Viral RNA to DNA

Viral RNA to DNA

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I have a question concerning reverse transcriptase. Why is it that when the viral rna is converted to viral dna( as in the case for hiv), the virus develops resistance to medicine? Under what circumstances does reverse transcriptase causes a viral mutation?


There are three different replication systems during the life cycle of a retrovirus. First of all, the reverse transcriptase synthesizes viral DNA from viral RNA, and then from newly made complementary DNA strand. The second replication process occurs when host cellular DNA polymerase replicates the integrated viral DNA. Lastly, RNA polymerase II transcribes the proviral DNA into RNA, which will be packed into virions. Therefore, mutation can occur during one or all of these replication steps.[17]

Reverse transcriptase has a high error rate when transcribing RNA into DNA since, unlike most other DNA polymerases, it has no proofreading ability. This high error rate allows mutations to accumulate at an accelerated rate relative to proofread forms of replication. The commercially available reverse transcriptases produced by Promega are quoted by their manuals as having error rates in the range of 1 in 17,000 bases for AMV and 1 in 30,000 bases for M-MLV.[18] (Emphasis added.)

Polymerases are proteins (enzymes) that make copies of genetic material: DNA or RNA.

These enzymes have different fidelity or error rates. This means that different polymerases can make fewer or more mistakes when copying genetic information.

To accommodate errors, DNA polymerases have proofreading mechanisms that go back and fix errors. Most of the time, this works as expected.

However, the reverse transcriptase that copies RNA into DNA does not do any proofreading, so there will be various mutations in some fraction of copies, depending on the transcriptase's fidelity rate.

For viruses, it is a pure numbers game. All they are programmed to do is make copies of themselves, and as many copies as possible, when they are in infectious, non-dormant state. and

Most mutations will be deleterious and the virus won't infect, integrate, and replicate successfully. A random mutation will often break a needed protein involved in the viral reproductive cycle.

Some mutations are "neutral" or "silent" and won't change how the virus copies itself. Consider that the genetic code is redundant - substitute a base here or there and you can still get the same amino acid sequence.

But if you have enough virus particles copying themselves, all you need are mutations in the parts of the virus genome that allow it to keep replicating and also change the proteins it makes, just enough to evade the host's immune system.

If a mutated virus can still replicate and also change the proteins it gets the infected cell to make on its behalf, it can be more successful at copying itself. Immune cells will have to "relearn" whatever changes were made in order to trigger the usual immune response and fight back.

In the case of HIV, it also attacks the immune system directly, which is another complication.

Medications try to interfere with the different ways in which HIV works to infect immune cells and to make copies of themselves.

For example, one class of medication tries to "compete" with the part of HIV that binds to the surface of T cells. It's like a night club, where the bouncers at the doors are more likely to keep HIV from getting into the cell/club and partying.

Other classes of medication interfere with a protein called integrase that HIV makes to integrate its viral DNA into the host DNA. Integration of the HIV DNA into the host cell's DNA is a critical step for infection, so that's one way to target the virus.

Still other drugs try to inhibit the reverse transcriptase that turns HIV RNA into DNA. If the virus RNA is inhibited from being made into DNA, then that can help keep further infection in check. PrEP is a combination of two drugs (tenofovir and emtricitabine) which are RT inhibitors.

An overview of some of these medications is available here:

These medications all try to target the proteins involved in how HIV infects and replicates inside immune cells.

In turn, reverse transcriptase is sloppy enough in turning HIV RNA into DNA that it can get lucky and mutate enough to make one or another medication less effective.

Treatments are sometimes put into so-called "cocktails" of multiple drugs. A multi-drug regimen that attacks the virus by different means will give HIV a harder time in getting lucky enough to mutate in ways that it can get past a multi-pronged attack in those who are HIV+. Another good summary of such medications - many of which target reverse transcriptase activity - is available here:

“DNA” vs. “RNA” vs. “mRNA”: The Differences Are Vital

COVID-19 has set off many unprecedented events that will most likely change the world forever. Fortunately, they haven’t all been bad: the virus led to the remarkable development of vaccines at a pace and scale the likes of which have never before been seen in history. Both the Pfizer-BioNTech vaccine and the Moderna vaccine use a relatively new technology that has been approved for the first time: mRNA vaccines. (The Oxford vaccine instead uses genetic material from what’s known as an adenovirus derived from chimpanzees.)

These incredible developments, naturally, have led many people to dust off those old biology textbooks and try to remember what they learned about mRNA back in Biology 101. What do all those letters in mRNA stand for? How is it different from RNA? For that matter, what even is RNA? Does it have anything to do with DNA? In this article, we will answer all of these questions.

But first, we should quickly answer the most pressing question you might have: is it safe to take the COVID-19 vaccines or any mRNA vaccine? The answer is “Yes.” The new COVID-19 vaccines have gone through the same rigorous testing process as every other vaccine, as will any new mRNA vaccines developed in the future. If you’d like to know more about how the COVID-19 vaccines were tested for safety and approved, you can read about them in more detail as provided by the CDC and the WHO.

Discovery Identifies a Highly Efficient Human Reverse Transcriptase that can Write RNA Sequences into DNA

Correction 6/18/21: The original version of this article stated that polymerase theta was the first mammalian polymerase with the ability to transcribe RNA into DNA. In fact, other polymerases have been shown to perform this function, albeit with much lower efficiency than HIV reverse transcriptase. The article has been corrected, and we regret the error.

PHILADELPHIA – Cells contain machinery that duplicates DNA into a new set that goes into a newly formed cell. That same class of machines, called polymerases, also build RNA messages, which are like notes copied from the central DNA repository of recipes, so they can be read more efficiently into proteins. But polymerases were thought to only work in one direction DNA into DNA or RNA. This prevents RNA messages from being rewritten back into the master recipe book of genomic DNA. Now, Thomas Jefferson University researchers provide evidence that RNA segments can be written back into DNA via a polymerase called theta, which could have wide implications affecting many fields of biology.

“This work opens the door to many other studies that will help us understand the significance of polymerases that can write RNA messages into DNA,” says Richard Pomerantz, PhD, associate professor of biochemistry and molecular biology at Thomas Jefferson University. “That polymerase theta can do this with high efficiency, raises many questions.” For example, this finding suggests that RNA messages can be used as templates for repairing or re-writing genomic DNA.

The work was published June 11 th in the journal Science Advances.

Together with first author Gurushankar Chandramouly and other collaborators, Dr. Pomerantz’s team started by investigating one very unusual polymerase, called polymerase theta. Of the 14 DNA polymerases in mammalian cells, only three do the bulk of the work of duplicating the entire genome to prepare for cell division. The remaining 11 are mostly involved in detecting and making repairs when there’s a break or error in the DNA strands. Polymerase theta repairs DNA, but is very error-prone and makes many errors or mutations. The researchers therefore noticed that some of polymerase theta’s “bad” qualities were ones it shared with another cellular machine, albeit one more common in viruses -- the reverse transcriptase. Like Pol theta, HIV reverse transcriptase acts as a DNA polymerase, but can also bind RNA and write RNA back into a DNA strand.

In a series of elegant experiments, the researchers tested polymerase theta against the reverse transcriptase from HIV, which is one of the best studied of its kind. They showed that polymerase theta was capable of converting RNA messages into DNA, which it did as well as HIV reverse transcriptase, and that it actually did a better job than when duplicating DNA to DNA. Polymerase theta was more efficient and introduced fewer errors when using an RNA template to write new DNA messages, than when duplicating DNA into DNA, suggesting that this function could be its primary purpose in the cell.

The group collaborated with Dr. Xiaojiang S. Chen’s lab at USC and used x-ray crystallography to define the structure and found that this molecule was able to change shape in order to accommodate the more bulky RNA molecule – a feat unique among polymerases.

“Our research suggests that polymerase theta’s main function is to act as a reverse transcriptase,” says Dr. Pomerantz. “In healthy cells, the purpose of this molecule may be toward RNA-mediated DNA repair. In unhealthy cells, such as cancer cells, polymerase theta is highly expressed and promotes cancer cell growth and drug resistance. It will be exciting to further understand how polymerase theta’s activity on RNA contributes to DNA repair and cancer-cell proliferation.”

This research was supported by NIH grants 1R01GM130889-01 and 1R01GM137124-01, and R01CA197506 and R01CA240392. This research was also supported in part by a Tower Cancer Research Foundation grant. The authors report no conflicts of interest.

Researchers reveal the inner workings of a viral DNA-packaging motor

Five proteins, shown here in different colors, make up a viral DNA-packaging motor. Credit: Duke University

Researchers have discovered the inner workings of the molecular motor that packages genetic material into double-stranded DNA viruses. The advance provides insight into a critical step in the reproduction cycle of viruses such as pox, herpes and adenoviruses. It could also inspire researchers creating microscopic machines based on naturally occurring biomotors.

The U.S. National Science Foundation-funded research was conducted by scientists at Duke University, the University of Minnesota, the University of Massachusetts and the University of Texas Medical Branch. The results appear in a trilogy of papers published in Science Advances, Proceedings of the National Academy of Sciences and Nucleic Acids Research.

"There were several missing pieces of information that prevented us from understanding how these kinds of DNA packaging motors work, which hindered our ability to design therapeutics or evolve new technologies," said Gaurav Arya, a mechanical engineer, biomedical engineer and chemist at Duke and a co-author of the papers. "But with new insights and simulations, we were able to piece together a model of this fantastic mechanism, which is the most detailed ever created for this kind of system."

Viruses come in many varieties, but their classification generally depends upon whether they encode their genetic blueprints into RNA or single- or double-stranded DNA. The difference affects how the genetic material is packaged into new viruses. While some viruses build a protein container called a capsid around newly produced RNA or DNA, others create the capsid first and then fill it with the genetic material.

Most double-stranded DNA viruses take the latter route, which presents many challenges. DNA is negatively charged and does not want to be crammed together into a small space. It is also packaged into an extremely dense, nearly crystalline structure, which requires a lot of force.

"The benefit of this is that, when the virus is ready to infect a new cell, the pressure helps inject DNA into the cell once it's punctured," said Joshua Pajak at Duke. "It's been estimated that the pressure exceeds 800 psi, which is almost ten times the pressure in a corked bottle of champagne."

Forcing DNA into a tiny capsid at that pressure requires an extremely powerful motor. Until recently, researchers only had a vague sense of how the motor worked. "This work demonstrates how even simple viruses have evolved very complex machinery," said Wilson Francisco, a program director in NSF's Division of Molecular and Cellular Biosciences.

Michael Woodson et al, A viral genome packaging motor transitions between cyclic and helical symmetry to translocate dsDNA, Science Advances (2021). DOI: 10.1126/sciadv.abc1955

Joshua Pajak et al, Viral packaging ATPases utilize a glutamate switch to couple ATPase activity and DNA translocation, Proceedings of the National Academy of Sciences (2021). DOI: 10.1073/pnas.2024928118

Researchers reveal the inner workings of a viral DNA-packaging motor

3D-model of DNA. Credit: Michael Ströck/Wikimedia/ GNU Free Documentation License

A group of researchers have discovered the detailed inner workings of the molecular motor that packages genetic material into double-stranded DNA viruses. The advance provides insight into a critical step in the reproduction cycle of viruses such as pox-, herpes- and adeno-viruses. It could also give inspiration to researchers creating microscopic machines based on naturally occurring biomotors.

The research was conducted by scientists from Duke University, the University of Minnesota, the University of Massachusetts and the University of Texas Medical Branch (UTMB). The results appear online in a trilogy of papers published in Science Advances, Proceedings of the National Academy of Sciences and Nucleic Acids Research.

"There were several missing pieces of information that prevented us from understanding how these kinds of DNA packaging motors work, which hindered our ability to design therapeutics or evolve new technologies," said Gaurav Arya, professor of mechanical engineering and materials science, biomedical engineering, and chemistry at Duke. "But with new insights and simulations, we were able to piece together a model of this fantastic mechanism, which is the most detailed ever created for this kind of system."

Viruses come in many varieties, but their classification generally depends upon whether they encode their genetic blueprints into RNA or single- or double-stranded DNA. The difference matters in many ways and affects how the genetic material is packaged into new viruses. While some viruses build a protein container called a capsid around newly produced RNA or DNA, others create the capsid first and then fill it with the genetic material.

A trio of studies has revealed how a viral DNA packaging motor works, potentially providing insights for new therapeutics or synthetic molecular machines. Each of five proteins scrunches up in turn, dragging the DNA up along with them, before releasing back into their original helical pattern. Credit: Joshua Pajak, Duke University

Most double-stranded DNA viruses take the latter route, which presents many challenges. DNA is negatively charged and does not want to be crammed together into a small space. And it's packaged into an extremely dense, nearly crystalline structure, which also requires a lot of force.

"The benefit of this is that, when the virus is ready to infect a new cell, the pressure helps inject DNA into the cell once it's punctured," said Joshua Pajak, a doctoral student working in Arya's laboratory. "It's been estimated that the pressure exceeds 800 PSI, which is almost ten times the pressure in a corked bottle of champagne."

Forcing DNA into a tiny capsid at that amount of pressure requires an extremely powerful motor. Until recently, researchers only had a vague sense of how that motor worked because of how difficult it is to visualize. The motor only assembles on the virus particle, which is enormous compared to the motor.

"Trying to see the motor attached to the virus is like trying to see the details in the Statue of Liberty's torch by taking a photo of the entire statue," said Pajak.

But at a recent conference, Pajak learned that Marc Morais, professor of biochemistry and molecular biology at UTMB, and Paul Jardine, professor of diagnostic and biological sciences at the University of Minnesota, had been working on this motor for years and had the equipment and skills needed to see the details. Some of their initial results appeared to match the models Pajak was building with what little information was already available. The group grew excited that their separate findings were converging toward a common mechanism and quickly set about solving the mystery of the viral motor together.

In a paper published in Science Advances, Morais and his colleagues resolved the details of the entire motor in one of its configurations. They found that the motor is made up of five proteins attached to one another in a ring-like formation. Each of these proteins are like two suction cups with a spring in between, which allows the bottom portion to move vertically in a helical formation so that it can grab onto the helical backbone of DNA.

"Because you could fit about 100,000 of these motors on the head of a pin and they're all jiggling around, getting a good look at them proved difficult," said Morais. "But after my UTMB colleagues Michael Woodson and Mark White helps us image them with a cryo-electron microscope, a general framework of the mechanism fell into place."

In a second paper, published in Nucleic Acids Research, the Morais group captured the motor in a second configuration using X-ray crystallography. This time the bottom suction cups of the motor were all scrunched up together in a planar ring, leading the researchers to imagine that the motor might move DNA into the virus by ratcheting between the two configurations.

To test this hypothesis, Pajak and Arya performed heavy-duty simulations on Anton 2, the fastest supercomputer currently available for running molecular dynamics simulations. Their results not only supported the proposed mechanism, but also provided information on how exactly the motor's cogs contort between the two configurations.

While the tops of the proteins remain statically attached to the virus particle, their bottom halves move up and down in a cyclic pattern powered by an energy-carrying molecule called ATP. Once all the proteins have moved up—dragging the DNA along with them—the proteins release the byproduct of the ATP chemical reaction. This causes the lower ring to release the DNA and reach back down into their original helical state, where they once again grab on to more ATP and DNA to repeat the process.

"Joshua pieced together lots of clues and information to create this model," said Arya. "But a model is only useful if it can predict new insights that we didn't already know."

At its core, the model is a series of mechanical actions that must fit together and take place in sequential order for everything to work properly. Pajak's simulations predicted a specific series of mechanical signals that tell the bottoms of the proteins whether or not they should be gripping the DNA. Like a line of dominoes falling, removing one of the signaling pathways from the middle should stop the chain reaction and block the signal.

To validate this prediction, the researchers turned to Jardine and colleagues Shelley Grimes and Dwight Anderson to see if removing one of the signaling dominoes actually stopped the motor from packaging DNA. A third paper, published in PNAS, shows that the sabotage worked. After mutating a domino in the signaling pathway so that it was unable to function, the motor could still bind and burn fuel just as well as ever, but it was much worse at actually packaging DNA.

"The new mechanism predicted by the high-resolution structures and the detailed predictions provided a level of detail greater than we ever previously had," said Jardine. "This allowed us to test the role of critical components of the motor, and therefore assess the validity of this new mechanism as we currently understand it."

The result is a strong indication that the model is very close to describing how the motor behaves in nature. The group plans to continue their highly integrated structural, biochemical and simulation approach to further test and refine the proposed model. They hope that that this fundamental understanding could potentially be used to someday fight disease or create a synthetic molecular motor.

"All technology is inspired by nature in one way or another," said Arya. "Now that we really know how this molecular motor works, hopefully it will inspire other researchers to create new inventions using these same mechanisms."

Viral Genomes | Chromosome

Viruses are a special class of infectious agents that are so small that they can be viewed only under electron microscope. A complete “viral particle” or “virion consists of a block of genetic material (DNA or RNA) surrounded by a protein coat and, sometimes by an additional membranous envelope.

The viruses contain neither cytoplasm nor exhibit any growth or metabolic activity. But when their genetic material enters into a suitable host cell, virus-specific protein synthesis replication of the viral chromosome occurs these processes utilize both cellular (of host) and viral enzymes.

On the basis of the host organisms, viruses are divided into three main groups:

Morphological Features of Viruses:

The viral chromosome is enclosed within a protein shell called capsid. The viral chromosome and its protein coat together are called nucleocapsid. Viruses vary considerably in their morphological features (Table 5.4).

1. Icosahedral virions:

Their capsid is icosahedral, i.e., the virion is a regular polyhedron with 20 triangular faces and 12 corners. Examples are, adenoviruses and bacteriophage φX174.

2. Helical virions:

The nucleic acid of such virions is enclosed in a cylindrical, rod shape capsid that forms a helical structure, e.g., TMV, bacteriophage M13.

3. In some cases, the nucleocapsid is icosahedral while in others, it is helical in some components. Such viruses are enveloped.

These viruses do not have a clearly identifiable capsid. The viral nucleic acid is present in the centre of the shell which is made up of protein molecules. Some of the shells are complex while others are simple. In Herpes, an animal virus that contains DNA as genetic material, the capsid has a diameter of 1000A it is further surrounded by an envelope making its diameter 1500A. (Fig. 5.19).

The capsid is mode up of protein subunits (capsomers) which form an icosahedron.

Bacteriophages have relatively complex structures: they contain a head, a tail, a base plate and several tail fibres (Fig. 5.20). The head is hexagonal (lateral side) and contains the viral DNA. The tail has a core tube surrounded by a sheath. At the tail end, there is a basal plate with 6 spikes from which 6 tail fibres emerge.

At the time of infection, the tail fibres bind to specific receptor sites on the host cell. The base plate is drawn to the cell surface and contraction of tube sheath occurs along with the removal of the base plate plug. The core of the tail penetrates the cell wall which is weakened by some hydrolytic enzymes present in the phage and the viral tail. DNA enters into the host cell through the core tube of the tail.

In the case of tobacco mosaic virus (TMV multiplying in tobacco plant cells) and some small bacterial viruses (e.g., F2, R17, QB), the protein coat contains a single type of protein. These protein molecules are arranged in either a helical symmetry or a cubical symmetry.

The shell of TMV contains about 2150 protein molecules which are identical, each molecule having the molecular weight of-17,000. These molecules are helically arranged around the RNA genome which contains 6,000 nucleotides.

The viruses which lyse or disrupt the host cell following infection are called lytic viruses. During infection, the nucleic acid is injected into the host cell. The enzymes required for viral DNA replication are then synthesized so that replication of DNA occurs to produce numerous copies of the viral chromosome.

The protein components of the capsid are synthesized in the later stages leading to the formation of heads and tails the viral DNA is then packed into the heads. In the end, the cell wall ruptures and the progeny phage particles are released (Fig. 5.21).

Lysogenic Viruses (Temperate Phages):

Lysogeny involves a symbiotic relationship between a temperate phage and its bacterial host. The viral chromosome becomes inserted into the bacterial chromosome, where it remains and replicates along with the latter. The viral DNA integrated into the bacterial genome is called a provirus or prophage (Fig. 5.22). The bacterium containing a prophage is immune to the infection by the same virus.

Viral Chromosomes:

Viruses contain either DNA or RNA as their genetic material. These nucleic acids may be either single or double-stranded (Table 5.5). Small viruses may contain 3 kb (kb =,kilo-bases = 1000 bases), while large viruses could have about 300 kb. in their genome. Thus the number of genes in viral genome may vary from only 3 to hundreds. The retroviruses arc diploid (have two copies of the genome per capsid), while the others are haploid.

Several viruses possess double-stranded DNA as their genetic material. The base composition of different viruses is modified leading to change in the physical properties of DNA such melting temperature, buoyant density in caesium chloride (CsCl) etc.

In some of the viruses, such as. T-even coliphages, cytosine (C) is modified into 5-hydroxymethyl- cytosine (HMC). In certain cases, thymine is converted into 5-hydroxy-methyl uracil or 5-di-hydroxymethyluracil, e.g., in B. subtilisbacteriophges. Certain physical properties of DNA, such as, buoyant density in CsCl or melting temperature are changed due to these substitutions.

Some of the viruses contain linear DNA, while others contain circular (cyclic) DNA (Table 5.5). In the case of phage lambda (λ), DNA can exist in both linear and cyclic forms. When isolated from a viral particle, the λ DNA is linear, but when it enters into the host cell, becomes circular. However, it enters into the host cell in its linear form.

The A. chromosome is a double- stranded DNA molecule containing 47,000 nucleotides it is 17 pm in length. There is single- stranded projection of 12 nucleotides at each 5′-end these projections are complementary to each other and thus they are called cohesive ends.

These cohesive ends are responsible for the circularization of the chromosome. Circularization of the chromosome protects it from degradation by the host exonucleases. Further, the linear DNA cannot replicate vegetatively the circularity therefore, provides an advantage in replication as well.

Single-stranded DNA occurs in very small bacteriophages (Table 5.4). The single-stranded DNA found in the virion is called the positive (+) strand as a rule only the plus (+) strand is found in the phage particles. However, in adeno-associated viruses, two complementary strands exist in different virions. The single-stranded DNA contains inverted repeating sequences that form hair pins. The hairpin structures have important role in circularization of the linear strands and in replication.

Double-stranded RNAs are found in several icosahedral viruses of animals and plants. The genomes of such viruses are segmented (Table 5.5). The different segments may be connected short stretches of base pairs. Transcription of each segment occurs separately and the enzyme involved is “Double-stranded RNA transcriptase”. Each mRNA, on translation produces a separate polypeptide chain.

Single-stranded RNA is the genetic material in a number of viruses (Table 5.5). Some viruses contain a single RNA molecule in their genome, while some other viruses contain several segments, e.g., influenza virus has 8 segments. The viruses contain either positive (+) or negative (-) strands of RNA in their capsids.

The viral RNA strand that functions as mRNA in the host cell is called the plus (+) strand or positive strand. The RNA genomes of animal viruses have a cap at their 5′-end and a poly (A) sequence at the 3′-end. However, in Picornavirus RNA, there is a special sequence at the 5′-end to which a small protein is covalently attached.

The RNA genomes of plant viruses possess a cap at the 5′-end but they do not contain the poly (A) at their 3′-ends their 3′-end is similar to tRNA. Each retrovirus particle contains two copies of the (+) RNA strand representing its genome these copies are held together near the 5′-end.

These RNAs do not contain a cap but terminate into a nucleoside triphosphate at their 5′-ends. These strands do not function as mRNA directly. Instead, they are transcribed by the enzyme “single-stranded RNA transcriptase” present in the virion, to produce the mRNA.

Packaging of Nucleic Acids in the Viruses:

Viral genome (DNA/RNA) is tightly packed into the protein shell (capsid). The density of the nucleic acid in the protein shell is higher than 500 mg/ml, which is much greater than the density of DNA in other organisms. For example, density of DNA in bacterium is about 10 mg/ml, while in the eukaryotic nucleus, it is about 100 mg/ml. This shows that the nucleic acid is very tightly packaged in the viral particles.

The genetic material of TMV is single-stranded RNA containing 6400 nucleotides, making up a length of 2 pm. This RNA is packaged into the rod-shaped compartment of 0.3 x 0.008 pm. Adenoviruses contain 11 pm long double-stranded DNA consisting of 35,000 bp: this is packaged into an icosahedron type capsid of 0.07 pm diameter.

Phage T4 has a very long double-stranded DNA molecule (55 pm) having 170,000 bp. The capsid containing this rather long DNA is an icosahedron with the dimensions of 1.0 x 0.065 pm. Unlike eukaryotic nucleus and bacterial nucleoid, the volume of the capsid is fully packaged with the nucleic acid.

Packaging of nucleic acid to form a nucleocapsid occurs in two general ways. In one mechanism, the protein molecules assemble around the nucleic acid, e.g., in TMV. In the other mechanism, the protein coat is formed first and then the nucleic acid is inserted in it. In TMV, a duplex hairpin structure occurs in the RNA.

The assembly of protein monomers begins at this nucleation centre and proceeds in both the directions, reaching the ends. A total of 17 protein units form a circular layer and two such layers together form a unit of capsid. This structure interacts with the RNA which is coiled to form a helix inside the shell.

In bacteriophage T4 and λ etc., the protein shell is formed first. The nucleic acid is inserted into the coat from one end and then the tail is joined to the head. In case of circular DNA, it must be first converted into a linear molecule for packaging.

The lambda (λ) genome is circular and contains two “cos” sites, cosL and cosR. The free end in λ DNA is produced by enzymatic cleavage at the cosL site. Insertion of DNA occurs from this end and continues till the cosR site enters the capsid a cleavage then occurs at the cosR site to produce the other end of the λ genome.

Some of the viruses, e.g., phage T4 and λ. have terminal redundancy in their genomes. In these viruses, multiple genomes join end-to-end to produce “concatemeric structure.” In case of T4, insertion of the viral chromosome starts at a “random” point and continues until the required amount of DNA has been inserted into the head. The DNA inserted into the head has a terminal redundancy.

One likely origin of the “concatermeric” DNA is recombination. Recombination between two chromosomes combines two genomes end-to-end. Then recombination with a third genome produces a concatemer through successive recombination’s (Fig. 5.23).

Another mechanism suggested for concatemer formation is the rolling circle replication. Specific endonuclease cuts the concatemer at the points that produce the genome of the “required length.” The genomic DNA has homologous ends due to the terminal redundancy. Therefore, some chromosomes may be heterozygous for the terminal genes.

Mechanisms of Lysogenic and Lytic Pathways:

Bacteriophage λ is a temperate phage that maintains a lysogenic relationship with its bacterial host. However, it can undergo lytic cycle also. Infection, as a rule, occurs in the linear form, but the chromosome converts into a circular one once it enters the host cell. A generalized map of the X chromosome showing different functions is presented in Fig. 5.24.

Genes related to similar functions are clustered. On the linear chromosome, genes for head formation are located on left end, while those for lysis are located at the right end. The regulatory region lies between the region for recombination and the region for replication. The genes present in the regulatory region are responsible for determining whether the X will enter into a lysogenic relationship with its host or it will follow the lytic pathway.

Regulatory genes are clustered and flanked by genes for recombination on their left side and those for replication on the right side (Fig. 5.25). Genes N (anti-terminator) and era (anti-repressor) are located within the regulatory region. These genes are called “immediate early genes” they are transcribed by the host RNA polymerase.

In the presence of anti-termination factor (p N ), transcription of both the genes (N and era) continues. These two genes are transcribed from different DNA strands in the opposite direction, the gene N being transcribed towards the left, while era is transcribed towards the right.

The transcription extends to other region of the genome for different functions (Fig. 5.25). In the absence of cl repressor protein, the host RNA polymerase binds to PL/OL sites so that the transcription of the “late genes” is initiated as a result, phage particles are produced and the cell is lysed.

The regulatory region contains the cl gene which is responsible for the lysogenic pathway. A mutation in this region causes the phage to undergo lytic cycle.

The cl gene is transcribed to produce mRNA the enzyme involved in transcription is RNA polymerase that binds to the promoter for repressor maintenance (PRM). The transcription occurs from right to left. This cl mRNA is translated to produce the repressor monomer (Fig. 5.25).

Repressor dimers are formed that bind to the PL/OR and PL/OL sites, thus preventing the RNA polymerase from binding to these promoters. This leads to the inhibition of transcription of N and cro genes. Later, the X chromosome is integrated into the bacterial chromosome its delayed early genes are not expressed and the phage remains as a “provirus”. Delayed early genes are the genes for recombination, replication and Q (anti-terminator). Late genes are tail, head and lysis genes.

When the cl repressor is bound to the 0L and 0R sites, RNA polymerase initiates transcription of the cl gene, and synthesis of repressor protein is continued. But in absence of the repressor, RNA polymerase binds to PL/OL and Pr/Or sites and transcription of N and cro genes begins.

Thus the presence of cl repressor itself is necessary for its synthesis. Continuous production of cl repressor is necessary for lysogeny to be maintained. During this period, the OL and OR sites are always bound by repressor.

When the lysogenized cell is infected by another phage X, the cl repressor protein produced by the “prophage” immediately binds to the OL and 0R sites of the infecting X genome. The function of the infecting X genes is thus inhibited and the cell remains immune to X infection.


The original central dogma of molecular biology held that DNA was transcribed to RNA, which in turn was translated into protein. However, this concept was challenged in the 1970s when two scientific teams, one led by Howard Temin at the University of Wisconsin and the other led by David Baltimore at MIT, independently identified new enzymes associated with replication of RNA viruses called retroviruses [1,2]. These enzymes convert the viral RNA genome into a complementary DNA (cDNA) molecule, which then is capable of integrating into the host’s genome. These are RNA-dependent DNA polymerases and are called reverse transcriptase because, in contrast to the DNA-to-RNA flow of the central dogma, they transcribe RNA templates into cDNA molecules (Figure 1). In 1975, Temin and Baltimore received the Nobel Prize in Physiology or Medicine (shared with Renato Dulbecco for related work on tumor-inducing viruses) for their pioneering work in identifying reverse transcriptases [3].


&ldquoIt is estimated that there may be tenfold more asymptomatic carriers of the disease, which means that there could be over seven-and-a-half million carriers worldwide,&rdquo said Subramani. &ldquoThis is a disease that is spreading very rapidly across the globe, so these faculty are here to share their knowledge regarding the biology of the virus and why this pandemic has brought the world to its knees.&rdquo

Emily Troemel, a professor who studies host-pathogen interactions in the Section of Cell and Developmental Biology, kicked off the discussion by describing basic biological aspects of coronaviruses, including how health workers test for the presence of SARS-CoV-2 infection and facets scientists have learned about the virus&rsquo genome.

Coronaviruses, as Troemel noted, feature RNA-based genomes, unlike most of life on the planet, which feature DNA genomes. RNA genomes in coronaviruses are positive-sense, which are similar to the cell&rsquos own messenger RNA and allows these viruses to immediately hijack the protein synthesis machinery of host cells. This feature enables these viruses to quickly and effectively take over host cells and rapidly expand.

&ldquoKnowing that it has RNA in its genome helps us understand how we test for the presence of coronavirus,&rdquo said Troemel. &ldquoIn addition, we are able to look at changes in the sequence in the viral genome and that&rsquos enabling us to track the spread of this virus around the globe&hellip. We can learn about how the biology of the virus is changing and how it may be altering the way it interacts with host cells, and also potentially different ways that we could treat it. It&rsquos part of an amazing open science effort with an unprecedented level of information acquisition and information sharing among researchers.&rdquo

Matt Daugherty, an assistant professor in the Section of Molecular Biology, studies the evolutionary arms race that pits the immune systems of hosts on one hand and pathogens on the other. He covered aspects such as how SARS-CoV-2 and other viruses enter the human population and become pandemics how SARS-CoV-2 relates to past and present epidemic viruses in the human population and, based on what scientists have learned from other viruses, what we can expect in terms of long-term immunity and co-existence with SARS-CoV-2.

&ldquoWe as a species are always being exposed to viruses,&rdquo Daugherty noted.

Since SARS-CoV-2 is so new, there are many key unknowns related to human immune defenses against it, Daugherty said. Even with coronaviruses that cause common colds, it&rsquos unclear whether humans develop long-term immunity to these viruses or need to continually develop new immunities.

&ldquoOne thing I take comfort in with all of these other viruses is knowing that we aren&rsquot constantly dealing with influenza pandemics and other pandemic viruses, and that&rsquos because of the largely effective role of our immune system in dealing with these viruses once the immune system has been prepared,&rdquo said Daugherty.

For a virus that originated in an animal species to successfully infect humans, it needs to adapt to a range of genetic differences between the original host species and humans. But effective vaccines can ultimately thwart such pathogens.

&ldquoWe have really good ways of making effective vaccines, and the hope is that this will hold for SARS-CoV-2 as well,&rdquo said Daugherty. &ldquoI take some comfort in knowing that these types of pandemics do pass and we will get through this.&rdquo

Justin Meyer, an assistant professor in the Section of Ecology, Behavior and Evolution, discussed concepts related to science and society&rsquos ability to predict future pandemics. These include variables that contribute to the spread of pathogens the increased likelihood of future pandemics and predictions for where the next pandemic is likely to occur.

Factors that boost the risk of pandemics include human exposure to pathogens through meat consumption and contact with wild animals, increased human encroachment in wild areas and the exotic animal trade. Increased urbanization&mdashmore people living in close proximity means more opportunities for viruses to spread&mdashand the rising consequences of climate change, also increase pandemic risks.

&ldquoWe&rsquore augmenting the temperature of the earth and environments in a way that we&rsquore making ourselves more susceptible to diseases,&rdquo said Meyer. &ldquoWhen we warm the earth, we create more habitats for mosquitoes that carry vectors like malaria by increasing their range. They can spread to new human populations. By increasing temperatures, we&rsquore increasing flooding and there are many pathogens that are waterborne, such as cholera, which we will be exposing more and more people to.&rdquo

During the roundtable discussion, Subramani prompted the scientists with a handful of questions, including: Since many coronaviruses are relatively harmless, what makes SARS-CoV-2 so damaging to the lungs? What is the appropriate vaccine target for SARS-CoV-2 and in what time frame&mdashfrom validation to FDA approval&mdashis a vaccine likely? Can we look to drug targets where vaccines have been developed for related viruses and would that timeline be the same? Is there any evidence that SARS-CoV-2 has a mutation rate that is extraordinarily high?


Most of the current antiviral therapeutics act for inhibiting specific viral proteins, e.g. essential viral enzymes. Unfortunately, this approach has been ineffective because of drug resistance developed by viruses, especially in the case of RNA viruses which can mutate very rapidly. The next‐generation antiviral therapeutics are emerging which target host proteins required by the pathogens, instead of targeting pathogen proteins. If these host factors are indispensable for pathogens, but not essential for host cells, their silencing may effectively inhibit infections without developing drug resistance rapidly 1, 21, 22. Another alternative approach is to inhibit the interactions between these host factors and pathogen proteins, instead of targeting the proteins 23. The development of these novel strategic therapeutic approaches against infectious diseases raises the need for enlightening the infection mechanisms through PHIs, in order to identify putative host‐oriented anti‐infective therapeutic targets. To understand the complex mechanisms of infections, computational analysis of underlying protein interaction networks may serve crucial insights to develop non𠄌onventional solutions 2, 14, 24. This study of computational analysis of virus–human interactomes aims to provide initial insights on the infection mechanisms of DNA and RNA viruses, comparatively, through the observation of the characteristics of human proteins interacting with viral proteins. The common and special infection strategies of DNA and RNA viruses found here may lead to the development of broad and specific next‐generation antiviral therapeutics.

Highly targeted human proteins

As the main viral infection strategy, all viruses manipulate cellular processes to proliferate within the host. Therefore, viral proteins highly interact with human proteins functioning in cell cycle, human transcription factors to promote viral genetic material transcription, nuclear membrane proteins for transporting viral genetic material across the nuclear membrane, and also regulatory proteins for translation and apoptosis 3, 15, 25, 26. We identified human proteins that are highly interacting with viral proteins, sequentially based on the total number of targeting virus families (Table 4 ). The list includes the top viral targets which interact with multiple viral families, within the most comprehensive PHI data. Some of these human proteins were previously reported as targets for multiple viruses, i.e. P53, NPM, ROA2, GBLP, and HNRPK 3, 15.

Our analyses revealed that there are six heterogeneous nuclear ribonucleoproteins (HNRPs) in the highly targeted human proteins list (HNRPK, ROA1, HNRPC, HNRH1, HNRPF, ROA2). HNRPs are RNA𠄋inding proteins, which function in processing heterogeneous nuclear RNAs into mature mRNAs and in regulating gene expression. Specifically, they take role in the export of mRNA from the nucleus to the cytoplasm. They also recruit regulatory proteins associated with pathways related to DNA and RNA metabolism 27, 28. Being targeted by multiple viruses, HNRPU was reported as a hotspot of viral infection, and proposed as a potential antiviral human protein 4. In the present study, HNRPU is found to be targeted by five viral families (see Data S3). Our data additionally indicate several other HNRPs, targeted by viral proteins (see Data S1–S3). For all virus‐targeted HNRPs, the number of targeting RNA virus families is found to be higher than that of DNA virus families (see Data S3), revealing that they may play crucial roles in viral RNA processing. The protein family of HNRPs may serve as host‐oriented antiviral drug targets.

Moreover, our analyses also reflected that proteins functioning in transport and localization related processes within the cell are targeted highly by both DNA and RNA viruses, i.e. IMA1, ADT2, TCPG, and TCPE. IMA1 (Karyopherin alpha 2, KPNA2) functions mainly in nuclear import as an adapter protein for nuclear receptor KPNB1 (Karyopherin beta 1). Interacting with IMA1 enables viruses to enter the nucleus and consequently to use the host's transcriptional machinery. Besides, viruses may interact with IMA1 in order to inhibit the host antiviral response, since nuclear import factors regulate the transport of innate immune regulatory proteins to the nucleus of cells to activate the antiviral response 3, 29, 30, 31. The transmembrane transporter activity of ADT2 is responsible for the exchange of cytoplasmic ADP with mitochondrial ATP across the mitochondrial membrane, serving crucial roles in metabolic processes 32. Attacking to human metabolic processes was reported as a common infection strategy of bacteria and viruses 15. The proteins, TCPG and TCPE are responsible for RNA localization activity and our results reveal that they are targeted by larger number of RNA families (Table 4 ). Highly targeted transporter proteins should be investigated further for their potential to be next‐generation antiviral target, because of their crucial roles in viral life cycle within the host organism.

EF1A1 and EF1A3 function as translation elongation factors in protein biosynthesis. EF1A proteins promote the GTP�pendent binding of aminoacyl‐tRNA to the A‐site of ribosomes during protein biosynthesis with a responsibility of achieving accuracy of translation 33. Translation elongation factors were reported as targets for viruses, in early studies 34, 35, 36. Since they are essential components of the cellular translational machinery, viruses interact with them for biosynthesis of viral proteins within the host cell. We found translational elongation as the top biological process, commonly targeted by both DNA and RNA viruses (Table 7 ).

Interacting with human transcription factors was reported as one of the main viral infection strategies 3, 15. Among the highly targeted human proteins, YBOX1 and P53 have transcription factor activity. Both of these proteins are multifunctional. YBOX1 functions in transcription of numerous genes, as a transcription factor. It also contributes to the regulation of translation. On the other hand, P53 is the famous tumor supressor acting as an activator for apoptotic cell death. Apoptosis is a very crucial process during the viral infection progress, and should be strategically controlled by viruses for a successful viral infection. Apoptosis is an innate immune response to viral infection. In the early stage of viral life cycle in the host cell, apoptosis is inhibited by corresponding virus–human protein interactions. After completion of transcription and translation of viral genetic material, viruses try to induce apoptosis to assist virus dissemination 37, 38, 39.

Among the highly targeted human proteins in Table 4 , EF1A1, ADT2, TBA1C, GRP78, TBB5, P53, TCPG, HS90B, and TBA1A were found as drug targets listed in DrugBank 40. However, only ADT2, GRP78, TBB5, P53, and TBA1A are approved for commercial drugs. Nevertheless, no antiviral therapeutic usage is available for these drug targets yet. Above‐mentioned human proteins ribonucleoproteins, proteins functioning in intracellular transport and localization, translation elongation factors and transcription factors require further investigation for their potential for serving as antiviral drug targets.

Targeted human mechanisms

Gene ontology and pathway enrichment analyses of pathogen‐targeted host proteins are widely used in bioinformatic analysis of PHI networks to understand the attack strategies of pathogens 3, 4, 15, 41, 42 as well as in verification of computationally predicted PHIs 43. Additionally, GO and pathway terms are widely used as features in computational PHI prediction studies 44, 45.

Our observation of the enriched GO process terms for human proteins targeted by only DNA viruses (Table 5 ) may lead to the conclusion that DNA viruses have specifically evolved to be able to attack human cellular and metabolic processes simultaneously, during infections. Using this PHI mechanism, DNA viruses can finely exploit the cellular and metabolic mechanisms of infected cells to their own advantage, generally resulting in chronic infections in human. On the other hand, GO process terms enriched in human proteins targeted by only RNA viruses are mostly related to RNA processing, intracellular transport and localization within the cell (Table 5 ). It was reported that RNA viruses extensively target human proteins that are involved in RNA metabolism and also protein and RNA transport to promote viral RNA processing for a successful infection 4.

Further investigation of the enriched processes of human proteins attacked by multiple DNA viruses (Table 6 ) pointed out their high preference to target cellular processes. It was reported that DNA viruses tend to target crosstalking human proteins linking the cell cycle with either transcription or chromosome biology, with a possible aim of promoting viral replication instead of cellular growth 4. For the RNA viruses, we found that the human proteins attacked by multiple RNA virus families are enriched in specific processes within the cellular mechanisms (Table 6 ). All viruses need host's transcriptional machinery for viral genetic material transcription.

In the case of human proteins targeted by both DNA and RNA viruses, the P‐values of the enriched GO process terms are very low, indicating statistically strong results (Table 7 ). The most highly‐targeted human process is translational elongation. Translational control of viral gene expression in eukaryotic hosts was reported repeatedly 46, 47, 48. Here, we presented translational elongation as the top GO process term enriched in human proteins targeted by both DNA and RNA viruses within the current experimental PHI data. The remaining list includes cellular and metabolic processes, which can be considered as targets of both virus types. Based on these observations, we can state that the common viral infection strategy is to target human proteins functioning within the processes of gene expression and protein synthesis, simply because of the lack of their own such machineries. All viruses depend on the cellular mechanisms for these processes and they recruit host ribosomes for translation of viral proteins.

A comparative investigation of the enriched pathway terms for human protein sets targeted by only DNA viruses and by only RNA viruses (Table 8 ) reveals additional support for the different infection strategies of these viral groups. There is no common term in these two lists of enriched human pathways. Cell cycle pathway targeted by only DNA viruses and RNA‐related pathways targeted by only RNA viruses, provide parallel results with GO enrichment analyses. The enriched pathway terms in 4𠄍NA viruses‐targeted human protein set are only Epstein�rr virus (EBV) infection and viral carcinogenesis (Table 9 ). EBV is a species of DNA virus family Herpesviridae, which constitute nearly half of the DNA viruses–human PHI data (Table 1 ). On the other hand, it is estimated that 15% of all human tumors are caused by viruses, mainly DNA viruses, i.e. Herpesviruses and Papillomaviruses 49. The pathway enrichment analysis of 4‐RNA viruses‐targeted set brings the terms of protein processing and immune system related terms forward (Table 9 ). Finally, for the common targets of two virus types, we obtained ribosome term enriched with a very small P‐value (Table 10 ). Both viruses use host ribosome for viral protein synthesis.

Types of Nucleic Acid

Unlike nearly all living organisms that use DNA as their genetic material, viruses may use either DNA or RNA. The virus core contains the genome—the total genetic content of the virus. Viral genomes tend to be small, containing only those genes that encode proteins which the virus cannot get from the host cell. This genetic material may be single- or double-stranded. It may also be linear or circular. While most viruses contain a single nucleic acid, others have genomes divided into several segments. The RNA genome of the influenza virus is segmented, which contributes to its variability and continuous evolution, and explains why it is difficult to develop a vaccine against it.

In DNA viruses, the viral DNA directs the host cell’s replication proteins to synthesize new copies of the viral genome and to transcribe and translate that genome into viral proteins. Human diseases caused by DNA viruses include chickenpox, hepatitis B, and adenoviruses. Sexually transmitted DNA viruses include the herpes virus and the human papilloma virus (HPV), which has been associated with cervical cancer and genital warts.

RNA viruses contain only RNA as their genetic material. To replicate their genomes in the host cell, the RNA viruses must encode their own enzymes that can replicate RNA into RNA or, in the retroviruses, into DNA. These RNA polymerase enzymes are more likely to make copying errors than DNA polymerases, and therefore often make mistakes during transcription. For this reason, mutations in RNA viruses occur more frequently than in DNA viruses. This causes them to change and adapt more rapidly to their host. Human diseases caused by RNA viruses include influenza, hepatitis C, measles, and rabies. The HIV virus, which is sexually transmitted, is an RNA retrovirus.

Summary – DNA vs RNA Viruses

DNA viruses and RNA viruses are the two main categories of viruses. As their names imply, DNA viruses contain DNA as their genetic material while RNA viruses contain RNA as their genetic material. Thus, this is one of the key differences between DNA and RNA viruses. Generally, DNA genomes are larger than RNA genomes. Furthermore, most DNA viruses contain double-stranded DNA while most RNA viruses contain single-stranded RNA. DNA viruses show accurate replications while RNA viruses show error-prone replication. Apart from that, DNA viruses are stable and show a lower mutation rate while RNA viruses are unstable and show a higher rate of mutation. This is the summary of the differences between DNA and RNA viruses.


1. “DNA Viruses.” NeuroImage, Academic Press, Available here.
2. “RNA Virus.” Wikipedia, Wikimedia Foundation, 20 Feb. 2019, Available here.


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