MadSci Network: Immunology

Re: What is the importance of protease in AIDS therapy? What is HIV protease?

Date: Sat May 8 01:06:15 2004
Posted By: Mike Conrad, Post-doc/Fellow, Microbiology, UNC
Area of science: Immunology
ID: 1083095435.Im

What is the importance of the protease in AIDS therapy?  What is the HIV protease?  

The Simple Facts Project gives a brief summary:
HIV is a virus that goes through many steps during its life cycle. Once HIV infects a human cell, 
the virus uses proteins and chemicals inside that cell to make more copies of itself. Protease is a 
chemical, known as an enzyme, that HIV needs in order to make new viruses. Protease inhibitors 
(PIs) block the protease enzyme. When protease is blocked, HIV makes copies of itself that can't 
infect new cells. Studies have shown that protease inhibitors can reduce the amount of virus in 
the blood and increase CD4 cell counts. In some cases these drugs have improved CD4 cell 
counts, even when they were very low or zero.

The Simple Facts Project is at:

I'm a molecular biologist, and it would be fun to elaborate on these questions.  
What is the HIV protease?  Living things are made of molecules called proteins.  The job of many 
proteins is to catalyze, or cause, various chemical reactions.  Proteins that catalyze reactions are 
called enzymes.  Some of the many reactions that enzymes catalyze involve cutting up other 
proteins into smaller proteins.  Enzymes that do this are called proteases.  One of the enzymes 
of HIV is a protease, and it cleaves several HIV proteins into smaller proteins. 

Why is this important for the HIV virus?  After the HIV has entered a cell it needs to make more 
copies of itself.  To do this it makes three large "polyproteins".  One of the polyproteins, called 
"Pol", contains the protease.  The protease actually cleaves itself off the Pol protein.  The 
protease then goes on to cleave the Pol protein into three other smaller proteins.  

The HIV virus does this to add to the efficiency and regulation of protein production.  Study of 
the HIV virus revealed that the HIV protease was a critical component of the HIV life cycle and 
blocking it would block the virus. Thus there was a specific target for the development of anti-
HIV drugs.

After trying many possibilities, drugs called protease inhibitors, or PIs, were developed that 
blocked the HIV protease but not other cellular proteases.  These drugs are small protein-like 
molecules with non-cleavable bonds in place of the normal bonds.  That is, the PIs look like the 
protein that the protease cleaves, but the protease canít cleave them.  And not only that, the PIs 
bind tightly to the protease and don't let go.  That way, the protease is blocked from cleaving 
any more proteins.  Developing these PIs was a major success of structure-assisted drug design.

The first drugs to fight HIV were the reverse transcriptase inhibitors, or RT inhibitors.  These 
drugs were effective, but HIV often developed resistance to them.  In 1996 protease inhibitors 
were introduced.  But HIV could also become resistant to protease inhibitors.  But when RT and 
Protease inhibitors were combined, the likelihood of an HIV becoming resistant to both at the 
same time was much less.  With "triple therapy", usually two RT inhibitors and a protease 
inhibitor, the level of virus can be reduced to "undetectable".  It is not a total cure, but it does 
allow HIV to become a manageable disease.  Mike Conrad.

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