RealHealthNews talks to Suzanne Sandmeyer of the Institute of Genomics and Bioinformatics at the University of California, Irvine.
Mobile genetic elements in single-celled yeast, which are models for the HIV virus, have yielded new secrets of how HIV might replicate in the human body. The result: over 60 new targets for HIV/AIDS drug development. But there is a problem – the targets are human.
Just like malaria, just like all pathogens exposed to drug treatments, the HIV virus is slowly developing drug resistance. But the virus is powerless alone: it needs certain human genes to replicate. These genes are a potential source of novel drug targets, but very few appropriate target genes have been identified so far.
Now a new study, conducted by Suzanne Sandmeyer and colleagues at the University of California, reports the discovery of 130 host genes that affect the replication of a model retrovirus – not HIV, but a free-floating cluster of genes with similar properties that lives in the cells of yeast.
These are so-called “mobile genetic elements”. Many organisms contain such elements, and they are non-pathogenic molecular relatives of retroviruses like HIV.
In budding yeast, these mobile elements (called Ty – or “transposable yeast” – elements) encode proteins that are homologues of HIV proteins. The proteins encoded by Ty elements and the steps of the life cycle in yeast are similar to the proteins encoded by retroviruses and their life cycles in animal cells.
Sandmeyer and other scientists believe that these simple Ty elements are a good model for understanding how HIV – and other retroviruses - interact with their hosts. Yeast has previously been used as a model to help scientists understand how human cancer cells replicate out of control – work that led to a Nobel Prize.
The Sandmeyer laboratory screened a collection of over 4457 mutant yeast strains representing most of the known genes in yeast. They then called in computer scientist Pierre Baldi, also at the University of California, to tease out genes of a form that might affect the Ty lifecycle. In total, they identified 130 genes that affect the replication of the retrovirus-like element Ty3.
Over half of the genes identified in this study have at least one clear relative or homologue in the human genome, thus providing a rich source of candidate critical genes – in the human host - for HIV replication.
Sandmeyer and colleagues hope that this study, along with other studies of retrovirus-like elements in yeast, will ultimately lead to the development of a new generation of anti-retroviral therapeutics.
RealHealthNews asked Sandmeyer: Are there any other clusters of anti-HIV targets on the same scale as your collection?
SS: There have been clusters identified in other yeast systems. So we have the Ty1 elements, and now the Ty3; those are the largest collections of would be potential host factors. These are retrovirus-like elements.
Now in retroviruses themselves, people are starting to perform screens, so there are some very basic proteins that have been found to be required for retrovirus replication; there also have been several reviews that discuss host genes. But we are talking of the order of a dozen, total, that have been found look like they are relatively specific for retroviruses. So there is the CD4 receptor, the chemokyne co-receptor, the TRIM 5-alpha gene for HIV which seems to be a human restriction factor, APOBEC 3G, cytidinedeaminase - these are the kind of genes that we think we are picking up in this large-scale screen.
RealHealthNews: One thing I don’t understand is this: if you identify genes in the human host that are necessary for the retrovirus to integrate and replicate, how does that give you a drug target? Because if you attack the person infected, you could cause harm.
SS: Well, for example, in some cancers it is possible to target some host kinases that still leave the individual relatively unharmed.
RHN: It does complicate things that you’d be actually attacking the host…
SS: Possibly, yes. But there are ways around. So you might try to find molecules to selectively attack cells that are infected, or target some proteins that are backed up by other proteins for host functions that are not backed up for retroviral function.
Currently in HIV there are of the order of 15 functions that you could target. Most of the effort has gone into targeting protease and reverse transcriptase – and integrase, not so successfully. It’s a limited number of targets, and now we see resistance developing because HIV can mutate very rapidly.
So the idea of the host targets is that true, a lot of them will be essential for host viability so won’t be usable, but there are so many that among them you might well find appropriate targets.
Another point is that we think we are going to find out more about how retroviruses replicate, because of this study; and with that understanding we might find additional ways to target retroviral proteins, or other proteins that would be non-essential.
And finally, for half the genes that we found – when we knock them out, Ty3 transposition went up. So that would suggest that those might represent naturally occurring retroviral antagonists [moelcules in the human that block HIV]. Just as we have interferon that naturally antagonizes viral infection. So the possibility would be that you could try to find a way to over-express some of these natural antagonist genes, and improve the attack of the host on the virus.
But it’s a very key point about targeting host proteins – you don’t want to shoot yourself!
RealHealthNews: Then you are working with yeast, not HIV; how do you translate these discoveries up to HIV?
SS: Well you know the Nobel Prize was awarded for work that began on cyclins in yeast! That work played out to be very important in cancer research in mammalian cells, so…
RealHealthNews: I’m not questioning the possibility, I just would like to know how you move up that step…
SS: What we and others are interested in doing is using siRNA [small interfering RNA] approaches basically to go in and screen for a subset of these genes that might have an effect on HIV replication. That’s the next logical step. A lot of us are preparing to do that on a larger scale, which siRNA makes possible.
RealHealthNews: The other yeast studies you mentioned – could you say a bit more about them?
SS: They were published a couple of years ago. What makes this work a little bit different is that Ty3 is more closely related to retroviruses than it is to the other yeast retrotransposons. Two very good screens were published by Ty1 labs but they didn’t overlap, so their significance was a little bit compromised.
Our screen not only overlaps with genes that can be identified known retrovirus factors, but it also overlaps with both of the previous Ty1 screens, in terms of genes recovered. So we think that that means that those genes must have a very ancient relationship with retrovirus-like replication processes. So we actually believe that those might be genes that would be likely to be also related to retroviruses. So it reinforces the results of those other studies. - RW
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