Site-Specific Amino Acid Frequency, Fitness and the Mutational Landscape Model of Adaptation in Human Immunodeficiency Virus Type 1

By Silva, Jack da | Genetics, November 2006 | Go to article overview

Site-Specific Amino Acid Frequency, Fitness and the Mutational Landscape Model of Adaptation in Human Immunodeficiency Virus Type 1


Silva, Jack da, Genetics


ABSTRACT

Analysis of the intensely studied HIV-1 gp120 V3 protein region reveals that the among-population mean site-specific frequency of an amino acid is a measure of its relative marginal fitness. This surprising result may arise if populations are displaced from mutation-selection equilibrium by fluctuating selection and if the probability of fixation of a beneficial amino acid is proportional to its selection coefficient.

(ProQuest Information and Learning: ... denotes formulae omitted.)

KNOWING the effect on fitness of every amino acid at every site of a protein would greatly facilitate the study of adaptive evolution at the molecular level. Such data would help determine the frequency distribution of fitness effects of newbeneficial mutations, which is key to understanding the dynamics of adaptation (ORR 2002), allowprotein variation tobemore easily interpreted, and allow the realistic simulation of protein evolution. But, such data are difficult to obtainempiricallyandare therefore not available for any protein. However, for human immunodeficiency virus type 1 (HIV-1) proteins, amino acid site-specific frequencies calculated across virus populations infecting different patients appear to correlate with the marginal fitness effects of the amino acids (HUNG et al. 1999; REZA et al. 2003), suggesting a simple method of estimating the site-specificmarginal fitnesses of amino acids.

HIV-1 third variable region: I investigated this correlation using sequence data from the third variable region (V3) of the HIV-1 exterior envelope glycoprotein (gp120), located on the surface of the virus particle (virion). V3 is themain determinant of which one of two cell-surface chemokine receptors (CCR5 or CXCR4) is used by a virion as a coreceptor to enter a cell, which determines the type of cell infected (SPECK et al. 1997). V3 also modulates the use of each coreceptor (DE JONG et al. 1992; HUNG et al. 1999) and thereby affects the ratelimiting step in cell entry (PLATT et al. 2005). Finally, V3 is also the main target of antibodies that interfere with cell entry (ZOLLA-PAZNER 2004). Because of its critical function and its exposure to neutralizing antibodies, V3 has been the focus of intense study, resulting in the data necessary to test the correlation.

Site-specific marginal fitness: Data on V3 site-specific fitness effects of amino acids are available from a study that employed site-directed mutagenesis to modify the amino acid at V3 site 25 (HUNG et al. 1999). This study measured the effects of different amino acids at site 25 on the number of cells infected (infectivity) in a standardized assay. Note that infectivity is the appropriate measure of the effect of V3 on fitness under the assay conditions; the sole function of V3 appears to be in cell entry, and this component of fitness is unlikely to trade off against the remaining components of fitness, such as the rate of viral genome integration into the host cell genome, the rate of provirus (integrated viral genome) replication, and virion budding, which are controlled by other viral proteins (COFFIN 1999). The site-directed mutagenesis study was conducted using CCR5-utilizing HIV-1 of subtype B, the phylogenetic clade most common in Europe and North America and the most sequenced and studied.

Site-specific amino acid frequency: I calculated site-specific frequencies of subtype B V3 amino acids for the viral population infecting a patient and then averaged frequencies across patients. Among-population means of frequencies were used because the site-specific frequency of an amino acid in any one population is expected to be dynamic, being dependent on the population's level of adaptation, and thus a poor predictor of the amino acid's marginal fitness. This procedure was repeated for each of the three coreceptor usage viral phenotypes: exclusively CCR5 utilizing (R5) (269 sequences from 58 patients), exclusively CXCR4 utilizing (X4) (109 sequences from11 patients), and dual coreceptor utilizing (R5X4) (60 sequences from16 patients). …

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