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Cloettapreis_2004_Nr_32

logical terms, fitness is best described by the relative replication rates of viruses in competition kinetics (Bleiber, 2001b). Adaptation to drug pressure. Although the fitness of resistant HIV-1 strains overlaps that of susceptible clinical isolates, resistant strains are overall less infectious and replication competent (Telenti, 1999, Kaufmann, 2000, Bleiber, 2001a, Bleiber, 2001b). Mutations selected by reverse transcriptase (RT) and protease (PR) inhibitors frequently involve changes of enzyme active site residues. Reduction in primer extension activity by mutant RT has been demonstrated in vitro (Back, 1996, Back, 1997). Mutant PR enzymes exhibit diminished catalytic efficiency in the processing of viral Gag and Gag-Pol polyproteins (Schock, 1996, Zhang, 1997, Rayner, 1997, Croteau, 1997, Carrillo, 1998). These modifications in enzyme processivity may translate into the accumulation of immature viral particles. Kinetic analysis of con- secutive proteolytic cleavages of the Gag-Pol polyprotein suggests that HIV-1 would cease being viable when the efficiency of a mutant pro- tease is less than 61% of the wild type activity for each step of cleavage (Rasnick, 1997). Mutation in both PR and RT can contribute to dimin- ished viral fitness, and either enzyme may display a profound impair- ment (Bleiber, 2001a). Resistance to HIV-1 fusion inhibitors is also associated with impaired fitness, while resistance to non-nucleoside reverse transcriptase inhibitors (NNRTI) modifies viral physiology only minimally (Schmit, 1996, Rayner, 1997). This has been attributed to drug binding remote from the RT active site (Esnouf, 1995), and explains the occasional identification of NNRTI resistance mutations as natural polymorphisms (Havlir, 1996). Given the remarkable plasticity of the HIV-1 genome, selection of com- pensatory mutations leading to improving enzyme function takes place. This process involves structurally relevant amino acid substitutions in tar- get enzymes (e.g., in the hinge or flap regions of the viral protease) (Schock, 1996, Borman, 1996), changes that improve processing of enzyme substrate (e.g., Gag cleavage sites) (Doyon, 1996, Zhang, 1997, Carrillo, 1998, Bally, 2000), or by compensation at distance (Nijhuis, 1999, Peters, 2001). However, these pathways of compensation may not provide an immediate or full remediation of viral fitness deficits (Mammano, 1998) 17

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