Genetic background & medicine, HIV & differences between blacks & whites

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The Duffy-null state is associated with a survival advantage in leukopenic HIV-infected persons of African ancestry:

Persons of African ancestry, on average, have lower white blood cell (WBC) counts than those of European descent (ethnic leukopenia), but whether this impacts negatively on HIV-1 disease course remains unknown. Here, in a large natural history cohort of HIV-infected subjects we show that although leukopenia…was associated with an accelerated HIV disease course, this effect was more prominent in leukopenic subjects of European than African ancestry. The African-specific -46C/C genotype of Duffy Antigen Receptor for Chemokines (DARC) confers the malaria-resisting, Duffy-null phenotype, and we found that the recently described association of this genotype with ethnic leukopenia extends to HIV-infected African Americans (AA). The association of Duffy-null status with HIV disease course differed according to WBC but not CD4+ T cell counts, such that leukopenic but not non-leukopenic HIV+ AAs with DARC -46C/C had a survival advantage compared with all Duffy-positive subjects. This survival advantage became increasingly pronounced in those with progressively lower WBC counts. These data highlight that the interaction between DARC genotype and the cellular milieu defined by WBC counts may influence HIV disease course, and this may provide a partial explanation of why ethnic leukopenia remains benign in HIV-infected African Americans, despite immunodeficiency.

Duffy status is a highly ancestrally informative trait. This is a case where the relatively low between population variance found among humans does not apply. Rather, it seems that the Duffy null phenotype is a recent adaptation to malaria among West Africans. Because malaria has such a strong fitness implication many independent genetic adaptations have emerged, many of them with other negative side effects. On net individuals with side effects may still have higher fitness in an environment where malaria is endemic. Sometimes the net benefit is most evidence on a population wide scale, sickle-cell anemia is a deleterious homozygote which exists because of the much higher frequency of heteryzogytes vis-a-vis wild type homozygotes. Many malaria adaptations exhibit the large effect dynamic and suboptimal characteristic which one might except from the early stages of natural selection in a Fisherian model. You deal with the adaptive pressures of the present and let the future take care of itself. In this case, the future involved HIV:

The researchers found that leukopenia was generally associated with a faster disease progression from HIV to AIDS, independent of known predictors of AIDS development. “On average, leukopenic European Americans progressed nearly three times faster than their non-leukopenic African or European counterparts,” explained Hemant Kulkarni, MD, first author of this study. “However, leukopenic African Americans had a slower disease course than leukopenic European Americans, even though twice as many African Americans in the study had leukopenia.”

The investigators found that the DARC variation, not race, explained the differences in WBC counts in African Americans with HIV. Among those who were leukopenic, only those with the DARC variation experienced a significant survival benefit. Additionally, this survival advantage became increasingly pronounced in those with progressively lower WBC counts, suggesting that the interaction between DARC and WBC counts was the primary influence on slowing HIV disease progression in African Americans.

There are no doubt details in the genetic architecture of those with the null genotype worth future investigation.

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  1. “it seems that the Duffy null phenotype is a recent adaptation to malaria among West Africans.” 
    I’m beginning to doubt this. The gene frequency is too high. Assuming that Duffy has any cost at all (which looks likely considering the leukopenia and geographically restricted distribution), you’d expect the frequency to stall out at a lower level – people without Duffy would then coast on crowd immunity.  
    A virulent African zoonosis that Duffy blocks might make for a better explanation. The protection against vivax malaria would then be a coincidence…

  2. Gcochran, you point out that a varmint with a nonhuman reservoir would be likelier to drive duffy-null near fixation – likelier than vivax. But it may be roughly as parsimonious to posit that the varmint was in fact vivax, but it has an undiscovered animal reservoir – or had one that no longer exists.  
    Even if no animal reservoir has ever existed, this rather tentative 2006 paper reports that certain duffy-negative individuals are sparsely infected by probable vivax. Even if the fitness burden is zero in duffy-null carriers, their presence (assuming they really exist) might still impact the degree of herd immunity. I would think the degree of herd immunity would have to be rather high to bring the allele into balanced polymorphism. But of course it depends on the cost of the neutropenia etc.

  3. The posited zoonosis could be a lot more lethal than vivax.

  4. This is kind of off-topic, but I had this question ever since I first heard about Duffy, and given the number of knowledgeable readers here I thought I’d see if anyone would know. 
    Despite the well-recognized role of Duffy as an obligatory, or near obligatory, receptor for malaria, and given the immense public expenditure on research related to this disease, I cannot manage to find one single high-throughput (or even “low”-throughput) screen for small molecule Duffy antagonists in the literature.  
    This is all the more surprising given that Duffy is related to the GPCR superfamily that is well-known for containing excellent drug targets, and also that a similar strategy with the HIV receptor CCR5 is widely considered viable. I’m wondering if it’s been tried and no hits have turned up.

  5. On average, prospects for inhibiting protein-protein interactions with small molecules have been considered questionable. Apparently the set of successful examples, including the CCR5 antagonists, is quite small – though some say an acceleration is afoot.

  6. Apologies if this is too off-topic, but whenever HIV articles come up, I always wonder about Duesberg and the other HIV-is-a-harmless-retrovirus folks. What do GNXP folks think of that stuff? I would be especially curious to here from gcochran.

  7. Duesberg is crazy. AIDs looked like a contagious disease from day one and the agent was clearly identified not much later. And the drugs (protease inhibitors and such) designed to block HIV greatly alleviate the disease: what more could you want, egg in your beer? 
    Looking at Wiki, I found a wonderful sentence: 
    “For example, the magazine Continuum, which consistently denied the existence of HIV/AIDS, shut down when its editors all died of AIDS-related causes.” 
    Only fair.

  8. The FAQ on Duesberg’s webpage has a high concentration of very low quality arguments – by far the highest I have ever seen from a person of his credentials. If Duesberg turns out to be right I will boil and eat my hat, then take my pants off and jump-kick a hive of killer bees. I recommend reading Steve Harris on the subject. He’s a powerful and fair reasoner who likes to hash it out with AIDS denialists in great detail. 

  9. You didn’t have to know anything about molecular biology, epidemiology, or virology to smell the rat in Duesberg’s argument. If AIDS was the result of recreational drug use, then it should have been rock musicians who were dropping like flies, not ballet dancers. 
    The sad case of Christine Maggiore and her daughter should have been the final, tragic nail in that coffin.

  10. Razib- Does the contact authors link work? I sent you a note regarding a paper you may be interested in. Don’t know if you received the email.

  11. ghoghogol, it works now. thanks for telling about the problem.

  12. To Eric: I’ve heard that about protein-protein interactions, but I just assumed people wouldn’t write off the possibility here, because many GPCRs bind peptides yet are still “druggable”. 
    And about Duesberg–I have had a chance to speak with him in person, and what I noticed was his tendency to use analogies that weren’t based on any real conceptual similarity. For instance, he compares the genome to a book, with the chromosomes as chapters whose pages, or genes, are organized in a particular order that determines physiology on a big-picture level. He gives no evidence from studies of gene expression to suggest that they are actually ever read in this order, though, most likely because there isn’t any.

  13. If AIDS were the result of toxic antiviral drugs, we’d also expect it to have occurred in the animals we used for testing. It did not. 
    For Duesberg to be correct, HIV would have to be harmless, both under normal and immune-depressed conditions, for rats, monkeys, and all great apes other than man – and stay that way. And somehow become virulent only in humans once a previously-undetected immune depression caused by drug use gave it a foothold. 
    The real problem isn’t that this scenario is ludicrously implausible, it’s that there’s never been a bit of evidence that supported it.

  14. You’re right, I didn’t realize things like chemokines had GPCR receptors. I looked it up and some of them are 75 residues in their mature secreted form. Vasoactive intestinal peptide is 28 residues, enkephalins five. I have no clue which ones have been drugged though, and of course there are lots of much smaller GPCR ligands. 
    A lot of people say many more protein-protein drugs have been published in recent years than in the past. So here’s hoping. It would certainly open up infinite possibilities. But that was also hoped in the past about combinatorial chemistry (which you gotta admit is an awesome idea) and other stuff. 
    I wonder if one factor isn’t cost. Malaria drugs pretty much have to be extremely cheap. Many people think protein-protein inhibitors will turn out to average larger than the average drug, though I don’t know if that is true of the ones that exist so far. Large drugs, if they have to be synth’d, are likely to be far dearer than small ones. And when you mention HTS I’m guessing you mean libraries that are primarily synthetic? My grasp of these matters is loose but I hear natural products are not really going strong these days.  
    One of the CCR5 inhibitors for HIV is only the size of tetracycline. Certainly smaller than taxol. But both of the latter are semi-synthed, like most antibacterials and opiates, and the antimalarial artemether.

  15. I was mistaken, natural products are quite far from total eclipse: