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, 30 (1), 8-16

The High Cost of Fidelity


The High Cost of Fidelity

Sarah B Lloyd et al. AIDS Res Hum Retroviruses.


The notoriously low fidelity of HIV-1 replication is largely responsible for the virus's rapid mutation rate, facilitating escape from immune or drug control. The error-prone activity of the viral reverse transcriptase (RT) is predicted to be the most influential mechanism for generating mutations. The low fidelity of RT has been successfully exploited by nucleoside and nucleotide analogue reverse transcriptase inhibitors (NRTIs) that halt viral replication upon incorporation. Consequently, drug-resistant strains have arisen in which the viral RT has an increased fidelity of replication, thus reducing analogue incorporation. Higher fidelity, however, impacts on viral fitness. The appearance of compensatory mutations in combination with higher fidelity NRTI resistance mutations and the subsequent reversion of NRTI-resistant mutations upon cessation of antiretroviral treatment lend support to the notion that higher fidelity exacts a fitness cost. Potential mechanisms for reduced viral fitness are a smaller pool of mutant strains available to respond to immune or drug pressure, slower rates of replication, and a limitation to the dNTP tropism of the virus. Unraveling the relationship between replication fidelity and fitness should lead to a greater understanding of the evolution and control of HIV.


<b>FIG. 1.</b>
FIG. 1.
Detail of the structure of wild-type HIV-1 reverse transcriptase cross-linked to dsDNA and AZTppppA66 generated from the NCBI Structure database (MMDB ID:85000) using Cn3D. The main diagram shows the polymerase active site in detail, with the full structure in the insert. The amino acid residues described in Table 1 are in yellow. The green line depicts the position of the primer and the orange line the template. The upper left side pink domain depicts the “fingers,” the lower central pink domain is the “palm,” containing the active site, and the gray domain is labeled the “thumb.” Color images available online at
<b>FIG. 2.</b>
FIG. 2.
Hypothetical saturation curve for an enzyme reaction that gives the relationship between the catalytic constants Vmax and Km.

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