US scientists have identified hundreds of human proteins targeted by HIV that could help develop therapies that overcome the drug resistance problems that limit the effect of current treatments.

The research was conducted by a team at Harvard Medical School (HMS), Boston, and is published in the January 10th online issue of Science Express.

HIV contains only nine genes that code for 15 proteins, but it has a powerful effect on the human immune system because it has learned to hijack hundreds of human proteins to carry out its deadly mission.

And therein lies its weakness. In this new work, researchers have found what they believe are the vast majority of the human proteins used by HIV, and opened a path toward new therapies that target the host proteins rather than the virus itself.

Science is running out of options by targetting the virus itself, because as has been shown by numerous studies, HIV is capable of rapid adaptation to new drugs. In fact in drug therapy that targets the virus itself, the only approach that works is to take a cocktail of drugs because the virus takes much longer to develop resistance to several drugs at the same time.

But the more drugs in a regime, the harder it is for the patient to stick to the programme. So regime adherence goes down, which actually increases the chance the virus will become resistant.

HMS professor and senior author of the study, Dr Stephen Elledge, explained why they decided to tackle the problem from the host end:

“Antiviral drugs are currently doing a good job of keeping people alive, but these therapeutics all suffer from the same problem, which is that you can get resistance, so we decided to take a different approach centered on the human proteins exploited by the virus.”

“The virus would not be able to mutate to overcome drugs that interact with these proteins,” he added.

Elledge also holds primary appointments in the HMS Department of Genetics and at Brigham and Women’s Hospital and is also a member of the HMS-Partners Health Care Center for Genetics and Genomics and investigator with the Howard Hughes Medical Institute.

Over the last 20 years, as HIV has ravaged the world, scientists have watched it carefully and discovered that it needs human proteins in order to propagate inside the host. In that time dozens of human proteins targeted by the virus have been identified.

In this new study, Elledge and colleagues took this search further, in effect hugely multiplying the number of known proteins targeted by HIV. The range of proteins they found is surprisingly diverse, from trafficking proteins to ones that programme a type of cell death called autophagy.

Elledge explained that the new expanded list they have found will be useful to other scientists as a “hypothesis generation machine”.

“Scientists can look at the list, predict why HIV needs a particular protein, and then test their hypothesis,” explained Elledge, who hopes that such research will lead to new types of HIV treatments.

The HMS team used a process based on short interfering RNAs (siRNAs). Each type of siRNA has the ability to disrupt a gene that codes for a specific protein. Using a library of siRNAs allowed the researchers to knock out one gene, and therefor one protein, at a time across the whole of the human genome, which is quite a task.

Staff at the Institute of Chemistry and Cell Biology at Longwood (ICCB-L) helped the HMS team place the siRNAs on thousands of human cells, and target one gene at a time in each well of cells. This created a situation where each well contained a collection of cells where only one protein was missing.

Then the HMS team released HIV into the wells and observed to see which wells inhibited HIV replication and which did not. The ones where HIV was inhibited were likely ones where a protein essential to HIV was missing. There were 273 such proteins altogether, of which previously only 36 were already known to be involved in HIV replication.

What is interesting, and probably serves to confirm the results, is that human immune cells, which come under attack from HIV, contain a high proportion of the 273 proteins.

Elledge said, “We’re closing in on a systems level understanding of HIV, which opens new therapeutic avenues.”

“We might be able to tweak various parts of the system to disrupt viral propagation without making our own cells sick,” he explained.

“This is the first whole genome screen for human proteins required by HIV, and we’re confident that it netted real results,” added first author, Abraham Brass.

“Given the method, we missed some proteins, but the majority of the ones we found are highly likely to play a role in HIV propagation,” said Brass.

“Identification of Host Proteins Required for HIV Infection Through a Functional Genomic Screen.”
Abraham L. Brass, Derek M. Dykxhoorn, Yair Benita, Nan Yan, Alan Engelman, Ramnik J. Xavier, Judy Lieberman, and Stephen J. Elledge.
Science Express, Published online January 10 2008.
DOI: 10.1126/science.1152725.

Click here for Abstract.

Sources: Harvard Medical School press release, journal article.

Written by: Catharine Paddock