Parallel Monte Carlo Simulation of HIV Molecular Evolution in Response to Immune Surveillance - Parallel Computing for Bioinformatics and Computational Biology - page 34

applied at a specified rate by testing each nucleotide of proviral DNA for mutation. If
a nucleotide is to be mutated, it then changes to one of the three other nucleotides with
equal probability or with a specified bias. Recombination is applied at a specified rate
by testing each nucleotide of a randomly chosen member of a pair of RNA genome
copies for a recombination event. If a nucleotide is the site of a recombination event,
then the portions of the RNA sequences to the left of the nucleotide are swapped
between the RNA genome copies.

2.3.4 Fitness

The fitness of a virion is partitioned into two components. One component is based
on the optimality of the interaction of V3 with a chemokine coreceptor and is the
probability that a virion enters a cell ( W func , the functional component). The other
component is based on the resistance of V3 to neutralization by antibodies and is the
probability that a virion escapes neutralization ( W neut , the neutralization component).
Total fitness is the product of the probabilities of these two independent events:

W = W func W neut .

Relative fitness refers to the fitness of a virion relative to the highest fitness in the
population:

W
W max

W rel = .

As the protein structures of a virion may be translated from either, both, or neither
of the two proviruses from which the two copies of its RNA genome were transcribed
(assuming there were more than two proviruses present in the cell), in reality a virion
may carry several different V3 loops (as regions of gp120 molecules) on its surface.
Assuming that the probability of a virion escaping neutralization and infecting a cell is
limited by the V3 loop with the highest fitness, the V3 amino acid sequence assigned
to a virion in the model, and therefore the fitness of the virion, is that of the provirus
with the highest fitness in the cell.

2.3.4.1 V3 Functional Component of Fitness

Coreceptor Usage Phenotype The component of fitness based on the interac-
tion between V3 and a coreceptor is referred to as the functional component, W func ,
because it reflects the presumed function ofV3. W func depends on the coreceptor usage
phenotype of V3. Coreceptor usage may be predicted fromV3's amino acid sequence
because V3 sequences from virions using different coreceptors vary in the amino
acids present at some sites and in the frequencies of amino acids observed at other
sites (Fig. 2.3). The site-specific amino acid frequencies of V3 from virions that use
CCR5 (R5 phenotype), CXCR4 (X4 phenotype), and virions that use both coreceptors
(X4R5 phenotype) were calculated from alignedV3 sequences from patients infected