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Biochemical data show that HIV-1 replicates extremely rapidly in infected individuals and that the viral
load is low in the early stages of the disease because the host immune system is initially successful in
limiting viral replication [28,29]. When patients are treated with either RT and/or protease inhibitors,
wild-type HIV-1 is rapidly replaced with drug-resistant variants. In fact, even in patients who have not
received treatment with any anti-RT drugs, HIV-1 variants that contain residues corresponding to both
NRTI- and NNRTI-resistance mutations in RT can be found as minor components of the viral
population [129]. Similarly, viral variants that contain residues in protease sequence corresponding to
protease inhibitor drug-resistance mutations have also been observed in patients prior to drug therapy
(see review [130]). Enzymatic components found in a wild-type virus, such as RT or protease, are
optimized for efficient viral replication [30]. In the absence of selective pressure (drug), the wild-type
virus has a fitness advantage over drug-resistant viral variants. However, in the presence of drugs, drugresistant
variants have a fitness advantage over the wild-type because the drug impairs efficiency of the
target enzyme in the wild-type virus [30].
Binding of an NRTI or an NNRTI to wild-type HIV-1 RT interferes with the polymerization reaction.
However, the presence of resistant variants in the population allows the virus to escape, and the variants
to rapidly replace the wild-type virus. Nevertheless, this escape has a price. When the optimized wildtype
virus is replaced by the less fit drug-resistant variants, the relative fitness of the virus decreases. In
other words, the enzymatic efficiency of a drug-resistant HIV-1 RT variant is impaired relative to the
wild-type enzyme (see review [131]). If the enzymatic efficiency of a drug-resistant viral variant is
sufficiently impaired, the replication of the variant virus would be significantly decreased. Thus, an
antiviral drug will be useful not because it would completely stop the growth of HIV-1 but because it
selects viral variants whose replication is significantly impaired. Positive clinical benefit results from the
fact that the viral load is decreased owing to reduced replication of the variant virus. As predicted by this
model, some HIV-1 RT and protease inhibitors seem to select for relatively less fit drug-resistant
variants. For example, treatment of HIV-1 infection with HBY 097, a quinoxaline inhibitor, induces
development of an HIV-1 RT variant containing the Gly190Glu mutation that appears to have
substantially decreased polymerase activity and replicates relatively slowly [22,84]. Replacement of the
hydrogen atom of Gly190 with an acidic side chain of Glu190 in the hydrophobic NNIBP apparently
interferes with the stability of the enzyme as well as the ability of the NNIBP to bind a hydrophobic
inhibitor. The relative inefficiency of HIV-1 variant containing the Gly190Glu mutation in RT can be
viewed as a positive outcome of the selection pressure provided by this particular inhibitor. However,
most of the HIV-1 variants selected by
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