Published online 28 April 2008 | Nature | doi:10.1038/news.2008.785

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Hit the host to target HIV

Novel tactic for stopping virus replication may lead to new antiretrovirals.

Moving target: If HIV is hard to hit, why not target the human host cells instead?Getty

A new method for halting the spread of HIV in the body could aid the search for drugs to manage infection. What's more, because the technique is aimed at proteins in the human immune system rather than the virus itself, it could potentially sidestep problems of resistance that have traditionally hampered HIV treatment regimes.

There is no cure for HIV infection, and so patients must take antiretroviral drugs to manage their condition. Current drug regimes attack parts of the virus, but these constantly mutate, making it difficult to avoid the emergence of resistant strains.

To complement such drugs, some researchers are pursuing the idea of targeting human cells to make it difficult or impossible for HIV to replicate there and cause disease. By interfering with a protein in the immune cells where the virus lives and breeds, HIV could be inhibited in a way that would avoid the problem of resistance.

Researchers led by Andrew Henderson of Pennsylvania State University in University Park and Pamela Schwartzberg of the National Human Genome Research Institute in Bethesda, Maryland, studied human immune cells and discovered that they are less vulnerable to HIV infection and replication when an enzyme called inducible T-cell kinase (ITK) is knocked out. Inhibiting ITK affected several processes in the HIV life cycle, including its entry into the cell, expression of viral genes and the production of new virus particles, the team reports in Proceedings of the National Academy of Sciences1. Mouse mutants lacking ITK were less vulnerable to HIV proliferation, the researchers confirmed.

The researchers have filed a patent for the strategy of inhibiting ITK to tackly HIV, and are now hoping that pharmaceutical companies will develop a drug that can successfully do this. That shouldn't be too difficult, predicts Henderson. "There are a number of compounds that target this," he says, although it's unclear whether such a drug would be effective enough in humans. "I think it remains to be seen whether it provides good enough inhibition of viral replication," says Schwartzberg.

Dangerous game

One reason HIV is difficult to treat is that the virus's own proteins change so rapidly. Its protein 'coat', as well as the enzymes it uses to commandeer the host cell's DNA machinery and churn out new virus particles, frequently mutate. ITK is far more predictable, the researchers argue.

But the immune cells involved, called CD4+ T cells, are major components of the body's immune defences, and not just against HIV. Previous attempts to interfere with other types of T cell have been unsuccessful because of these cells' wide-ranging functions — as shown in the disaster at London's Northwick Park Hospital, when six people were hospitalized by a trial drug that played havoc with their immune systems.

But interfering with ITK does not wipe out the entire function of CD4+ cells; instead it slows them down, Schwartzberg explains. "Animals with inhibited ITK can still clear viral infections — it's delayed but it works," she says.

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ITK is also a promising target for other autoimmune conditions besides HIV/AIDS, such as asthma, suggesting that it might offer a solution to conditions in which the immune system is its own worst enemy, while still protecting against other infections that the immune system is designed to fight.

The advance won't offer hope for efforts to develop an HIV vaccine, however, which are currently becalmed, Schwartzberg says. This will be a strategy for helping those already infected with HIV, she predicts, not as a prophylactic measure. "It strikes me that you wouldn't want to put in a drug that manipulates the immune system before you got infected," she explains. 

  • References

    1. Readinger, J. A. et al. Proc. Natl Acad. Sci. USA doi:10.1073/pnas.0709659105 (2008).
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