Jlang, Holy smokes, I guess we disagree even mo

Jlang,

Holy smokes, I guess we disagree even more this afternoon. However, I'll try to address your claims that I have a "drastically less than complete grasp" of the topic under discussion.

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Mutation rate isn't moot, it's baseline.. this is about Variants of Concern vs previous variants they're outclassing. For the nth time. They all have roughly the same mutation rate regardless of host.. it's non-relevant with respect to this comparison, not irrelevant in general. You don't comprehend this.

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I agree mutation rate isn't moot, though I don't believe that "baseline" is anywhere in the world a synonym for moot. Mutation is the basis from which evolution of variants has the opportunity to occur. Higher mutation rate, equals greater opportunity for change.

I am glad that you finally appreciate that mutations occur roughly at the same rate, irrespective of host immune competence. Until the virus clears (a few weeks in healthy patients, many months in immune compromised patients) viral replication continues with resultant mutations.

Previously you argued:

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You're approaching it from a mathematical standpoint.. it's not about mutation opportunities, it's about selective pressures. They're uniquely geared towards improving binding affinity and virulence in the immunocompromised.. of which those with HIV are a significant part.

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For review, selective pressures are unable to drive development of variants without mutations, some of which may have increased fitness.

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Again, immune evasion is not the only or I'd argue even the primary selective force for a novel virus.. binding affinity and transmission are of higher relative importance. The strength of the host immune system does matter: in that weaker ones allow the pathogen more time to become familiar and increase binding affinity to the pathogens receptors of choice. This is elementary. You don't comprehend this.

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All three characteristics, immune evasion, binding affinity / viral entry and transmission can drive viral fitness.

Immune evasion undoubtedly matters, as improved immune evasion allows covid to persist among a population. This is the crux of the concern that neutralizing antibodies and vaccines will fail to protect.

Weakened host immune response allows continued viral replication, it is unequivocally NOT a selective pressure driving improved binding affinity. The compromised host allows relatively unimpeded viral reproduction, in fact permitting reproduction of "less fit" visions which would be eradicated by a healthy immune system, the exact opposite of what you claim.

I'll try to make this even more simple. Imagine two herd of goats, one living in a valley with enough food and water, but hungry wolves (representing a competent immune system). The goats have an opportunity to reproduce and thrive, but are constantly under attack by wolves. Variation through procreation occurs in these goats, but the presence of the wolves selects for the goats that are the most fleet of foot, wary, and able to reproduce with precocious young (able to run and flee at birth). The eventual result is a population of fast, evasive, and precocious goats.

The second valley, our incompetent immune system, allows the goats to reproduce with just a few lazy third rate goats. Variation among the goats will still occur during reproduction, but without a significant threat from the wolves, the goats remain unchanged without increased wariness, evasion, precious young and accelerated reproduction.The goats, if isolated and separated from predatory threats remain a mixed bag, perhaps even become slower and more slothful (evolution island hypothesis). Only the goats who leave there valley and are tested by wolves and other existential threats will become a more fit variant.

Again compromised host - valley without wolves = mutation opportunity

Valley full of threats = selective pressure

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A strong, functional host doesn't allow the pathogen the luxury of time to increase binding affinity, as evidenced by the multitude of papers describing weeks-months long, active covid infections in the immunocompromised, with several advantage conferring mutations, with sequential viral samples/references exquisitely building the roadmap of these accumulated mutations... And literally zero of the same detailing a similar process in hosts that have a disease course that lasts for days, max. I've posted several, read them on repeat until it sinks in.

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I concur that prolonged infection in immunocompromised hosts presents an increased opportunity for mutation and variant emergence. However, immune competent patients still generate very high viral loads, as previously discussed. With high mutation rate, each of the virions, presents a new opportunity for a variant to emerge.

Each virion exists as an independent infective agent, not needing "luxury of time to increase binding affinity." It is either sufficiently fit to bind to the requisite cell surface protein (ACE2, or if it's lucky, a new protein with which it is now able to fuse), enter the cell and reproduce or it is not. Every organism that does not reproduce is an evolutionary dead end.

Please recall RNA virus can explode from a single copy to 100K in 10 hours, with viral loads of 10^12. Again, I concur that immune suppressed patients maintaining high viral titers are an increased opportunity for variant emergence, but so is ongoing infection amongst many millions worldwide.

https://www.researchgate.net/publication/2033...NA_viruses

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And literally zero of the same detailing a similar process in hosts that have a disease course that lasts for days, max.

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Jlang, are your truly arguing that viral mutation only occurs among the immunocompromised?

No viral, bacterial or fungal evolution occurred prior to HIV, chemotherapy and steroids?

Laughable.

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The immunocompromised allow for mutations in the most crucial of those factors.. for a Novel Virus.. binding affinity to a new species receptor.

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I concur, again, that immune compromised patients allow ongoing viral replication and mutation.

Mutation is simply the results of erroneous nucleotide substitution during transcription. Most errors are deleterious, some are neutral and a chance few are advantageous. The advantageous mutations will not reveal themselves, and potentially result in variants, until they emerge and "try their hand" infecting the immune competent, or even more challenging, the immune competent and vaccinated or previously infected.

There is no selective pressure exerted by the weak favoring the strong. Covid virions in immunocompromised patients have already demonstrated the ability to infect via ACE2 or the patient would not be infected. The hurdles for further infection may actually decrease over time in the infected host through syncytia formation.

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The non-compromised hosts don't have "healthier locks".. they have roughly the same ACE2 receptors as the immunocompromised. The virus has less time trying to pick at ACE2 in a healthy host. Less mutations.. even you can't argue this. And what you don't understand is, this process is iterative and *greater at driving the increase in binding affinity of the viral spike protein and ACE2 in compromised hosts*. The exact opposite of what you're suggesting.

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The selective pressures are in fact the opposite of what YOU suggest. A more fit variant is one that is is successful even when "The virus has less time trying to pick at ACE2 in a healthy host."

Ever watched sport competitions? I'm impressed by the contestants on American Ninja Warrior.

Now, if we send a thousand people out of the course and gave them weeks to practice, eventually one will finish. However, who is the better athlete (successful varian), the one who FINALLY prevails or the one who races out of the gate and flashes the course in record time, the first time.

That is your new and dangerous variant.

Don't give up. You'll get it eventually.

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