Fellay et al, Fig 2I swear this was coincidence. Last Thursday, after talking about CTL-based selection on HIV sequences, I blogged the musical question, “What other selection pressures on HIV, within a single individual, have been shown?”. One day later,1 a paper in Science offers a partial answer.

The paper is:
Fellay, J., Shianna, K. V., Ge, D., Colombo, S., Ledergerber, B., Weale, M., et al. (2007).A whole-genome association study of major determinants for host control of HIV-1. Science, 317(5840), 944-947.

There’s a huge amount of individual variation in the outcome of HIV infection. Some people progress rapidly to AIDS, others more slowly, and a very few are “long-term non-progressors” (LTNP) who seem to control the virus for long periods, even without treatment. Over the years there’s been a lot of attention focused on LTNP, and one of the factors that’s been linked to slow progression is a particular MHC class I allele, HLA-B*5701.Different HLA alleles are able to bind to different viral peptide epitopes and act as targets for CTL. The presumption about the role of HLA-B*5701 has been that the particular peptides it binds to, in the virus, include very critical regions of the virus. That means (the reasoning has gone) that as HIV mutates to avoid the CTL that are targeting those particular peptides, the virus gives up a lot of fitness — it’s had to trade, say, replication ability, for the ability to avoid CTL. There were a couple puzzles with that explanation — what’s so special about the regions these particular CTLs targeted? And how come the virus seems to be somewhat inhibited quite early on in infection, even before CTL were thought to be important? — but it was a decent explanation. And it may even be right, but Fellay et al throw another possible explanation into the mix.

What these guys are did is look at more than the extremes of the resistance spectrum (which let them use far more patients than in LTNP studies — some 30,000 patients), and compare variations in HIV susceptibility to genomic markers (looking at 535,101 variations in the genome):

One striking and largely unexplained difference is the level of circulating virus in the plasma during the nonsymptomatic phase preceding the progression to AIDS. This is known as the viral set point and can vary among individuals by as much as 4 to 5 logs. We aimed to identify human genetic differences that influence this variation.

They found three links to viral set point.2 “Together, the three polymorphisms explain 14.1% of the variation in HIV-1 set point.”

One of the links was to an RNA polymerase, and I’m not going to talk about that one because I don’t know enough about the potential biological relevance.3

The other two links are both MHC class I-associated. (The complicated figure at the top is from Fellay at al, showing part of the MHC class I region, the genomic polymorphisms they were analyzing, and the links. HCP5 genomicTo the right is a much simpler diagram of the same region,4 with the two genetically-linked genes highlighted in red and HLA-B in green.One link, a relatively simple story, was with HLA-C. That’s an MHC class I molecule, and it’s recognized by CTL. The genetic polymorphism they found turns out5 to influence the amount of HLA-C expressed:


The protective allele leads to a lower VL6 and is associated with higher expression of the HLA-C gene. This strong and independent association with HLA-C expression levels suggests that genetic control of expression levels of a classical HLA gene influences viral control.

Simple and straightforward, but there’s a potential and very interesting complication. The HLA-C genes are indeed recognized by CTL, but they also interact with natural killer (NK) cells. Could this be a sign that NK cells are important in controlling HIV? Certainly that wouldn’t be surprising, and there are some relatively recent studies that link NK cells to HIV resistance,7 but as far as I know this HLA-C thing hasn’t been previously connected. It may have nothing to do with NK cells, but hey, it’s worth looking at.

The other link in the MHC class I region is more complicated. The actual genetic polymorphism they found was in a gene called “HCP5”, but because HCP5 variants are linked to HLA-B variants, it’s possible that the actual resistance comes from HLA-B*5701, and the HCP5 variation piggybacks along with that:


Given the strong functional data supporting a role for HLA-B*5701 in restricting HIV-1, our first hypothesis is that the association observed here is due to the effect of HLA-B*5701, reflected in its tagging a SNP within HCP5. 8

However, the biological plausibility of HCP5 having a role in HIV protection is high, because HCP5 is a HERV!OK, when I read that part I was all, like, “Whoa! No way, man!” but maybe not everyone reacts that way. “HERVs” are human endogenous retroviruses, fossilized retroviral sequences that, long ago, were viruses that inserted into the genome and then stayed there. There are huge numbers of these HERVs in the human genome, and it’s generally accepted that they have little if any function.9 In mice, though, (which are also riddled with endogenous retroviruses) resistance to various retroviruses is linked with some of their endogenous retroviral sequences.10 Could HCP5 do something similar in humans? The authors clearly like this idea, pointing not only to aspects of HCP5 that make the idea plausible (it has polymorphisms in the right place, contains proteins, and is expressed in the right cells), but also to the weaknesses of the HLA-B*5701 connection:

In fact, as a human endogenous retroviral element (HERV) with sequence homology to retroviral pol genes and confirmed expression in lymphocytes, HCP5 is itself a good candidate to interact with HIV-1, possibly through an antisense mechanism. Moreover, HCP5 is predicted to encode two proteins, and the associated polymorphism results in an amino acid substitution in one of these proteins.A model in which HCP5 and HLA-B*5701 have a combined haplotypic effect on the HIV-1 set point is consistent with the observation that suppression of viremia can be maintained in B*5701 patients with undetectable VL, even after HIV-1 undergoes mutations that allow escape from cytotoxic T lymphocyte (CTL)-mediated restriction.

So the bottom line is that, while this large-scale study hasn’t offered direct answers to what makes HIV progress slowly or rapidly, it has raised a couple of really intriguing questions. I’m looking forward to seeing more studies on HIV resistance and HCP5 and, perhaps, NK cells, in the next few years.

  1. That would be Friday, if you’re playing along at home[]
  2. They also found a link or two to another aspect of HIV resistance — slow progression — but I won’t talk about those now.[]
  3. Though it seems pretty biologically plausible that an RNA virus might have its life cycle affected by an RNA polymerase.[]
  4. Drawn with XPlasMap v.0.96 from the GenBank sequence[]
  5. They actually tested this; it’s great to see these hypotheses actually being tested at the same time they’re generated by these big-science type studies[]
  6. VL: “Viral load”, like viral set point[]
  7. Reviews include Barbour, J. D., Sriram, U., Caillier, S. J., Levy, J. A., Hecht, F. M., & Oksenberg, J. R. (2007). Synergy or independence? Deciphering the interaction of HLA Class I and NK cell KIR alleles in early HIV-1 disease progression. PLoS Pathog, 3(4), e43. and Fauci, A. S., Mavilio, D., & Kottilil, S. (2005). NK cells in HIV infection: paradigm for protection or targets for ambush. Nat Rev Immunol, 5(11), 835-843. []
  8. Looking at the map, I wonder if there might (also? Or instead?) be a link with the MICA and/or MICB genes that flank HCP5. MICA and MICB are NK receptors, so the same argument as with the HLA-C link applies. The authors don’t mention this possibility, and I don’t know if MICA and MICB are as tightly linked to HCP5 variation as is HLA-B. []
  9. There are lots of papers that have looked for functions, but few if any are convincing. For a review, see Griffiths, D. J. (2001). Endogenous retroviruses in the human genome sequence. Genome Biol, 2(6), REVIEWS1017. []
  10. For example, Best, S., Le Tissier, P., Towers, G., & Stoye, J. P. (1996). Positional cloning of the mouse retrovirus restriction gene Fv1. Nature, 382(6594), 826-829. and Ikeda, H. & Sugimura, H. (1989). Fv-4 resistance gene: a truncated endogenous murine leukemia virus with ecotropic interference properties. J Virol, 63(12), 5405-5412.[]