Questionable use
A second mutation has been found that protects against HIV
However, it causes a rare kind of muscular dystrophy in its carriers
Scientists from Spain and Belgium infected the cells of patients with muscular dystrophy with the human immunodeficiency virus and found that it reproduces much worse in them than in the cells of healthy people. Thus, the mutation in the gene that causes this disease makes its owners resistant to HIV – however, at the cost of the ability to walk. This is the second such mutation known to scientists.
The most discussed mutation over the past year was, of course, CCR5Δ32. According to the plan of the head of the experiment Jiankui He, she had to make genetically modified girls who were born in the fall of 2018 in China, resistant to HIV. Later there was information that similar studies are being prepared in Russia. At the same time, it was found that CCR5Δ32 can affect mental abilities and increase the risk of death. It became clear that this mutation is not the best candidate to stop the spread of HIV, even if we imagine that human genetic editing itself does not carry other risks.
A group of researchers from Spain and Belgium decided to check how another mutation in the TPNO3 gene, which occurs in patients with pelvic-brachial muscular dystrophy, is associated with infection. With this disease, the muscles of the extremities in patients gradually weaken and may even atrophy. Like the more well-known Duchenne myodystrophy, pelvic-brachial dystrophy is incurable, but it proceeds more easily: carriers can live to old age, and with a mild form even retain mobility.
The functions of the TPNO3 protein are not fully understood, but, apparently, it participates in the transport of other proteins from the cytoplasm of the cell into the nucleus. This is an important stage in the HIV life cycle: in order to reproduce, the virus genome must be embedded in the DNA of the cell, and for this it is necessary to penetrate into the nucleus.
The mutation in TPNO3, which causes myodystrophy, makes the protein 15 amino acids longer. How its functions change in this case is not entirely clear, but it is likely that the transport to the nucleus is disrupted, and this could prevent the reproduction of HIV
The scientists worked with a family of Spanish patients in which pelvic-brachial myodystrophy was diagnosed in 32 people in six generations. Among them, the researchers selected 29 patients. All of them were heterozygotes, that is, one variant of the TPNO3 gene was healthy, and the other was mutant. They took their blood, isolated immune cells from it and tried to infect them with HIV particles. Scientists have embedded a luciferase gene into the genome of these particles so that the cell glows depending on how actively the virus multiplies inside it. The control group in the experiment were the cells of 34 healthy blood donors. It turned out that the cells of patients with myodystrophy glow much weaker than the cells of the control group – that is, the virus multiplies in them, but much worse.
The researchers verified that it was precisely in transport: they constructed a virus that passed into the core independently of TNPO3. This type of virus infected both control cells and patients' cells, and multiplied in them equally intensively.
Despite the fact that the cells of all patients, compared with healthy cells, resisted infection much better, their reaction to the virus was heterogeneous: some shone stronger, others weaker. The degree of muscle atrophy in such patients also varies: some have almost no symptoms, while others find it difficult to walk up the stairs and raise their hands. Apparently, this means that some mechanisms are activated in the cell that compensate for the mutation, and they manifest themselves individually.
The discovery of a new mutation can shed light on both diseases at the same time, because neither the mechanisms of HIV reproduction in the cell nor the causes of pelvic-brachial myodystrophy have been fully studied. However, it is unlikely that this mutation will be used to fight the virus: its carriers have to pay too high a price. However, in patients with myodystrophy, apparently, only muscles suffer – at least, their immune system is no different from healthy people, and judging by new data, in some places it is even stronger.
Article by Rodríguez-Mora et al. The mutation of Transportin 3 gene that causes limb girdle muscular dystrophy 1F induces protection against HIV-1 infection is published in the journal PLOS Pathogens.
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