slower replication speed, more difficulty infecting the host, requirement of much greater volume of replication to accomplish the same rate of infection.
think of it this way: every cool feature you add to a living thing has an overhead.
you want your little bacteria to have antibiotic resistance? fine.
but it'll need that much more energy to grow relative to the bacteria which don't have the added burden.
this means that unless there's the selective pressure of antibiotics in the environment, your little antibiotic resistant microbe won't stand a chance -- it's a fraction less efficient under normal conditions, so it's effectively out-competed when in the wild.
as far as massive adaptations like airborne spreading, that's not something that can just mutate overnight. HIV is fragile, so you'd need to engineer an entirely new viral envelope, or, more likely, an entirely new carrier particle that the virus can reconstruct on its own without impacting its infectivity. viruses like the flu have these adaptations by default. but once again, if you decide to turn the flu into HIV, it's going to be at a disadvantage in the wild.
not to say that it is impossible to make virions which are able to out-compete their wild-type cousins when infecting hosts in the real world. far from it. it's just not as easy to make it work as a quick look might find.
What would be the overhead for just something "simple" though? Like making HIV airborne? (Or rather what the lay person perceives as a small change)
It seems like there are plenty of diseases out there where a (apparently) "small" modification could have a dramatic effect on how it spreads. And I'll admit my naivety to the subject and do not know if such small changes are actually small, or the related overhead associated with them.
to answer your question, the overhead is very small for a small change. you can add a bit of noncoding DNA to a virus' genome without ruining its ability to compete in the wild. but the survival margins are very thin. on a population scale, natural selection is very harsh. anything that is superfluous given the environment is an inefficiency which eventually results in extinction. of course, between organisms this isn't that frightening because there are different niches, so sometimes a large change can be more viable than a small change even if it's a lot more expensive, provided that the large change lets the organism live in a new niche.
making HIV airborne isn't a simple change, however. it's more like a massive change of niche. it's a change in the transmission modality of the virus -- for comparison, consider the scale of the changes you'd need to make to turn a car into a plane. or maybe a car into a boat.
it's doable, artificially. but the result won't be as good at being a car, plane, or boat as something which was purpose-built for that application and didn't have to carry the features of something intended for a different purpose.
many of the "small" changes that make a disease spread more easily are actually mutations which don't change the ability of the disease to weather external conditions, but rather change the ability of the disease to survive first contact with the host's immune system.
the flu is a great example here. we need a new flu vaccine every year because the flu mutates constantly and drastically. the flu never becomes capable of surviving outside a host for longer than before, though. it just becomes more effective at evading the immune systems of most hosts.
What about starting with the flu and giving it an HIV-like ability to wreck your immune system? Is the “attack” part too intertwined with everything else to be able to do that sort of mix-and-match operation?
the flu gaining deadlier characteristics via engineering is more realistic. unfortunately, i believe that is well within the scope of our present capability. the exact magnitude of how dangerous such engineering could make a virus based on the flu is unclear to me, but i'd estimate somewhere between "globally apocalyptic" and "continentally destabilizing".
the mixing and matching of attack characteristics is probably possible under certain circumstances, but i don't know of any specific instances where it has been done. theoretically, it's easy to swap A for B, but making such changes nearly always has unintended downstream problems.
in the lab we used to do all sorts of mixing and matching, but for defensive characteristics (mostly to see if certain isomorphs were more vulnerable than others).
long story short, generating virus and isolating it is a real PITA for a slew of reasons. experimental cycles might be as long as a week for each trial of "mixing and matching".
think of it this way: every cool feature you add to a living thing has an overhead.
you want your little bacteria to have antibiotic resistance? fine.
but it'll need that much more energy to grow relative to the bacteria which don't have the added burden.
this means that unless there's the selective pressure of antibiotics in the environment, your little antibiotic resistant microbe won't stand a chance -- it's a fraction less efficient under normal conditions, so it's effectively out-competed when in the wild.
as far as massive adaptations like airborne spreading, that's not something that can just mutate overnight. HIV is fragile, so you'd need to engineer an entirely new viral envelope, or, more likely, an entirely new carrier particle that the virus can reconstruct on its own without impacting its infectivity. viruses like the flu have these adaptations by default. but once again, if you decide to turn the flu into HIV, it's going to be at a disadvantage in the wild.
not to say that it is impossible to make virions which are able to out-compete their wild-type cousins when infecting hosts in the real world. far from it. it's just not as easy to make it work as a quick look might find.