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Chapter 9
Simulation of HIV-1 Molecular Evolution in Response
to Chemokine Coreceptors and Antibodies
Jack da Silva
School of Molecular and Biomedical Science, The University of Adelaide, Adelaide, SA5005,
Australia, jack.dasilva@adelaide.edu.au
Abstract.
The form of the neutralizing antibody response to human immunodeficiency virus
type 1 (HIV-1) and the evolutionary response by the virus are poorly understood. In order for
a virus particle (virion) to infect a cell, exterior envelope glycoprotein (gp120) molecules on
the virion's surface must interact with receptors on the cell's surface. Antibodies that bind to
gp120 may neutralize a virion by interfering with these interactions. Therefore, gp120 is ex-
pected to evolve in response to selection by both cell-surface receptors and antibodies. The
rate of such adaptation and the constraints imposed by a response to one selective force on the
response to the other are unknown. Here, I describe a simulation modeling approach to these
problems. The population of viral genomes infecting a single patient is represented by the
intensely studied third variable (V3) region of gp120, the main determinant of which
chemokine coreceptor a virion uses to enter a cell, and an important target of neutralizing
antibodies. Mutation and recombination are applied by realistically simulating the viral repli-
cation cycle. Selection by chemokine coreceptors is simulated by taking advantage of the fact
that mean site-specific amino acid frequencies are measures of the site-specific marginal
fitnesses of amino acids in relation to coreceptor interactions. Selection by antibodies is im-
posed by simulating the affinity maturation of B-cell lineages that produce neutralizing anti-
bodies to HIV-1 V3. These simulations make clear predictions about the functional cost
of adaptation to antibody surveillance, which may help explain the pattern of chemokine
coreceptor usage by HIV-1.
9.1 Introduction
Understanding the immunology and evolution of infectious disease is not only a
fundamental requirement of the successful treatment and prevention of disease, it
also provides an exceptional opportunity to study adaptive evolution at the molecu-
lar level
(Frank 2002). Arguably, the main barrier to the development of an effec-
tive vaccine against infection by human immunodeficiency virus type 1 (HIV-1) is
our lack of detailed understanding of the process by which the virus adapts to im-
mune surveillance. We lack an understanding of how viral mutation, recombination,
cell superinfection, and protein structural and functional constraints affect HIV's
