framework to interpret anatomical and physiological similarities shared among organisms. Owen saw these mutual features as manifestations of a common blueprint—an archetype that arose out of the Mind of the One True Cause.
The RTB creation model employs Owen’s insight by interpreting the shared features in the genomes of organisms as manifestations of genomic archetypes. In other words, the genetic similarities in the genomes of humans and the great apes were intentionally introduced by the Creator. To justify this interpretation, the shared genomic features must serve a function. And, indeed, this is the case for ERVs. These sequence elements appear to function as part of the innate immune system, helping to ward off retroviral infections through a variety of mechanisms that life scientists are just beginning to understand.
The antiviral role played by ERVs is largely possible because of the similarity between these DNA sequences and the genetic material of retroviruses. This requirement explains why a Creator would introduce genetic elements into the human genome (and the genome of other creatures) that share sequence elements with retroviruses.
If the last decade or so has taught us anything, it is this: Science is in its infancy when it comes to understanding the human genome. Increasingly, features that we originally thought were junk sequences turn out to make critical contributions. Such is the case for ERVs. The more we learn about these abundant sequence elements in the human genome, the more sense these sequence elements make for those of us who view biology through the lens of a creation model.
“Koala Endogenous Retroviruses (ERVs) Protect Against Retroviral Infections” by Fazale Rana (article)
“Questioning Evolutionary Presuppositions about Endogenous Retroviruses” by Anjeanette Roberts (article)
“A Common Design View of ERVs Encourages Scientific Investigation” by Anjeanette Roberts (article)
“Archetype or Ancestor? Sir Richard Owen and the Case for Design” by Fazale Rana (article)
1. Liguo Zhang et al., “Reverse-Transcribed SARS-CoV-2 RNA Can Integrate into the Genome of Cultured Human Cells and Can Be Expressed in Patient-Derived Tissues,” Proceedings of the National Academy of Sciences, USA 118, no. 21 (May 25, 2021): e2105968118, doi:10.1073/pnas.2105968118.
2. Philip V’kovski et al., “Coronavirus Biology and Replication: Implications for SARS-CoV-2” Nature Reviews Microbiology 19 (March 2021): 155–170, doi:10.1038/s41579-020-00468-6.
3. Paul Klenerman, Hans Hengartner and Rolf M. Zinkernagel, “A Non-Retroviral RNA Virus Persists in DNA Form,” Nature 390 (November 20, 1997): 298–301 doi:10.1038/36876.
4. Bin Zhou et al., “Endogenous Retrovirus-Derived Long Noncoding RNA Enhances Innate Immune Responses via Derepressing RELA Expression,” mBio 10, no. 4 (July/August 2019): e00937-19, doi:10.1128/mBio.00937-19.
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