Okay, so like, we suck at making HIV-1 vaccines. Im trying to make our vaccines more logical/efficacious/etc, but right now, we suck. No HIV-1 vaccine.
There are other ways to prevent HIV-1 infection via sex– like condoms. YAY! HIV-1 doesnt ‘swim’. It doesnt move on its own. It has to be carried by semen. But since semen cant go through a condom, YAY! No HIV-1 goes through either.
Well, condoms break. People dont always wear them right. And condoms are a male-centered HIV-prevention method. Not every woman on planet earth is in a position to say ‘Honey, put on a condom.’
So we have been trying real hard to make vaginal lubricants and such with anti-HIV-1 compounds in them. Woman-centered HIV-prevention method!
One idea has been to put PSC-RANTES in lubricants. You know how some people dont have CCR5, so they cant be infected with some kinds of HIV-1? PSC-RANTES is a compound that sticks to CCR5, kinda making all of us ‘delta CCR5’. You have to have it at really high concentrations at the site of infection for it to work well, and lubricants can do that, so researchers tried it out in macaques. At really high doses (1 mM), it was 100% effective at preventing infection.
Because while that particular experiment gave us really cool results, there are variants in the HIV-1 quasispecies that dont give a rats ass about PSC-RANTES.
When normal people think about HIV-1 and how it mutates, they imagine all the sequence changing all the time. But its not really like that. There are some regions that are the same between every subtype of HIV-1. There are some regions that are totally variable in one subtype, but not another. And there are little patters, motifs, all over the place.
One such pattern is in the part of Env that binds to coreceptor (CCR5 or CXCR4 or ‘other’)– GPGX. In this region, you always see Glycine-Proline-Glycine-Anything. ‘Anything’ isnt technically anything– like HIV-1 hates lysine in that position, but theoretically it can be anything.
All HIV-1 needs to get around PSC-RANTES is GPG-Arginine.
The SHIV (half SIV, half HIV) used in the macaque study didnt originally have GPGR. But in the presence of sub-optimal levels of PSC-RANTES, enough replication could occur to rebuild the SHIV quasispecies. When GPGR popped up, it went to town. But most of our lab strains of HIV-1 (the ‘white mice’ of HIV-1)? They have an arginine at that fourth position. This variant is kinda stock-standard in HIV-1.
But real people arent lab strains– lets say you just have a mixed quasispecies. When you have less-than-optimal concentrations of PSC-RANTES (say, you wanna get it on a few hours after you first applied the drug), minority components of the HIV-1 quasispecies (GPGR) do the same damn thing that minority components of a quasispecies do when drugs are around: evolve to be highly fit and resistant to the compound.