Re: Why has a remedy to kill the common adenovirus been so elusive?

This is a long answer, but given your professional interest and the 
importance of the underlying question, I think this is warranted.

You have zeroed in on the problem in the final part of your question, 
namely killing viruses without damaging the host.  That is a major problem 
when we talk about antiviral drugs, as I hope will be made clear below.  
However, I do not agree with your premise that "most viruses are relative 
wimps".  In fact, we do not have effective and specific drugs for very many 
viruses at all.  The ones that we can treat specifically tend to be part of 
select viral groups (e.g. retroviruses and herpes viruses) for reasons I 
will discuss below.  But there are many other viral groups for which no 
specific treatment exists.

First, a little background.  Virus particles, or virions, are a piece of 
nucleic acid (DNA or RNA) wrapped in a protein/lipid "coat" called a capsid 
and/or envelope.  When viruses infect people, the viral particles get taken 
up into the cells of the body.  Once inside your cells, the nucleic acid 
genome of the virus starts to make proteins that ultimately turn the cell 
into a little virus making factory.  These new viruses are released and 
move on to infect more cells, creating a cycle of infection.  An important 
point is that once it is inside your cell the virus is no longer a simple 
particle, in fact it can be considered part of that cell itself.

Before we consider how you might design a drug to fight a virus, let us 
first consider how your body fights viral infections.  Very briefly, the 
body’s immune system does two things.  First, it makes proteins called 
antibodies that bind to free viral particles, which ultimately leads to 
their destruction.  Thus, these virions are not able to infect more cells, 
which helps stop the cycle of infection.  Second, your body has cells 
(called cytotoxic T cells, killer T cells, CD8 cells) that are able to 
recognize infected cells and kill them.  The killer T cells do this by 
using a collection of special proteins called "antigen receptors" that 
recognize viral proteins on the surface of an infected cell as "foreign".  
The killing is then done by a highly sophisticated and complex mechanism 
that targets only the "foreign-tagged" cell.  The net effect is to destroy 
the source of viral production, again interrupting the cycle of infection.

With that in mind, we might consider designing a drug or treatment to 
achieve the same two things, i.e. to clear free virus and/or to stop 
infected cells from making more virus.  As suggested by your question, free 
viral particles are often easily destroyed (rendered non-infectious) by a 
wide variety of antiseptic agents (many cleaning supplies, etc).  These 
agents generally act by dissolving, or more correctly "denaturing", the 
protein/lipid component of the viral particle.  But I think it is apparent 
that such agents have no preference for viral proteins, and will just as 
easily denature your eye (do not put lye soap in your eye, please!!).  To 
say this a different way, viruses are made of the same raw materials as you 
are, and things that denature viruses will also denature you.  Thus, 
treatments to get rid of free virus are essentially all aimed at increasing 
the level of antibody directed against the virus.  Vaccines increase 
antibody levels before infection ever occurs, while we can actually give 
antibody directly to people with certain kinds of viral infections.

The other very important problem in treating viral infections is to get rid 
of the cells that are infected with the virus, or at least to prevent them 
from making more virus while the immune system does its job.  But, you must 
kill the infected cells without killing (too many) non-infected cells, 
since this would lead to severe toxicity of the drug.  This is most 
definitely not an easy task.  Similar to the immune system, your drug must 
recognize an infected cell as "foreign", but unlike the immune system you 
must do this with a single agent and not a huge array of different antigen 
receptors.  What an antiviral drug must do is attack a protein or component 
that is unique to the virally infected cell, almost always by inhibiting 
the function of a viral-specific protein.  Unfortunately, by far the 
majority of the proteins used by the virus are actually normal host cell 
proteins, and the few virus-specific proteins are often very similar to 
host cell proteins (contrast this with bacteria, which are generally free 
cells that have a variety of proteins present only in the bacteria).

The best way to understand how antiviral drugs can work is to consider some 
examples.  HIV, the AIDS virus, is a retrovirus now treated by two primary 
types of drugs.  The first inhibits a retrovirus-specific enzyme called 
reverse transcriptase, the second inhibits an HIV-specific enzyme called a 
protease.  Herpes viruses (like Herpes Simplex and Cytomegalovirus) are 
treated with drugs that inhibit a viral protein called a DNA polymerase.  
The key points are that these proteins are "encoded" by the virus itself 
(and not the host cell), needed for viral replication and production, AND 
that they are sufficiently different from host proteins that drugs inhibit 
only the viral protein and not the related host proteins.  This last point 
is often only partially achieved.  So, for example, drugs that inhibit 
viral DNA polymerases often do inhibit host DNA polymerase to some degree, 
and that fact is responsible for some of their toxicity.

So, finally, what about adenovirus?  Actually, this is a very highly 
studied virus, and we know many things about it including its genome 
sequence.  It is somewhat related to herpes viruses, and does have a 
viral-specific DNA polymerase.  For this reason, researchers have tried to 
apply some of the drugs designed to treat Cytomegalovirus infection of the 
eye to the treatment of adenovirus conjunctivitis.  Specifically, 
gancyclovir and a new drug called Cidofovir (S-HPMPC) have been 
preliminarily seen to have some efficacy against adenovirus.  I am not part 
of this area of investigation, but my understanding is that there are 
clinical trials currently underway investigating the relative safety and 
efficacy of these drugs for adenovirus infection of the eye.  I do not know 
if and/or when these would be approved for this purpose.

I hope this provides some insight for you and other readers into the 
problem of treating viral infections - there is nothing unusual about 
adenovirus in this regard.  There are still other factors I haven’t 
detailed, like the fact that for many viral infections the worst symptoms 
occur as a result of the inflammation that is coincident with immune 
clearance of the virus, so that once symptoms occur killing the virus won’t 
help!  When you add on top of all of this the fact that research to analyze 
viral proteins is very intensive and expensive, it becomes clear that 
creating new and useful antiviral drugs is a formidable task.  The "common 
cold" may be common, but it isn’t easy to treat!

Tom Wilson, MD PhD