[theory.bio.uu.nl]

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The Role of CD8 immune responses in HIV
infection
Tendai Mugwagwa
Supervisor: Dr. Gareth Witten.
(University of Cape Town)
An essay submitted in partial fulfilment of the requirements for AIMS Diploma in
Mathematical Sciences.
May 2004.
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Acknowledgements
I would like to thank the following for their contribution in the success of this essay : Dr
Gareth Witten (My supervisor), Dr Mike Pickles, Carl Scheffler and Prof Wesley Kotze. I
am grateful to Prof Neil Turok, Prof Fritz Hahne and all my lecturers at AIMS in 2003-2004
for helping me through an exciting mathematical journey and the discovery of my passion for
epidemiology. I would also like to thank the sponsors of AIMS and all its collaborators for
making all this possible. Lastly I dedicate this essay to my family for their unconditional love
and encouragement. Thank you Mom.
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Abstract
Mathematical models and experiments have shown the importance of CD8 responses in control
of HIV infection. In this paper we review the theoretical and empirical evidence and how the
two compliment each other as they shed more light on the progression of HIV infection. This
paper also highlights the controversies pertaining the subject. We present some models that
investigate the role of a CTL response and a CTL memory in control of HIV. These models
show that a strong CTL response can control the viral load, however, in some cases the virus
has been known to persist regardless of the immune response. We extend the basic immune
response model to account for the escape of HIV from CTL responses via epitope mutations.
We find that a broad and long lived CTL response efficiently controls the virus even in the event
of mutations. On the other hand, a gradual switch from a slow replicating HIV strain to a faster
replication kinetics, has also been suggested as amechanism fordisease progression. To explore
the factors influencing this switch, we extend the CTL memory model to include macrophage
cells, non-lytic CD8 responses and the evolution of HIV from a slow replicating strain(R5)
towards a faster replicating strain (X4). We find that macrophages act as a reservoir for the virus
hence promote viral persistence. However in the course of the infection, the success of a switch
from the R5 strain to the X4 strain dependson the cytopathicity of the individual strains. The
cytopathicity, evolution rate, infection rate and the strength of the immune response determine
the time lapse before a switch occurs. We conlude that these factors determine the length of the
asymptomatic period of HIV infection.

Contents
Abstract 2
1 Cellular immune response and disease progression 2
1.1 The stages of HIV infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
1.2 Dynamics of HIV infection and the role of CD8 cells. . . . . . . . . . . . . . . 4
1.3 The role of CTLs in HIV infection . . . . . . . . . . . . . . . . . . . . . . . . 6
1.4 Lytic and non-lytic CD8 responses . . . . . . . . . . . . . . . . . . . . . . . . 13
2 Examples of mathematical models for the interaction between CD8 cells and HIV 18
2.1 The Basic model . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.2 The effect of Immune response on viral dynamics . . . . . . . . . . . . . . . . 20
2.3 CTL memory and viral dynamics . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.4 Multiple epitopes and viral dynamics . . . . . . . . . . . . . . . . . . . . . . . 27
3 Gradual evolution of HIV as a mechanism for disease progression 32
3.1 Developments of the model . . . . . . . . . . . . . . . . . . . . . . . . . . . . 33
3.2 Results and analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 35
3.3 Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 40
4 Conclusions 43
Bibliography 44
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Chapter 1
Cellular immune response and disease
progression
HIV is a retrovirus which means that its genome is RNA and is translated into DNA during its
life cycle. HIV attaches itself to target cell using a coreceptor (CCR5 or CXCR4). It then gains
entry into the target cell and uses its machinery to complete its life cycle however destroys
them in the process. Target cells include macrophages and T cells. A healthy human adult
has about 1000 CD4 cells per micro litre of blood, but in an infected patient, the CD4 count
can drop to lower levels. Currently, if a patient has a CD4 count of below 200 CD4 cells per
micro litre, he or she is said to have AIDS. Like any other pathogen, invasion of the body by
HIV stimulates an immune response. Although there is a wide range of immune responses, we
will focus on T helper cells and CD8 cells, also known as cytotoxic T lymphocytes (CTLs).
CD8 cells control the virus by either lysing the infected cell or inhibiting HIV replication and
entry into target cells. It is unfortunate that the main target cell of HIV are CD4 cells because
these play a major role in fighting viral infections [49]. In this chapter we review models and
experimental evidence that has been presented to explain the relationship between CD8 cells
and disease progression.
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