3rd Conf Retro and Opportun Infect. 1996 Jan 28-Feb 1;:166. Unique
HIV-1 protease enzyme mediates the cleavage of the viral polyprotein
precursors during maturation of the newly produced infectious virion;
inhibition of the enzyme results in the formation of non-infectious,
immature viral particles. Intensive research efforts over the last
decade have resulted in the discovery of many specific and potent
inhibitors. Within the past several years, a number of these compounds
have advanced to clinical evaluation. The in vivo antiviral activities
exhibited by the inhibitors have been variable, with effects ranging
from none to greater than 99% suppression of circulating HIV-1 RNA
levels. These variations have proven to be predominantly the result of
differences in bioavailability, pharmacokinetic and serum protein
binding characteristics. The profound viral suppression engendered by
the more potent inhibitors is usually accompanied by significant CD4
cell count elevations. These elevations are typically sustained even
when the inhibitor-mediated antiviral suppression is lost. The loss of
the suppression, when it occurs, is typically the result of selection
for HIV-1 isolates exhibiting reduced inhibitor susceptibility.
Considerable diversity has been noted in the frequency and timing of
this selection. The genetic basis of reduced susceptibility has been
extensively studied as has the potential for cross resistance among the
available inhibitors. The understanding derived from these studies has
important implications for the appropriate clinical use of protease
inhibitors, particularly with regard to potentially forestalling the
development of resistance.
Biological Availability CD4 Lymphocyte Count Drug Resistance,
Microbial HIV Protease/METABOLISM HIV Protease
Inhibitors/*PHARMACOLOGY/PHARMACOKINETICS HIV-1/DRUG
EFFECTS/*ENZYMOLOGY/ISOLATION & PURIF Hydrolysis RNA, Viral/BLOOD
ABSTRACT