Modeling HIV quasispecies evolutionary dynamics

Sguanci Luca, Bagnoli Franco, Liò, Liò Pietro

Description

During the HIV infection several quasispecies of the virus arise, which are able to use different coreceptors, in particular the CCR5 and CXCR4 coreceptors (R5 and X4 phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster progression of the disease to the AIDS phase. As several pharmaceutical companies are starting large phase III trials for R5 and X4 drugs, models are needed to predict the co-evolutionary and competitive dynamics of virus strains. Results We present a model of HIV early infection which describes the dynamics of R5 quasispecies and a model of HIV late infection which describes the R5 to X4 switch. We report the following findings: after superinfection (multiple infections at different times) or coinfection (simultaneous infection by different strains), quasispecies dynamics has time scales of several months and becomes even slower at low number of CD4+ T cells. Phylogenetic inference of chemokine receptors suggests that viral mutational pathway may generate a large variety of R5 variants able to interact with chemokine receptors different from CXCR4. The decrease of CD4+ T cells, during AIDS late stage, can be described taking into account the X4-related Tumor Necrosis Factor dynamics. Conclusion The results of this study bridge the gap between the within-patient and the inter-patients (i.e. world-wide) evolutionary processes during HIV infection and may represent a framework relevant for modeling vaccination and therapy.

Informations

• Publié par: biomed
• Publié le: 01 janvier 2007
• Nombre de lectures: 6
• Langue: English

Extrait

BioMed CentralBMC Evolutionary Biology
Open AccessResearch
Modeling HIV quasispecies evolutionary dynamics
1,2 1,3,4 2Luca Sguanci , Franco Bagnoli and Pietro Liò*
1 2Address: CSDC, Center for the Study of Complex Systems, Firenze, Italy, Computer Laboratory, University of Cambridge, CB3 0FD Cambridge,
3 4UK, Dipartimento di Energetica, Università di Firenze, Via S. Marta 3, 50139 Firenze, Italy and INFN, sezione di Firenze, Italy
Email: Luca Sguanci - [e-mail]; Franco Bagnoli - [e-mail]; Pietro Liò* - [e-mail]
* Corresponding author
from Second Congress of Italian Evolutionary Biologists (First Congress of the Italian Society for Evolutionary Biology)
Florence, Italy. 4–7 September 2006
Published: 16 August 2007
BMC Evolutionary Biology 2007, 7(Suppl 2):S5 doi:10.1186/1471-2148-7-S2-S5
<supplement> <title> <p>Second Congress of Italian Evolutionary Biologists (First Congress of the Italian Society for Evolutionary Biology)</p> </title> <editor>Renato Fani, David Caramelli, Pietro Liò</editor> <sponsor> <note>The supplement organisers would like to acknowledge the following organisations for their financial support of the meeting: Ente Cassa di Risparmio di Firenze, Sarstedt, CelBio, Università degli Studi di Firenze.</note> </sponsor> <note>Research</note> <url>http://www.biomedcentral.com/content/pdf/1471-2148-7-S2-info.pdf</url> </supplement>
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© 2007 Sguanci et al; licensee BioMed Central Ltd.
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Abstract
Background: During the HIV infection several quasispecies of the virus arise, which are able to
use different coreceptors, in particular the CCR5 and CXCR4 coreceptors (R5 and X4
phenotypes, respectively). The switch in coreceptor usage has been correlated with a faster
progression of the disease to the AIDS phase. As several pharmaceutical companies are starting
large phase III trials for R5 and X4 drugs, models are needed to predict the co-evolutionary and
competitive dynamics of virus strains.
Results: We present a model of HIV early infection which describes the dynamics of R5
quasispecies and a model of HIV late infection which describes the R5 to X4 switch. We report the
following findings: after superinfection (multiple infections at different times) or coinfection
(simultaneous infection by different strains), quasispecies dynamics has time scales of several
months and becomes even slower at low number of CD4+ T cells. Phylogenetic inference of
chemokine receptors suggests that viral mutational pathway may generate a large variety of R5
variants able to interact with chemokine receptors different from CXCR4. The decrease of CD4+
T cells, during AIDS late stage, can be described taking into account the X4-related Tumor
Necrosis Factor dynamics.
Conclusion: The results of this study bridge the gap between the within-patient and the
interpatients (i.e. world-wide) evolutionary processes during HIV infection and may represent a
framework relevant for modeling vaccination and therapy.
tor vital for the entry into the target cell. Human immun-Background
The relationship between phenotype and survival of the odeficiency virus type 1 (HIV-1) infection is characterized
genotype is central to both genetics and evolution. Viruses by the progressive loss of CD4+ T cells. Infection by most
represent a good sized-complexity phenotype to study strains of HIV-1 requires interaction with CD4 and a
and they show rapid evolution. Selection pressures chemokine receptor, either CXCR4 or CCR5. During early
mainly depend on the interaction strength with the recep- stages of HIV-1 infection, viral isolates most often use
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CCR5 to enter cells and are known as R5 HIV-1. Later in and of co-infection (simultaneous infection),
superinfecthe course of HIV-1 infection, viruses that use CXCR4 in tion (delayed secondary infection) and selection, that
addition to CCR5 (R5X4) or CXCR4 alone (X4 variants) keep variability low. HIV-1-infected individuals show
hetemerge in about 50% patients (switch virus patients) erogeneous viral populations, best described as viral
qua[1,2]. These strains are syncytium-inducing and are capa- sispecies [16]. Infact, the infection capacity of mutants
ble of infecting not only memory T lymphocytes but also may vary and also their speed of replication [17].
naive CD4+ T cells and thymocytes through the CXCR4
coreceptor. The switch to using CXCR4 has been linked to Moreover, since the number of targets (the substrate) is
an increased virulence and progression to AIDS, probably limited, fitter clones tend to eliminate less fit mutants,
through the formation of cell syncytia and apoptosis of T which are subsequently regenerated by the mutation
cell precursors. X4 HIV strains are rarely, if ever, transmit- mechanism. Mutations are a key ingredient for exploring
ted, even when the donor predominantly carries X4 virus. the genetic space in the search for the fitness maximum,
Clevestig [3] found that in children, the X4 virus devel- but are also responsible for the disappearance of the
quaoped from their own R5 population, and was not caused sispecies when exceeding a critical mutation rate, the error
by transmission from the mother. CXCR4 is expressed on threshold [18].
a majority of CD4+ T cells and thymocytes, whereas only
about 5 to 25% of mature T cells and 1 to 5% of thymo- Taking into account state-of-the-art models of HIV
infeccytes express detectable levels of CCR5 on the cell surface tion, we address the issue of studying the coevolutive and
[4]. It is noteworthy that X4 HIV strains stimulate the pro- competitive dynamics of different strains of HIV-1 virus
duction of cellular factor called Tumor Necrosis Factor also leading to the R5 to X4 phenotype switching. Ribeiro
(TNF), which is associated with immune hyperstimula- and colleagues [19] have recently presented a model of R5
tion, a state often implicated in T-cell depletion [5]. to X4 switch based on the hypothesis that X4 and R5
viruses have a preferential tropism for naive and memory
Tumor necrosis factor (TNF)-related apoptosis-inducing T cells, respectively. Here we prefer to follow the
mutaligand (TRAIL) is produced mainly by monocytes; it is a tional hypothesis supported by several experiments [1-4].
type II transmembrane protein belonging to the TNF fam- In the next section we introduce two models: a
quasispeily, homologous to Fas ligand (FasL), which is a well-char- cies model for R5 phase in which several R5 strains appear
acterized apoptosis-inducing ligand. In particular the Fas- by mutations, co-infection and superinfection. In the
associated domain or a Fas-associated domain-like adap- limit of a single quasispecies we are able to find the same
tor molecule leads to activation of the caspase cascade, values observed experimentally and in other models
resulting in apoptotic cell death. TNF seems able to both (most notably Perelson's standard model). We test the
inhibit the replication of R5 HIV strains while having no model in the scenarios of co-infection and superinfection
effect on X4 HIV and to down regulate the number of using parameters derived from biological and medical
litCCR5 co-receptors that appear on the surface of T-cells erature. A second model focuses on the R5 to X4 shift and
[6]. Plasma TRAIL is elevated in HIV-1 infected patients the hyperstimulation of T cell precursors through TNF.
and is decreased by Highly Active Anti Retroviral Therapy The results of the numerics reproduce well the decreasing
(HAART). Thus, when HAART decreased viral load, there dynamics of CD4+ after the appearance of X4 strains and
is a concomitant decrease in plasma TRAIL, which may be make the model suitable for further investigations on
one of the reasons for the efficacy of antiviral therapy [7]. antiretroviral therapies and their effects on disease
progression. The R5 to X4 switch is also investigated by using
Mathematical modeling phylogenetic models of the amino acid sequences of the
The use of mathematical models is an insightful and human and mice chemokine receptor families. The
analyessential complement to in vivo and in vitro experimental sis of the mutational pathway suggests that the switch
design and interpretation. Indeed mathematical models from R5 to X4 may allow the HIV to bind to other
chemof HIV dynamics have proven valuable in understanding okine receptors, thus likely leading to immune system
sigthe mechanisms of many of the observed features of the naling disfunctions.
progression of the HIV infection, see for example [8-15].
Results and discussion
A powerful concept in understanding HIV variability and Modeling HIV dynamics and the immune response
its consequences is that of quasispecies, accounting for the The basic model of HIV-1 dynamics, first introduced by
result of evolution not being the selection of a single Perelson and colleagues in 1995 [8], is a class model
consequ