How can mutation of viruses lead to loss of fit to antibodies without loss of fit to antigen of cells they infect?

Question

Viruses are known to mutate, thereby escaping immune cells and evading vaccination. Given that there is one and the same specificity of the key to both the receptor on the infected cell causing the disease after cell entry as well as to the antibodies or immune cell receptors of the immune cells how can it be that a virus that has mutated thus escaping defense is still able to connect to cells of the body?

It should be one and the same key to one and the same lock. As it is the same key it seems logical that both locks - antibodies' and antigens' are identical, as they fit to the same key. If mutation leads to "unfitness" in respect of antibody, how can the key still fit to the body?

In the context of mutation and vaccination this question might intuitively be answered by "different epitopes".

Is there any opinion on that at all? Textbooks seem to be not explicit at all. Is it too trivial a question? Are there are two epitopes on viruses: one for the antibody, one for the body cell? Mutation somehow deliberately restricts itself to the former?

One line of thought added: if you think of some shared (intersectional) epitope it's one and the same mutation that influences both sides, adhesion to antibody and, plus, adhesion to target receptor. Logically, it is possible that there is one mutation that is successful in both ends, i.e. results in loss of antibody fit and improves adhesion to target cell at the same time. But then, illustrating my question, it is a question of probability - as on the antibody side it is the loss of fitness which should be - at the same time - be a gain on the side of adhesion to receptor. Intuitively, this is highly unlikely, with a shared epitope.

The above speaks for different, non shared epitopes, and a multistep strategy in the evolution of virus. Is it possible and is there any authority on my assuming that it is among those virus clones that do not lose their affinity to antibody and remain under attack (as losing antibody fit, see above, means losing target fit, in probability) that selection takes place: those who do not mutate away from antibody attack evolve receptor affinity, and become "a little bit better", in speed, attain advantage in targeting against being caught antibodies. This might explain and be coherent with CoV-2 making appearance not as a variant of CoV that antibodies would not reach anymore, but much more so as a variant that has improved its target cell affinity.

So, assuming relevant mutations being selected among those strains that remain within the reach of existiting antibodies and do not mutate away from the antibody side epitope would be consistent with findings that existing vaccines and the antibodies they induce remain valid against new and upcoming strains of CoV-19. If it were found that new strains are more pathogenic, that would be coherent with that assumpton, too.

For better understanding compare this passage of the answer giben: "... which do lose their fitness against the immune system, but undergo gene reshuffling with similar viruses and again become infectious." "Lose fitness against the immune system" in strict meaning of words would mean gaining fit the to the antibody - however, the author speaks of "becoming infectious", thus refering to target cells. This made me rethink the above to the following:

If you do not assume any shared, identical epitope of body cell (lose the fit to antibody means gaining fitness against the immune system, however at the same time losing fit against the target cells that define the disease) there is some successful "moving out" of the reach of antibody which means "sucess" and that same "moving out" of the realm of target cell epitope which means "failure", losing infectivity. At both sides it's just "into the negative", to lose a fit (however, success and failure very set apart). One has to acknowledge that both sides make sense: just losing fit to antibody is success (epitope to body receptor remains unchanged). For success of the virus on the body cell side, however, no loss will do, there must be a gain of fit to another receptor on body cell. Why then, to illustrate my question further, should a selective stress prefer to take the hard way: gain of function towards body cell, and not easily "fall apart" from the antibody fit, thus becoming fit against the immune system?

To sum up, two alternative answers seem possible: a. there are two separate epitopes; virus escape the antibody fit, and this suffices b. there indeed is a shared, common epitope: it is not enough to "opt out" and exit the antibody fit but one and the same mutation - as the primise is the existence of a shared, no separate epitope - must find a new fit on the body cell receptors side.

A third answer emerges, to me: Epitopes are separate, not shared, and mutation is a multi-step process. Then first, interestingly, the mutation to a new fit on the body target cell side should come first, as only this sequence - not the opposite - presevers selective pressure to escape the immune system in the following second mutation.

Answer 1

I'll address this q and ignore the rest of the (way too long) post/theories:

Given that there is one and the same specificity of the key to both the receptor on the infected cell causing the disease after cell entry as well as to the antibodies or immune cell receptors of the immune cells how can it be that a virus that has mutated thus escaping defense is still able to connect to cells of the body?

As it is the same key it seems logical that both locks - antibodies' and antigens' are identical, as they fit to the same key. If mutation leads to "unfitness" in respect of antibody, how can the key still fit to the body?

This premise is wrong in several ways.

First, affinity is not a binary (yes/no) proposition. More technically speaking, what matters for virus binding to a receptor is avidity, which is the combination effect of affinities at multiple points in a protein, but many papers in virology nonetheless use the former term when talking about viruses binding to receptors.

You can probably already see that multiple "solutions" or "keys" are (thus) actually possible for the same "lock". For example, the SARS-CoV and SARS-CoV-2 RBD (receptor binding domains) are only about 73% similar, even though both viruses bind to the ACE2 receptor in humans, "well enough" to infect (and ultimately replicate).

Furthermore, the "lock and key" metaphor is only a very crude approximation of the more complex mechanism of viral entry. But to single out one aspect of that, the "key" basically can "shape-shift" (undergo conformational change) so that it "looks different" during viral entry than it might otherwise look to antibodies, e.g.

The RBD in coronaviruses can be in either a standing-up state, which enables receptor binding, or a lying-down state, which does not bind to the host receptors. Cryo-EM studies have shown that, in SARS-CoV spike, the RBD is mostly in the standing-up state; however, in SARS-CoV-2 spike, the RBD is mostly in the lying-down state. Therefore, compared to SARS-CoV, although SARS-CoV-2 RBD has higher hACE2 binding affinity, it is less accessible, resulting in comparable or lower hACE2 binding affinity for SARS-CoV-2 spike. To maintain its high infectivity while keeping its RBD less accessible, SARS-CoV-2 relies on a second strategy—host protease activation. [...] Protease activation of coronavirus spikes potentially leads to the final structural change of coronavirus S2 needed for membrane fusion; this process is irreversible and needs to be tightly regulated.

As further discussed in that paper, RBD masking/shielding is actually rather common in several other virus types (HIV, Hepatis C, Ebola etc.)

As an interesting point here showing how affinity can decrease but avidity can increase (probably in tandem with antigenic drift), a 2017 paper on H3N2 finds that:

Recent reports have suggested that current human H3N2 viruses no longer have strict specificity toward human-type receptors [using typical hemagglutination tests]. Using an influenza receptor glycan microarray with extended airway glycans, we find that H3N2 viruses have in fact maintained human-type specificity, but they have evolved preference for a subset of receptors comprising branched glycans with extended poly-N-acetyl-lactosamine (poly-LacNAc) chains, a specificity shared with the 2009 pandemic H1N1 (Cal/04) hemagglutinin. [...] Remarkably, these human-type receptors with elongated branches have the potential to increase avidity by simultaneously binding to two subunits of a single hemagglutinin trimer.

As final "food for though" as to the [in]appropriateness of the key-lock analogy, poxviruses don't seem to use any particular receptor to bind to cells, being capable of attaching to glycosaminoglycans (GAGs), which are present in all eukaryotic membranes, although various cells differ in degree of sulfation of their GAGs, which in turn changes affinity with poxviruses.

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The second reason for which your premise is wrong, antibodies are not mere copies of the receptors found the on the actual cells that the virus may enter. Antibodies need to "solve" a simpler problem than the virus-cell entry; namely an antibody (if we restrict discussion to those targeting a receptor binding domain) only needs to "screw up" the RBD somehow, so the latter doesn't "fit" with the cell receptor anymore. For example, these two antibody fragments against SARS both manage that disruption, even though one only binds to the side of the RBD:

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Third, there is actually a rapid evolution process of antibodies themselves known as antibody affinity maturation:

The extensive sequence diversity of antibody molecules derives from several sources: (i) combinatorial diversification, whereby two sets of light (L) chain gene segments, VL and JL, and three sets of heavy (H) chain gene segments, VH, D, and JH, rearrange to produce functional variable (V) regions; (ii) imprecise joining of these gene segments; and (iii) somatic hypermutation, by which point mutations, as well as insertions and deletions (indels), are introduced throughout the sequences encoding L and H chains. B cells expressing antibodies with improved affinity are better equipped to compete for antigen and thus receive signals that result in preferential expansion and further antibody sequence diversification via additional rounds of somatic hypermutation. Through this rapid evolutionary process of mutation and selection, antibody affinity typically improves 10- to 5,000-fold during the course of an immune response, bolstering host defense.

If the host is lucky, it might even produce antibodies that work against multiple viruses. E.g. there's a known example of an antibody from a Covid-19 patient which also neutralizes the orignal SARS, even though this patient had no history of infection with the latter/older virus. This is basically known as cross-reactivity of anti-bodies. However note that this antibody is not equally effective against both viruses, it needs higher concentration to achieve the same affect against SARS-CoV than avainst SARS-CoV-2.

The antibody COVA1-16 was recently isolated from an individual recovering from COVID-19 and cross-neutralizes SARS-CoV-2 (half-maximal inhibitory concentration [IC50], 0.13 μg/mL) and SARS-CoV (IC50, 2.5 μg/mL) pseudovirus.

Answer 2

One has to distinguish the cause and the consequence: the only viruses that survive the natural selection are those that can evade the immune defenses while effectively infecting cells. A virus strain not successful at either of these tasks is less fit and likely goes extinct.

One can pose a question of what modifications in virus proteins allow it to be so specific in what it (does not) binds to. However, the answer will necessarily depend on the specific virus/strain and specific conditions (which may mean the epidemiological conditions during the time of its spread, the existing vaccines, or even the specific patient).

It is also necessary to point out that statement Viruses are known to mutate, thereby escaping immune cells and evading vaccination. is generally not true, but presents only one possible evolutionary strategy for virus survival, characterized by establishing a chronic infection. The typical example here is HIV. To some extent one could also use this description for influenza-like viruses, which do lose their fitness against the immune system, but undergo gene reshuffling with similar viruses and again become infectious. However one could argue that this is not a mutation, but a new virus.

Other strategies that viruses use to survive include (viewed from the point of view of population genetics rather than virology):

• Hit and run approach, characteristic of cold-like viruses, which succeed to replicate before triggering the response of adaptive immune system, and thus being able to reinfect the same hosts.
• Coexistence, characteristic of herpes-like viruses, which avoid extinction by being relatively low-key, i.e., not triggering substantial immune response, while establishing a lasting infection (e.g., by integrating in the host DNA).
• Permanent circulation - the most well-known case is smallpox, which continued to exist in the human population for thousands of years by simply moving around the globe. This entailed no adaptation, which is why it was possible to make this virus extinct by vaccination.
• No strategy - Ebola epidemies in humans are an evolutionary dead end, as the virus killing nearly all of its hosts is bound to become extinct. The reason that Ebola outbreaks still happen is because this virus exhibits a relatively harmless, flu-like, behavior in some animals and only occasionally spills to humans. Thee difference with the smallpox is mostly a quantitative one: Ebola kills its victims too fast, to spread efficiently.

References
J. Flint et al., Principles of Virology