New antiviral strategies

3 December 2008

Vaccines have provided considerable success in preventing viral disease, but they have modest or no therapeutic effect for individuals who are already infected. Consequently, our second arm of antiviral defense has been the development and use of antiviral drugs: they can stop an infection once it has started.

However, despite 50 years of research, our arsenal of antiviral drugs is dangerously small. Only about 30 antiviral drugs are available on the US market, most against herpesviruses and HIV-1. There are many reasons for this paucity of antiviral drugs. Compounds interfering with virus growth can adversely affect the host cell, leading to unacceptable toxicity. Many medically important viruses are dangerous, cannot be propagated in the laboratory or tested in animal systems. Another requirement often difficult to fulfill is that the drugs must completely block virus replication. Many acute virus infections are of short duration; by the time the patient feels ill, virus replication is declining.

Perhaps the most important problem is the emergence of drug-resistant mutants. High mutation rates among the RNA viruses preclude the use of antiviral drugs, with the exception of HIV-1. Given the magnitude of global infection with HIV-1, many antivirals have been developed which target different viral proteins. These drugs are used in various combinations of three, reducing the problem of drug resistance. The mutation rates among DNA viruses are orders of magnitude less than for RNA viruses, explaining the availability of inhibitors of herpesviruses. Nevertheless, resistance to anti-herpesvirus drugs do occur.

Recently several groups have explored the development of new antiviral drugs that target not viral proteins, but host proteins essential for viral replication. The idea is that direct mutation of the drug target is not possible. Unfortunately, resistance to such drugs has been observed. Brefeldin A inhibits poliovirus replication by interfering with the cellular secretory apparatus. Resistance to the drug is achieved by amino acid changes in viral proteins that modulate cellular secretion. Similarly, herpes simplex virus can become resistant to an antiviral drug that targets a nuclear export factor. These and other examples suggest that the strategy of targeting a cellular protein may not preclude the development of viral resistance.

A paper published in 2007 in Genes and Development provides some hope for this approach. The authors show that an inhibitor of the cellular protein Hsp90, a drug called Geldanamycin, blocks poliovirus replication. This cellular protein is apparently required for proper folding of the viral capsid protein precursor, P1. Despite extended attempts, the authors were not able to isolate poliovirus mutants resistant to Geldanamycin. The drug also blocked poliovirus infection of mice, and again no resistant mutants were found. Because Geldanamycin derivatives are currently being tested in humans for anti-cancer activity, they may soon be evaluated for their antiviral properties.

Another novel antiviral approach was reported in Nature Genetics in 2005. The authors identified changes in poliovirus proteins that confer a dominant negative phenotype, e.g. the viruses with altered proteins interfere with the replication of wild-type virus. The idea is that such viral proteins would be excellent drug targets because drug-sensitive viruses would interfere with the replication of drug-resistant variants. They validated this hypothesis by showing that a virus sensitive to an antiviral drug inhibited the replication of drug-resistant viruses.

These recent developments illustrate that creative approaches to antiviral drug development can still be productive. Nevertheless, it is important to remember that, with 10,000,000,000,000,000 HIV genomes on the planet today, it is likely that HIV genomes exist that are resistant to all the antiviral drugs that we have now, or ever will have!