There is some percentage of the population who have a better prognosis if infected with HIV-1 than the rest of us. Remember those pirate flags and sombreros I talk about sometimes? Major histocompatibility complexes, type I. Some people put up HIV-1 flags that are easily recognizable as 'NOT SELF!!' to their cytotoxic T-cells, so they (sometimes) can control the virus better, thus are slower to progress to AIDS than people with different MHC I alleles.
You notice the (sometimes) in parentheses up there.
Having a 'protective' MHC I allele just means that you have ~50%:50% chance of not progressing.
Why is it just 50%-50%? Why is the allele not enough for some, and enough for others?
Though the genetic diversity of humans isnt exactly huge, it could be that 50% of people with the 'protective' allele have one more little genetic difference that makes the allele genuinely protective, thus they do not progress, while 50% of the people with the 'protective' allele dont have that 'helper' genetic variant, thus gain no real protection from the 'protective' allele.
Does that make sense?
Furthermore, there could be lots of other protective alleles out there that we dont know about. Some people progress to AIDS quickly after infection, some progress slowly, why? A part of that could be the individuals genetics.
So a whole bunch of scientists did a whole bunch of work looking at a whole bunch of genetic variation in a whole bunch of HIV-1 patients (progressors and non-progressors). Whole bunch of work... to basically tell us what we have known for a really long time (MHC I alleles matter) and not much else.
I thought for sure they would find something. Hell, with a 'Science EXPRESS!!!!!' paper I thought they did find something. But they didnt.
So, to sum things up, HIV-1s opinion of humans is "Theyre all pink on the inside. Pink, and CD4+ T-cells". It doesnt particularly give a rats ass about our personal genetics.
What I found particularly disappointing about this paper, is that with literally hundreds of authors, not one of them saw the evolutionary implications of their research.
Yes, there are 'protective' MHC I alleles. There is not much else, on the humans genetic side, playing a role. But apparently HIV-1 can mutate away from the sequence that is harmful to it (beneficial for us controlling the virus), but this is not a 'simple' mutation. If the 'answer' to the MHC I problem were easy (1 mutation, or say 10 mutations that accumulate fitness in a stepwise manner), 100% of people with the 'protective' allele would progress (much like what happens with antiretroviral resistance). If it were impossible (the edge of evolution?) then 100% would be protected.
But its 50%-50%.
I think this means that HIV-1 must travel from one fitness peak to another to escape MHC I presentation and retrain functionality. Its not a simple or step-wise mutation-- it needs like, 20 mutations to happen all at the same time, and its scott free. If only 11 of those 20 mutations happen, its down in a low-fitness valley (or maybe non-functional entirely). A collection of mutations that is low probability, but not impossible. Im just making up these numbers-- I have no idea what the real ones are, and they are almost certainly different for every viral population in every patient. Just using them as an example. But thats the conclusion I get from this high-workload, high-PR, limited-content paper.
I think thats much more interesting than what they published. *shrug*
When they measure progression, is there some sort of time-frame? Is it like people with decent CD4 counts after 5 years are classed as non-progressors, and those with poor ones as progressors? It seems important for your hypothesis. If it is indeed a fitness peak hopping issue, then we would expect everyone to eventually progress, given enough time. If it was some other as yet undetected host factor, then those that don't progress after a while will likely never progress. Do you know anything about the quality of the time-to-progression data? You might be able to tell the two apart from the distribution.
Basically any GWAS looking at a disease that has an immunological component is going to turn up MHC has the major locus. For autoimmune disorders for instance, all the SNPs that are considered protective or risk factors are orders of magnitude lower than basic MHC variants.
Considering the dependence of HIV control on CD8 T-cells, this paper reads like "By spending millions of dollars using the most advanced spectrophotometric technology, we determined that the sky is blue."
Did you read the commentary?
"Examination of all the polymorphic amino acids in HLA class I revealed that amino acid positions 67, 70, and particularly 97, in the peptide binding groove of HLA class I had stronger statistical associations with HIV-1 protection than the whole HLA molecules. Valine, asparagine, and tryptophan occur at position 97 in the B*57:01, B*27:05, and B*14 protective haplotypes, respectively, whereas arginine occurs in risk HLA molecules B*35, B*53, and C*07. This implies that these residues influence control of HIV-1 infection independently of the rest of the HLA molecule."
This seems like an order of magnitude higher resolution understanding of what's going on, plus it offers a unifying explanation for a bunch of prior allele association data. I'd have thought this level of detail would be extremely helpful if you want to understand how viral mutations affect HIV peptide presentation by these class I receptors? Or am I misunderstanding something? For ages I thought HLA genes also encoded CD8 T cell receptors, so I can't pretend to be an expert on immunogenetics.
I thought you were being much too kind in your review of this paper. All 7,000 of the authors should be completely ashamed. I mean, how many times can these groups publish the same data? I would love to hear their opinion as to how this data moves us closer to an HIV vaccine? In short, it doesn't. And anyone who claims is does is either lying or doesn't understand the data. This paper is not merely a lack of content. It is a travesty.