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Kirill Dmitriev
Kirill Dmitriev

Viral Shapeshifter.pdf



Nuclear magnetic resonance (NMR) studies have re-affirmed the presence of long and short disordered regions in the p17 of HIV [59]. Furthermore, several studies have shown that the HIV matrix has an ability to induce B-cell growth [60,61]. One particular study has shown that when p17 becomes more disordered as a result of a point mutation, it loses its ability to elicit B-cell growth, even though the precise binding sites responsible for such elicitation are unknown [61]. Such experiments are important as they prove that the HIV matrix can affect interactions of antibodies with HIV, thereby providing support to the viral shapeshifting paradigm. Experimental evidence is also accumulated to show that the rate of evolution of viruses is correlated with their modes of transmission. For example, it has been shown that HSV that has been paternally transmitted is genetically different from those transmitted via other modes [62]. Computational and empirical models using methodology similar to the already described one have been able to establish the relationships between the levels of shell disorder and modes of transmission among coronaviruses. The model was so accurate that it was able to predict that MERS-CoV has a strong fecal-oral transmission component and therefore would not spread as easily as its cousin, SARS-CoV [20,22]. These studies showed the important roles that shell disorder plays in the evolution of viral transmission, which gives additional credence to viral shapeshifting theory. In yet another study, high positive correlation between Ebola nucleocapsid disorder and virulence was seen [25]. Similar correlations could be found between flavivirus capsid and virulence [26]. Since these studies involve inner shells of the related viruses, they provide further validation for the existence of viral shapeshifters of a different kind contrasting the HIV, which has a disordered outer shell and is a shapeshifter of a unique kind.




Viral Shapeshifter.pdf



A major obstacle for both phage and oncolytic virotherapies is the accurate delivery of the viruses to the target. One factor is that the host immune system will attempt to neutralize the therapeutic virus even before it reaches its target and thereby will render the viral agent ineffective [68]. This is where the concept of viral shapeshifting will come in handy. Viruses can be engineered to behave like HIV-1, which, as we have seen evades the immune system efficiently and moves easily to organs that are normally difficult to reach, like the brain [54]. Another factor is that cancer cells can hide out in poorly accessible places, such as the brain. Here again, the concept of shell disorder can come in handy, as protein intrinsic disorder allows for greater binding promiscuity [30] and therefore can help viruses to enter into vital organs, such as the brain [12]. In line with these considerations is the fact that HIV enters the brain and other vital organs with ease.


Protease inhibitors (PIs) are medications that act by interfering with enzymes that cleave proteins. Some of the most well known are antiviral drugs widely used to treat HIV/AIDS hepatitis C and COVID-19. These protease inhibitors prevent viral replication by selectively binding to viral proteases (e.g. HIV-1 protease) and blocking proteolytic cleavage of protein precursors that are necessary for the production of infectious viral particles.


Callaway paired the glycoprotein with a human antibody, which helped her pinpoint one site where the viral structure is vulnerable to antibody attacks. The researchers then captured a 3D image of the glycoprotein using cutting-edge cryo-electron microscope equipment at LJI.


The new 3D structure highlights several key features researchers hadn't seen before. Importantly, the structure shows two key pieces of the virus structure, called the fusion peptides, the way they appear in real life. These two sequences link the bottom of the glycoprotein to the viral membrane, but project into the target cell during infection. It is very hard to get a stable image of these sequences. In fact, other rabies researchers have had to cut them off to try to get images of the glycoprotein.


And yet, under the right conditions, basic viral components can accomplish what many natural phenomena cannot: a process called self-assembly, combining their bits into neat, structured particles without any external forces to guide them, like cake ingredients mixing themselves into batter or snowflakes sprouting spontaneously out of room-temperature water.


Jasmine Cubuk, a biochemist and biophysicist at Washington University in St. Louis, is using a microscopy technique called fluorescence resonance energy transfer, or FRET, to monitor these molecular tangos in real time. In a study that has not yet been published in a scientific journal, Ms. Cubuk and her colleagues showed that nucleocapsids are wiggly, which might help them shimmy around a host cell in search of their viral RNA partners. 041b061a72


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