MATH35032: Mathematical Biology Coursework

Due by 3:00 PM, Friday 18 March 2016

Please write out answers to the following problems and hand them in, along with by a standard
Cover Sheet, at the reception desk of the Alan Turing Building.

HIV viral dynamics

HIV-1, the virus responsible for the current AIDS pandemic, attacks many kinds of cells in the
body, but its major target is a particular family of white blood cells, the CD-4+ T-lymphocytes or
helper T-cells whose destruction leads to the comprehensive failure of the immune system that
characterises full-blown AIDS. The typical course of untreated HIV infection is sketched in the
following passage, which Ive abridged from a recent book by Steve Ellner and John Guckenheimer1
Disease progression after HIV infection, if untreated, has three phases. An initial acute
phase is marked by high viral loads and flu-like symptoms. The second phase is largely
asymptomatic: viral loads fall to a quasi-steady-state and remain there for a period of
a few months to a decade. During this time T-cells slowly decline. Finally, there is
immune system failure followed by death from opportunistic infections.

This same progression is sketched2 in greater detail in in Figure 1 and both accounts prompt the
question: What is happening during the long, asymptomatic phase?

Eclipse Fiebig Stages

Phase I II III IV V VI
vRNA + Eclipse 10 d
p24Ag + I 7d
II 5d
Plasma virus RNA (copies/ml)

ELISA + III 3d
Western blot +/- IV 6d
106 V 70 d
Western blot + (p31-)
VI open-ended
105
Western blot + (p31+)
104

103

102 Plasma vRNA cut-off

101

10 20 30 40 50 100
Days following HIV-1 transmission

Figure 1: The stages of early HIV infection as definedin terms of standard diagnostic testsby
Eberhard Fiebig and his collaborators. The solid curve shows a measure of the concentration of
circulating virus that rises to a sharp peak in the first weeks after infection, then falls back to a
steady level that persists throughout the long intermediate phase of the disease, Fiebig stage VI.

1 Ellner and Guckenheimer (2006), Dynamic Models in Biology, Princeton University Press.
2 The figure is derived from one in Keele et al. (2008), Identification and characterisation of transmitted and
early founder virus envelopes in primary HIV-1 infection, Proc. Natl Acad. Sci. USA, 105(21):75527557. DOI:
10.1073/pnas.0802203105. The Fiebig stages were defined in Fiebig et al. (2003), Dynamics of HIV viremia and
antibody seroconversion in plasma donors: implications for diagnosis and staging of primary HIV infection, AIDS,
17(13):18711879.
 The advent of effective anti-HIV drugs in the mid-1990s, in combination with mathematical
modelling, produced a surprising answer to this question. The virus is reproducing and evolving
at a tremendous rateso fast that the virologist John Coffin has estimated3 that each and every
single-point mutation (in HIV) occurs between 104 and 105 times per day in an infected individual.
The same models, some of which we will study, helped motivate the multi-drug therapies that are
now the standard treatments for HIV.

Mathematical models
All the models discussed below concern HIV infection within a single patient and are treated in
much greater detail in a review article by Alan Perelson and Patrick Nelson4 . The simplest one
involves three populations: target cells T , productively infected cells I (after infection, but before
death, these cells produce virus) and virions (virus particles) V . These evolve according to the
ODEs
 
dT T
= s + rT T 1 kV T dT T
dt K
dI
= kV T dI I
dt
dV
= rV I cV. (1)
dt
All the parameters are positive real numbers and have the following interpretations:
s is the rate at which new target cells are created from other cells within the body;
rT and K are the parameters of a logistic growth term describing proliferation of target cells;
k is the rate parameter of a mass-action term describing the process of infection;

dT and dI are death rates for respectively, target cells and infected cells;
rV is the rate of virus production by infected cells;
c is the rate at which viruses are cleared from the blood stream.

Two kinds of drugs

Viruses reproduce by hijacking the machinery of the cells they infect and using it to produce
viral proteins and genetic material. HIV is a retrovirus, which means that it carries its genetic
information in RNA molecules, as opposed to the DNA used by its target cells. Retroviruses rely
on a special enzyme, reverse transcriptase (RT), to convert their RNA into DNA molecules that
the target cells machinery can interpret and this makes RT an attractive drug target: if a drug
can disable reverse transcriptase, it cripples the virus without affecting normal human cells at all.
Such drugs are called reverse transcriptase inhibitors (RTIs) and in terms of the model sketched
above, they act by disrupting the process that converts target cells into infected ones. Thus the
introduction of an RTI modifies only the second equation in the system equations (1), changing it
to
dI
= (1 R )kV T dI I (2)
dt
where 0 < R 1 is a measure of the inhibitors effectiveness: R = 1 corresponds to perfect
inhibition.
3 Coffin (1995), HIV population dynamics in vivo: implications for genetic variation, pathogenesis, and therapy,

Science, 267:483489. DOI: 10.1126/science.7824947

4 Perelson and Nelson (1999), Mathematical Analysis of HIV-1 Dynamics in Vivo, SIAM Review, 41(1):344.

DOI: 10.1137/S0036144598335107
 A second family of drugs, the protease inhibitors (PI), act more subtly: they cause infected
cells to produce malformed viruses that cannot go on to infect further targets. To model the action
of these drugs we need to introduce a second viral population N , the non-infectious virions. The
system (1) then becomes
 
dT T
= s + rT T 1 dT T kV T
dt K
dI
= kV T dI I
dt
dV
= (1 P )rV I cV
dt
dN
= P rV I cN (3)
dt
where 0 < P 1 is, as above, a measure of the drugs effectiveness.

Warning Against Plagiarism

Plagiarism is the presentation of other peoples work as your own. It is both dishonest and unfair
to other students. The University takes plagiarism very seriously and so will I: if your coursework
submission contains material copied without proper attribution from textbooks (including Mur-
rays), Wikipedia or other web sites or any other source except the lecture notes, problem sets and
solutions from this module, I will refer you to the Schools Academic Malpractice Panel. Standard
penalties include a mark of zero for the entire coursework. If you are unsure whether or how to
acknowledge a source that you have used, please consult the Schools Undergraduate Handbook5
or check with me well before the due date.
5 See the Schools Undergraduate Handbook page on academic malpractice.
Problems
You may find it helpful to look at Chapter 10 of Murrays bookespecially his Sections 10.5 and
10.6while working on these problems. There are a number of misprints, and notation used here
differs from his, but the basic analysis is the same.

(1) (Dimensionless form) Show that by a suitable change of variables one can reduce the
system (1) to the form

x = + x (1 x) xv 1 x
y = xv 2 y
v = y 3 v. (4)

where the dots on the left hand side indicate differentiation with respect to the dimensionless time
variable . Your answer should include expressions for , and the j in terms of the parameters
of (1).

(2) (Two important equilibria) Find equilibria of (4) that correspond to the following condi-
tions.
(a) A person who has never been exposed to HIV and so has no virus and no infected cells.
(b) An untreated patient in the long asymptomatic phase of the disease, Fiebig Stage VI, who has
constant, nonzero levels of T , I and V . Ill refer to this untreated equilibrium as (x0 , y0 , v0 ).

(3) (RTI therapy) Now consider what happens when a patient begins drug treatment.
(a) Explain how treatment with a reverse transcriptase inhibitor modifies the model (4).
(b) The ODEs describing treatment with RTIs have an equilibrium with x > 0 and y = v = 0.
Analyse the stability of this equilibrium for all values of R .

(4) (Multi-drug therapy) Finally, consider treatment with both a protease inhibitor and a
reverse transcriptase inhibitor.
(a) Write down the analogue of the system (3) for treatment with both types of drug and show
that it can be reduced to

x = + x (1 x) xv 1 x
y = (1 R )xv 2 y
v = (1 P )y 3 v
n = P y 3 n (5)

(b) The system (5) has an equilibrium with x = x? > 0 and y = v = n = 0. Show that it is
stable provided
x0
(1 R )(1 P ) < ,
x?
where x0 is as in Problem 2(b) above.
(c) Given that Fiebig stage VI patients typically have x0 /x? 0.2, determine which combinations
of drug effectiveness (R , P ) lead to successful therapy.