This is really the same question as "Why do some people catch COVID and some not?" or "Why did I not get measles when my brother did?"

The answer is going to disappoint you: It's chance.

The odds of getting infected with anything is a combination of the amount of the pathogen, the environmental conditions, and the personal resistance. Are you exposed to a huge amount of pathogen, in optimal conditions, when you're under immunosuppressive treatment for an organ transplant? Pretty good chance you'll be infected. Are you exposed to a very small amount of respiratory pathogen, in a place with great ventilation, after you've been vaccinated? Pretty good chance you won't be infected.

But none of these are absolute on/off switches. If you were to look at exposure levels, you'd see a bell curve (a normal distribution) -- the sign that there are many influences on the factor. If you were to somehow plot your resistance levels, you'd see a bell curve. Same for environmental conditions. You're not adding together three on/off switches, you're adding together three complex pathways and getting a fourth complex pathway out of it.

Of course the bell curve can shift right or left. If you're exposed to someone with measles, you're probably exposed to much more pathogen than the minimal infectious dose - the pathogen curve is shifted over to the left. But if you're vaccinated with the very effective measles vaccine, your personal resistance is extremely high - the resistance curve is way over to the right. Still, measles vaccine is "only" 99% effective -- there's still a chance you can be infected.

With HIV, then, you can think about the three components of risk. If you were unfortunate enough to receive a blood transfusion from an infected person, then the pathogen dose would likely be high, the environment (blood stored carefully to keep the cells happy) would be ideal for the virus, and personal resistance would be very low because it's bypassed many protective levels. The chance of infection would be pretty high.

If you're exposed by sexual contact, the dose of virus is much lower. There are many more layers of protection (intact skin or mucous membranes, innate immune protection). The environment isn't ideal for the virus. You end up with a lower chance of infection, but not zero.

Of course there are situations where one or more of the three components does drop to zero, or nearly so. You're constantly exposed to vast doses of Pepper mild mottle virus, but there's no amount of PMMoV that will harm a human -- that pathogen risk is zero. There are genetic variations that might make someone extremely resistant to HIV -- that person's individual risk is nearly zero. (At this point someone is about to jump in and claim that that variation was driven by the Black Death, which isn't true. See previous posts.)

But for viruses that are medically relevant to humans, the reason they're relevant is that those three risk curves aren't set to zero, and that means it becomes an odds game. People who try to prevent diseases are aiming to moving those odds in our favor, perhaps through vaccination (resistance curve) or ventilation (the environment curve) or masking (reducing the pathogen curve) or, usually, some combination of all of them. You may never reduce everything to zero, but even reducing each of them by 50% can lead to an overall major win.

In general, viruses can’t infect through intact skin. It’s generally believed that infection through skin requires some amount of skin damage, even in the case of herpes simplex I (HSV1, the “cold sore virus”) which is highly adapted to humans and spreads pretty effectively.

On the other hand, it’s probably relatively common to have some amount of skin damage just from normal day-to-day living, so this doesn’t present a complete block to infections.

The details of how HSV gets through skin are still surprisingly unclear, including the amount of damage needed to penetrate.

> The general assumption is that skin lesions can serve as entry portals for HSV-1. Under in vivo conditions, damaged skin can result from various sources ranging from mechanical abrasions or burns to impaired epidermal barriers and dysfunctional immune responses causing eczema herpeticum … Taken together, we hypothesize that successful viral invasion via skin lesions in vivo requires more than mechanically disrupted intercellular junctions.

—Ex Vivo Infection of Human Skin with Herpes Simplex Virus 1 Reveals Mechanical Wounds as Insufficient Entry Portals via the Skin Surface

There aren’t any natural cases of mammalian parthogenesis, but it’s been done in the lab - with a fair bit of tricky intervention.

> Parthenogenesis, a way of generating offspring solely from unfertilized oocytes, is limited in mammals because of problems arising from genomic imprinting … Parthenogenetic offspring, in which an individual develops from a single unfertilized oocyte, have not been reported in mammals … Here, we report live mammalian offspring derived from single unfertilized oocytes, which was achieved by targeted DNA methylation rewriting of seven imprinting control regions. Oocyte coinjection of catalytically inactive Cas9 (dCas9)-Dnmt3a or dCpf1-Tet1 messenger RNA (mRNA) with single-guide RNAs (sgRNAs) targeting specific regions induced de novo methylation or demethylation, respectively, of the targeted region.

—Viable offspring derived from single unfertilized mammalian oocytes

I don’t know about ANA tests in particular, but nuclear proteins in general tend to be highly conserved (I.e. similar across a wide range of species). This makes sense because the basics of DNA replication and RNA production are virtually identical across hundreds of millions of years of evolution. Wikipedia’s article on conserved sequences notes that many of them are the “proteins required for transcription and translation, which are assumed to have been conserved from the last universal common ancestor of all life”.

Many coronaviruses that are extremely closely related to SARS-CoV-2 have been found in bats - both before the COVID outbreak, and after.

Coronaviruses in bats don’t tend to exist as clear, unambiguous, stable populations. There’s extensive recombination and rapid evolution, and the many small semi-distinct populations of bats means that there are many small, transient populations of coronaviruses in these populations.

On top of that, it’s probable that SARS-CoV-2 isn’t strictly a bat virus - coronaviruses recombine rapidly and readily, and recombination with a non-bat coronavirus is likely for both SARS and SARS-CoV-2 (pangolins, in the case of SARS-CoV-2). So there’s no reason to believe that SARS-CoV-2 exactly ever circulated in bats.

So the notion that it should be easy, or even possible, to identify exactly the same virus in bats over many years is obviously mistaken. Nevertheless, many very close relatives of SARS-CoV-2 have been found in Asian bats, including several that seem to be very capable of replicating in humans and that share the receptor specificity of SARS-CoV-2.

> We found that the receptor-binding domains of these viruses differ from that of SARS-CoV-2 by only one or two residues at the interface with ACE2, bind more efficiently to the hACE2 protein than that of the SARS-CoV-2 strain isolated in Wuhan from early human cases, and mediate hACE2-dependent entry and replication in human cells, which is inhibited by antibodies that neutralize SARS-CoV-2. … Our findings therefore indicate that bat-borne SARS-CoV-2-like viruses that are potentially infectious for humans circulate in Rhinolophus spp. in the Indochinese peninsula.

-Bat coronaviruses related to SARS-CoV-2 and infectious for human cells

It’s important to remember that there are vast numbers of bats, and that they have been very superficially sampled. In spite of this, it’s been very easy to find these close hits, showing that these very dangerous, human-preadapted viruses are very common in bats.

Virologists have been warning about this for decades, specifically calling out that the next pandemic was likely to arise from bat coronaviruses. It shouldn’t be surprising that the prediction actually came true.

It's extremely variable, of course. Some proteins have half-lives of a few seconds, others can be in the millions of years.

Dinosaur proteins have been (debatably) discovered:

>Ancient proteins dating back 195 million years have been found inside a dinosaur bone. ... The discovery pushes back the oldest evidence for preserved proteins by 100 million years. ... "This discovery tells us that yes, you really can probably preserve soft, microscopic proteins inside dinosaur bones for tens or hundreds of millions of years," Dr Brusatte added.

--'Startling' dinosaur protein discovery

The record for identifiable, sequence-able DNA is around a couple million years:

>Here we report an ancient environmental DNA (eDNA) record describing the rich plant and animal assemblages of the Kap København Formation in North Greenland, dated to around two million years ago.

--A 2-million-year-old ecosystem in Greenland uncovered by environmental DNA

Of course these are not the normal circumstances. DNA in a rain forest would be completely gone in probably a year or less. Most proteins are far less stable than the collagen found in dinosaur fossils. But it gives you a sense of the upper limits.

It kind of depends what you mean by "target". The immune system can certainly recognize elements inside the cell, and determine that they are foreign and need to be destroyed. The immune system can't really specifically remove those foreign elements, though (though there have been arguments that under some conditions it can). In general if a cell contains harmful foreign elements, the immune system rapidly identifies it and destroys the whole cell.

You ask about mitochondria specifically. In fact mitochondria are strongly recognized by the immune system and treated as harmful. This shouldn't be surprising in principle, because of course mitochondria are symbiotic bacteria, and the immune system is tuned to recognize and destroy bacteria. Normally, though, mitochondria are invisible to immunity because they are intracellular; it's mainly after cells are damaged that mitochondria are exposed to the immune system and can lead to responses.

>Mitochondrial damage-associated molecular patterns (DAMPs) are molecules that are released from mitochondria to extracellular space during cell death and include not only proteins but also DNA or lipids. Mitochondrial DAMPs induce inflammatory responses and are critically involved in the pathogenesis of various diseases. ..

--The Roles of Mitochondrial Damage-Associated Molecular Patterns in Diseases

There are two major pathways by which cells provide information about their internal components, to the cellular components of the immune system like lymphocytes and neutrophils.

In one, there are a large number of intracellular sensors that monitor cells for general pathogen-associated molecular patterns (wikipedia link). These trigger pathways that eventually result in the cell producing cytokines, like interferons, that activate and recruit immune responses.

In another branch, there's a complex process that constantly surveys intracellular protein production, and moves samples to the outside of the cell where lymphocytes can analyze the cell and respond to those that have abnormal components. This is called antigen presentation.

But again, the response is not so subtle. Instead of delicately removing the abnormal component, the whole cell is typically destroyed, presumably preventing the intracellular pathogen from completing its life cycle and amplifying its numbers.

"Immune system" covers a lot of ground. The "immune system" that humans and other vertebrates have is a mishmash of evolutionary inventions going back well over half a billion years, that have been patched together with duct tape and bubblegum to form the rickety, clumsy and complicated apparatus that we know and love today.

Broadly speaking, the "immune system" gets divided into "innate" and "adaptive" branches. The "adaptive" part is what most people probably think of as "immunity:; it involved antibodies (B cells) and T cells. This arose in the ancestors of sharks, something like 400 million years ago.

Sharks and agnathans (jawless vertebrates, today represented by lampreys and hagfish) had a common ancestor maybe 550 million years ago, which did not have T and B cells as we know them, because lampreys and hagfish do not have T and B cells. (They do have their own analogies of antibodies, but they are a separate invention with very little in common with our antibodies.)

Although there have been some relatively minor changes in the vertebrate lineage, fundamentally we (and other mammals, fish, birds, reptiles) have the same immune system as sharks did.

The innate immune system is much older. We share recognizable components of innate immunity with insects. These include various pathways that recognize broad categories of pathogens, such as bacterial cell wall components. In vertebrates the innate immune system offers a large amount of rapid protection and also recruits adaptive immunity, which provides an initially slower but much longer-lasting protection.

Non-vertebrates don't have immune memory (you can't really vaccinate a bee, for example, though I know there are things that are rather sloppily called "vaccines") because "immune memory" is what the adaptive immune system does. Generalizing wildly, many invertebrates tend to be short-lived compared to vertebrates, which might make them less dependent on immune memory.

But of course there are very long-lived invertebrates too. In some cases invertebrates make much more extensive use of these innate immune components than vertebrates do. For example

>Detailed annotation of the Pacific oyster (Crassostrea gigas) genome, a protostome invertebrate, reveals large-scale duplication and divergence of multigene families encoding molecules that effect innate immunity.

--Massive expansion and functional divergence of innate immune genes in a protostome

Once you get much older than the vertebrate/insect split, immune molecules are harder to clearly identify. In bacteria, there are paths that protect against virus infection, but they are very different from the innate and adaptive immune molecules we see in eukaryotes. These include things like CRISPR and so on.

It’s actually relatively easy to freeze cells and recover them. It’s harder to freeze tissues and have them come back.

Cell lines are routinely frozen and stored for decades. The American Type culture Collection (ATCC) has some guidelines and explains “Most cell cultures can be stored for many years, if not indefinitely, using cryopreservation.” In general this also applies to egg cells.

Tissues are harder (though not necessarily impossible) because the structure is easily disrupted and because it’s harder to evenly freeze the cells that are part of it. The smaller the tissue, the better the chance of successful freeze and recovery. Embryos are tissues, with multiple cells, but they are frozen when they are very tiny - at an early-enough stage (100 cells or fewer) that they can be readily permeated by cryoprotectants.

Yes, birds, mammals, and fish have dramatically changed their migration timing as climate change has changed the timing of spring and fall. For example

> … we show phenological shifts in migration of five species – red-backed shrike, spotted flycatcher, common sandpiper, white-winged tern (Palearctic migrants), and diederik cuckoo (intra-African migrant) – between two atlas periods: 1987–1991 and 2007–2012. During this time period, Palearctic migrants advanced their departure from their South African nonbreeding grounds. This trend was mainly driven by waterbirds. No consistent changes were observed for intra-African migrants. Our results suggest that the most consistent drivers of migration phenological shifts act in the northern hemisphere, probably at the breeding grounds.

—Patterns of bird migration phenology in South Africa suggest northern hemisphere climate as the most consistent driver of change

> Globally, bird migration is occurring earlier in the year, consistent with climate-related changes in breeding resources. … Using direct observations of bar-tailed godwits (Limosa lapponica) departing New Zealand on a 16,000-km journey to Alaska, we show that migration advanced by six days during 2008–2020, and that within-individual advancement was sufficient to explain this population-level change.

—Advancement in long-distance bird migration through individual plasticity in departure

> From 2004 to 2016, we found that the average start of green-up on the calving area advanced by 7.25 days, while the start of migration advanced by 13.64 days, the end of migration advanced by 6.02 days, and the date of peak calving advanced by 9.42 days.

—Response of barren-ground caribou to advancing spring phenology

> We reviewed the evidence for phenotypic responses to recent climate change in fish. Changes in the timing of migration and reproduction, age at maturity, age at juvenile migration, growth, survival and fecundity were associated primarily with changes in temperature.

—Plastic and evolutionary responses to climate change in fish

There are literally hundreds of studies on this.

Facial scars occur in 40% of the <20% of children who had scars, which is therefore less than 8% of the unvaccinated population, who are mainly over 30 at this point, so that’s now about 5% of the US population, not 40. And since most the scars are not lifelong, probably fewer than 2% of the population of the US carries chickenpox scars on their face. That’s not incredibly common.

You’re trying to force reality into your preconception, but it doesn’t work.

If you will read the second sentence in my post, you will see that “Only about 20% of children with chickenpox ended up with scars.”

Your premise is probably wrong: The face in general might be slightly over-represented as a place for chickenpox scars, but not by much. Only about 20% of children with chickenpox ended up with scars, and of those fewer than half had scars on their face; nearly 60% had scars on their abdomen.

>The scars were found on the face in 75 (40.8%), neck 2 (1.1%), shoulders 8 (4.3%), upper limbs 15 (8.2%), anterior thorax 50 (27.2%), abdomen 106 (57.6%), back 65 (35.3%), buttocks 9 (4.9%), and lower limbs 12 (6.5%) affected children. The mean number of scars in the 184 children was 2.8 (standard deviation 1.9).

--Scarring Resulting from Chickenpox

Obviously you're more likely to be looking at peoples' faces than their bare abdomens most days, so there's a lot of selection bias going on here.

As for why the scars end up in those locations, it's probably because those are the same places that the actual chickenpox lesions occur:

>The distribution of chickenpox lesions is typically central, with the greatest concentration on the trunk (2). Facial lesions are also common (2). The distribution of residual scars from chickenpox in the present study is in agreement with the anatomic distribution of chickenpox lesions.

--Scarring Resulting from Chickenpox

But that just moves it back a step because we don't really understand why chickenpox lesions tend to occur on the abdomen and face. A part of it is probably because of the type of skin cells involved, which changes the molecules on the cells and makes them more or less attractive to the virus (Molecular mechanisms of varicella zoster virus pathogenesis); this may explain why chickenpox lesions on the hands and feet are relatively rare, but I don't think it's understood why, say, the back is relatively under-represented.

Depends what he’s calling “this scenario”. OP is specifically asking about developing T cells in the thymus. Those do occasionally bind with high affinity to the MHC/self peptide combination in the thymus, and those T cells are destroyed - it’s a normal part of T cell development, aimed at preventing autoimmunity (because if those T cells were allowed to survive and become mature, functional T cells, they could indeed cause autoimmunity - though there are further checks and balances even there).

T cells have to bind to MHC plus peptide for their function; if they don’t bind at all, they’re never going to be useful. So this is screening for the basic ability to bind MHC.

Why don’t they get screened against MHC with no peptide, instead of MHC with self peptide? Because there’s effectively no such thing as empty MHC on the cell surface. MHC (either class I or II) needs peptide to reach the surface and remain stable.

By requiring moderate affinity to MHC plus self peptide and screening out high affinity binding, the thymus ensures that self peptide won’t be recognized with enough affinity to actually trigger a mature T cell (which has a different signaling threshold than the developing T cell), but also ensures that the receptor has a chance to bind to MHC plus something non-self.

Of course it’s a very low chance - the vast majority of T cells produced never find a target, and most may well not have any possible target in the entire universe of possible peptides - but that’s fine, there are plenty of other T cells in the immune repertoire ocean.

T cell development is a reminder of how weird evolution’s solutions can be, to our human eyes. But it’s worked pretty well for 400 million years so far.

(As usual this is all wildly oversimplified.)

It's extremely unlikely that any strain of HIV will evade detection by either PCR or antibodies.

You probably misunderstand what's meant when we say HIV mutates a huge amount. Parts of the virus certainly do change wildly. but there are parts of it that stay very constant ("conserved"). And those parts have to stay constant, because they're what makes the virus a virus.

You can take a motorcycle and change its paint, swap out the handlebars, change the tires. You can even wrap it up in some lightweight costume and make it look like an X-wing starfighter for a parade, if you want. But if you pull out the pistons, or replace them with spaghetti, you don't have a functional motorcycle any more.

Tests for HIV don't depend on the equivalent of paint color or handlebars, they look for the functional components of the virus without which the virus can't replicate. For example, PCR tests often look for the Long Terminal Repeat (LTR), which are required for turning on the viral genes; these regions have minor variations, but can't change too much or the virus breaks.

The same is true with antibodies against HIV. Certainly there are antibodies against the rapidly-mutating regions, but for standard testing you don't look at those, you look at antibodies against the highly conserved regions.

(Why don't those antibodies against the highly conserved regions protect against HIV infection? Because, simplistically, many antibodies against any pathogen are not protective, and HIV has evolved so that the regions protective antibodies target do change rapidly.)

Genes associated with immunity are generally among the fastest-evolving genes, and this is because they are doing exactly what you ask about - reacting to changes in pathogens as they in turn react to changes in the host. This is one of the classic examples of the Red Queen’s Race (“running as fast as you can to stay in the same place”).

Just as one example: The poster children for rapid evolution are the genes of the major histocompatibility complex (MHC). These genes are critical for T cells to recognize pathogen antigens and they change very rapidly (see for example The rise and fall of great class I genes).

More generally:

> Adaptation is elevated in virus-interacting proteins across all functional categories, including both immune and non-immune functions. We conservatively estimate that viruses have driven close to 30% of all adaptive amino acid changes in the part of the human proteome conserved within mammals. Our results suggest that viruses are one of the most dominant drivers of evolutionary change across mammalian and human proteomes.

—Viruses are a dominant driver of protein adaptation in mammals

> So is mostly like, for whatever reason, it seems like female hybrids from Neardenthal mothers, probably won’t be fertil in a regular basis.

That is not at all true. All modern humans have a single Mitochondrial Eve, and aside from her all other mitochondrial lineages from modern humans of her era are extinct. By your logic, that would mean that all other (fully human) females from that period were sterile, which is obviously not true.

Reading the wiki article linked above should help you understand what it could actually mean.

To give OP an example: Imagine two books, 10 chapters long, almost exactly the same, but each page has a typo or two. In Chapter 7, say, one book may say "teh" instead of "the" on page 2, and the other may say "Neandertal" instead of "Neanderthal" on page 3; and so on. Overall, the books are 99.9% identical, but each chapter has a set of diagnostic typos.

Now we create a third book, by replacing chapter 7 of book 1 with chapter 7 of book 2. By comparing the pattern of typos with the parent books, we can clearly tell that chapter 7 comes from a different source.

Are the books 99.9% identical? Yes. Did book 3 get 10% of its content from a different source? Also yes.

> , being ‘pedantic’ is a pretty healthy trait for a scientist is it not?

Where did this idea come from? People whose only exposure to science comes from Mrs Brown in fourth grade? Pedantry like this is the opposite of science - the ignorant and incurious sneering at a legitimate question because of their mistaken and limited understanding.

Answer the question, don’t simply snigger at the questioner, especially when you’re wrong.

I don’t know of any, but the question is reasonable - only a pedantic blowhard ignorant of language would insist on “writing” as the only meaning of “record”.

Records of pandemics could include pathological evidence (like bone lesions, as seen in say the treponema lesions on T. rex bones); archaeological evidence (inhabitation followed by abrupt disappearance); and/or genetic evidence (genome sequencing of pathogens associated with skeletons, for example, as has been done for the Black Plague and leprosy in the Middle Ages).

The existence of North American pandemics immediately following European contact is well known, although the cause (probably multiple, probably including measles, smallpox, and possibly some unknown pathogens) and the extent (did they kill off 75%, 90%, 99% of the population) remain unclear. There are some written records of this as well, of course.

Otherwise I don’t know of clear evidence of prehistoric pandemics or panzootics (i.e. in non-humans). All of the record types I mentioned have been used to identify infections on a smaller scale, but I don’t know of them used for widespread disease.

But it’s possible I’ve missed some, and the question makes perfect sense to ask.

In the US, human rabies is extremely rare, so the very small risk from the vaccine might still be higher than the avoided risk of rabies. (If there are 1 in a million serious side effects, that would still be 100 times more risky than the actual case rate.).

Note that people genuinely at high risk - veterinarians, mainly - do in fact get vaccinated, because that changes the risk calculation.

In African countries, and India, it becomes more of a cost calculation. There are almost certainly more effective ways to use that money to save lives in those countries.

If the money was available, it would almost certainly be more cost and safety effective to increase vaccination of animals - the US approach. Removing the source of human rabies, while not putting humans at any increased risk, is probably a much better approach.

Mostly that’s true. But given the right background, and a significant amount of luck, very small founder populations can expand enormously. This is very common in invasive species. The 200 million starlings in North America today arose from a few dozen in the late 1800s. Bull trout in Montana arose from two founders. A million Barbary Ground Squirrels arose from a single female.

Again, this is possible but not inevitable. Most such introductions will collapse due to inbreeding. But occasionally explosions can happen.

Are you arguing that the royalty of Europe have entirely gone extinct due to inbreeding? Or are you arguing that occasional members showed deleterious recessives, while most (like Charles) have been spared those effects, as you’d see with purging of recessives?

I know you just made a throwaway joke, but if you’re actually going to make an argument of it, you should think through what you’re actually claiming.

Sure, it’s possible there was outside gene flow (the genetics papers I linked address some of that). But the question is is it possible, not how far can moose swim.