Retrocyclins: a defence against HIV, reawakened after 7 million years

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HIV is an elusive adversary. The virus is so good at fooling the immune system that the quest for an HIV vaccine, or even a countermeasure to resist infections, has spanned two fruitless decades. But maybe a defence has been lurking in our genomes all this time.

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Nitya Venkataraman from the University of Central Florida has managed to reawaken a guardian gene that has been lying dormant in our genomes for 7 million years. These genes, known as retrocyclins, protect monkeys from HIV-like viruses. The hope is that by rousing them from their slumber, they could do the same for us. The technique is several safety tests and clinical trials away from actual use, but it’s promising nonetheless.

Retrocyclins are the only circular proteins in our bodies, and are formed from a ring of 18 amino acids. They belong to a group of proteins called defensins that, as their name suggests, defend the body against bacteria, viruses, fungi and other foreign invaders. There are three types: alpha-, beta- and theta-defensins. The last group is the one that retrocyclins belong to. They were the last to be discovered, and have only been found in the white blood cells of macaques, baboons and orang-utans.

In previous experiments, Venkataraman’s group, led by Alexander Cole, showed that retrocyclins were remarkably good at protecting cells from HIV infections. They are molecular bouncers that stop the virus from infiltrating a host cell. The trouble is that in humans, the genes that produce retrocyclins don’t work. Over the course of human evolution, these genes developed a mutation that forces the protein-producing machinery of our cells to stop early. The result is an abridged and useless retrocyclin.

But aside from this lone crippling mutation, the genes are intact and 90% identical to the monkey versions. Now, Venkataraman has awakened them. She found two ways to fix the fault in human white blood cells, one involving gene transfer and the other using a simple antibiotic. Either way, she restored the cells’ ability to manufacture the protective proteins. And the resurrected retrocyclins did their job well – they stopped HIV from infecting a variety of human immune cells.

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Venkataraman says that we can think of retrocyclin deficiency as “an inherited disorder, albeit one with an incidence of 100%. To “cure” it, she created corrected versions of the faulty human retrocyclin genes and loaded them into white blood cells. Using glowing antibodies designed to stick to retrocyclins, she saw gleaming evidence under the microscope that the cells had made their own stock of these proteins. She even managed to purify the rekindled proteins themselves.

This clearly tells us that our cells have all the right machinery needed to actually make retrocyclins – it’s just that the instructions have a typo in them. Most importantly, the restored proteins worked. They prevented HIV from infecting up to 80% of the cells, and even reduced the levels of virus in cells that had already been infected.

Obviously, gene transfer techniques like this are hardly practical for poor African nations where HIV is most rampant. For retrocyclins to really play a role in the fight against HIV, we need a cheaper and easier way of reactivating them. And Venkataraman thinks she has found one – a group of antibiotics called aminoglycosides.

In bacteria, these drugs work by blocking them from creating proteins. But in the more complex cells of animals, they do something different – they react with the protein-making machinery of our cells so that they make slightly more mistakes than usual. Normally, that would be a bad thing but for retrocyclins, it’s an unexpected boon. It means that the machinery barrels straight through the mutation that causes retrocyclins to be built half-finished. It doesn’t stop prematurely, and produces a full-length protein.

Venkataraman found that one of these drugs, tobramycin, was especially good at restoring retrocyclins, and did so in both white blood cells and actual vaginal tissue. The drug slashed the rate of HIV infection by about 50% – a respectable figure but clearly a smaller one compared to the sizeable benefits bestowed by the gene transfer method. On the plus side, the technique didn’t seem to harm the cells in any way.

These results are promising ones indeed, and Venkataraman thinks that with more work, aminoglycoside-based creams could be used to prevent HIV infections in the real world.

HIV kills by infecting the very cells that are meant to defend us from infections and destroying them. But retrocyclins are something it hasn’t encountered before. Humans lost the ability to create these guardians millions of years ago and by reawakening them, we could have a new but ancient weapon against this sneakiest of foes.

Reference: Venkataraman, N., Cole, A., Ruchala, P., Waring, A., Lehrer, R., Stuchlik, O., Pohl, J., & Cole, A. (2009). Reawakening Retrocyclins: Ancestral Human Defensins Active Against HIV-1 PLoS Biology, 7 (4) DOI: 10.1371/journal.pbio.1000095

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