There are two questions I get over and over and over again from friends, family members, readers, etc about HIV-1:
1. Will we ever get a vaccine?
2. How come some people who are infected with HIV-1 never get AIDS, and some people succumb very quickly?
From my sterile perspective as a researcher, we categorize patients by how fast they progress to AIDS. Usually people are just ‘progressors’, they get infected and slowly progress to AIDS over the course of a decade or so. However, there is a gradient of how quickly patients progress, from ‘rapid progressors’ to ‘long-term non-progressors.’ Rapid progressors never really recover from their acute HIV-1 infection, and die very quickly (many of the infants I study died within a year after infection). On the other end of the spectrum, I study infants who are long-term non-progressors– they are infected with HIV-1, they are on no drugs, and their CD4+ T-cell numbers are relatively stable.
Then there is a group we really, really want to learn more about– the Elite Suppressors. These folks have anti-HIV-1 antibodies, are on no anti-retrovirals, but they have very little virus floating around their blood. Less than 50 viruses per milliliter (‘normal’ HIV-1 patient? 10^7 copies per ml). Its also really hard to find infected T-cells in these people too. This is what we ‘want’ HIV-1 infection to be if we cant figure out how to make a vaccine! Yeah, youre infected, it sucks, but its not going to kill you (at least, for a very long time– there are Elite Suppressors that have been infected for +25 years and are still fine), drug costs arent going to bankrupt you (Elites are on no drugs), and its harder to pass on the virus to other people (if your viral load is extremely low, the odds are lower you will pass one on to someone else).
So the question is: How do they do it, and how can we make sure everyone who is infected with HIV-1 can react the same way?
It could be the virus.
The reason why an individual is a rapid progressor or an elite suppressor might be because of the virus they were infected with in the first place. Some HIV-1 variants are ‘meaner’ than others– For an easy example, HIV-2 isnt as ‘bad’ as HIV-1. Theyre related, but there are enough differences between them (LIKE VPU LOL!) to make one more pathogenic than the other.
There was also an interesting case in Australia, where a group of individuals were infected (through a blood transfusion) with HIV-1 viruses that had a deletion in an accessory gene, nef. These folks held up pretty well… but vaccine efforts centering around deleting nef (or other accessory genes) making a live attenuated vaccine didnt work.
It could be the person.
There are so many variables within one human, you guys. So many…
It could have something to do with the receptors HIV-1 needs to infect your cells. Maybe my CCR5 binds super tight to HIV-1, and yours dont bind HIV-1 very well. Maybe yours cant bind HIV-1 at all, like the ‘Delta 32s‘. People with a mutation in their CCR5 gene cant be infected with certain kinds of HIV-1 because they just dont have the receptor it needs to infect you. Along those same lines, maybe you express a lot of CCL3L1 (the natural ligand for CCR5), and HIV-1 never gets a chance to bind to CCR5 because they are never available– theyre always bound to CCL3L1.
Your genes also come into the equation when it comes to your HLA type. Remember this from the MHC-Mate fiasco?
MHC Class I molecules are on the surface of all of your cells. Proteins that your cells make eventually get degraded, and MHC molecules present little bits of these proteins at the cell surface. Its a signal to cytotoxic T-cells that everything is fine.
When your cells are infected with a virus, or have become cancerous, its MHCs start presenting proteins that arent ‘normal’– they become a signal to CTLs that something is wrong, and the cell needs to be killed.
I might present a set of bits of HIV-1 proteins in my MHC, but you might have a different HLA type, so you present different bits of the same proteins. Maybe your cytotoxic T-cells get into a murderous rage over your bits and kill infected cells very effectively, and my CTLs dont even notice anything is wrong. There are HLA types that seem to have a protective effect against HIV-1 when you look at a population, but when it comes down to individual cases, just because you have a ‘protective’ HLA type, doesnt mean you will be an elite suppressor.
It could have something to do with variations in your immune cells– B cells, T cells, macrophages, dendritic cells, etc.
We dont think it has much to do with antibodies and B cells anymore. Everyone infected with HIV-1 makes ‘neutralizing antibodies’ (antibodies that prevent HIV-1 from binding and infecting cells). The problem is The Red Queen. Your antibodies are always a step behind the virus. And, there doesnt seem to be any difference between the antibodies of a rapid progressor vs a non-progressor. Its probably not antibodies that make an elite suppressor.
It might have something to do with those cytotoxic T-cells. As your activated CTL numbers go up, HIV-1 viral load goes down… but we all know the mantra: Correlation does not equal causation. People are still looking into this.
Dendritic cells have ‘toll like receptors‘ that recognize patterns, like bacterial walls or viral genomes, and release ‘warning’ signals to recruit other immune cells. Maybe my receptors are better than yours. Maybe your cells release more of the warning signal than mine.
There are many, many more variables.
Theoretically, if this were a different disease, what we would do experiments on mice. We have inbred mouse strains, which means that the mice are all clones of one another. If you leave one of those clones alone, and create a different line of mice that is 100% identical to the clone, but doesnt have, say, T regulatory cells, its becomes easier to tease out the contribution of each potential variable.
But we cant infect mice with HIV-1.
The best animal model we have are macaques, and they sure arent clones of one another.
And you sure cant knock out an elite suppressors T regulatory cells ‘just to see what happens’…
So, long story short, while we have lots of ideas for why one person might progress to AIDS more slowly than another person… we dont know why.