ABSTRACT
Sequel to the earlier works by Omenyi et al which established the role of surface
thermodynamics in various biological processes from the electrostatic repulsion and van der
Waals attraction mechanisms, HIV-blood interactions were modeled. This involved the use of
the Hamaker coefficient approach as a thermodynamic tool in determining the interaction
processes. It therefore became necessary to apply the Lifshitz derivation for van der Waals forces
as an alternative to the contact angle approach which has been widely used in other biological
systems. The methodology involved taking blood samples from twenty HIV-infected persons and
from twenty uninfected persons for absorbance measurement using Ultraviolet Visible
Spectrophotometer (Ultrospec3100pro). From the absorbance data various variables (e.g.
dielectric constant, etc) required for computations with the Lifshitz formula were derived. CD4
counts using the digital CD4 counter were also obtained. Due to the very large body of data
involved, MATLAB software tools were employed in solving the ensuing mathematics. The
Hamaker constants A11, A22, A33 and the combined Hamaker coefficients A132 were obtained
using the values of the dielectric constant together with the Lifshitz equation. The harmonized
Hamaker coefficients A132har and the absolute combined Hamaker coefficient, A132abs (an integral
of all the values of the various Hamaker coefficients) for the infected blood samples were then
calculated. The value of A132abs = 0.2587×10-21Joule (i.e. 0.2587×10-14erg) was obtained for HIVinfected
blood. This value lies within the range of values derived by various researchers for other
biological systems. Another significance of this result is the positive sense of the absolute
combined Hamaker coefficient which implies net positive van der Waals forces indicating an
attraction between the virus and the lymphocyte. This in effect suggests that infection has
occurred thus confirming the role of this principle in HIV-blood interactions. A lower value of
A131abs = 0.1026×10-21 Joule obtained for the uninfected blood samples is also an indicator that a
zero or negative absolute combined Hamaker coefficient is attainable. A mathematical model for
the HIV-blood interaction mechanism was developed from the principle of particle-particle
interaction mechanism. To propose a solution to HIV infection, it is necessary to find a way to
render the absolute combined Hamaker coefficient A132abs negative. As a first step to this, a
mathematical derivation for A33 ≥ 0.9763×10-21Joule which satisfies this condition for a negative
A132abs was obtained. To achieve the condition of the stated A33 above with possible additive(s)
in form of drugs to the serum as the intervening medium will be the next step. This forms part of
the suggested areas for further research.
vii
TABLE OF CONTENTS
Page
CERTIFICATION ii
APPROVAL iii
DEDICATION iv
ACKNOWLEDEMENT v
ABSTRACT vi
TABLE OF CONTENTS vii
LIST OF FIGURES xi
LIST OF TABLES xiv
SYMBOLS xxii
CHAPTER ONE 2
INTRODUCTION 3
1.1 Rationale 3
1.2 Background to Study 3
1.3 Statement of Problem 9
1.4 Objective of The Study 9
1.5 Scope and Limits of the Study 9
CHAPTER TWO 11
2.0 LITERATURE REVIEW 12
2.1 The Role of Surface Thermodynamics in Thromboresistance of Biomaterials 12
2.2 Adhesion of Platelet to a Homogeneous Solid Surface 12
2.3 Adhesion of Platelet in the Absence of Proteins 14
2.4 Adhesion of Platelet in the Presence of Proteins and Non-ideal Surfaces 15
2.5 Use of Critical Surface Tension of Wetting 15
viii
2.6 Empirical Correlations between Surface Tension and Quantities Related to
Thromboresistance 16
2.7 Measurement of Surface Tensions of Blood Cells and Proteins 17
2.8 Repulsive Van Der Waals Interactions: Their Role in Various Seperation Methods19
2.9 Separation of Proteins by Hydrophobic Chromatography 20
2.10 Separation of Antigens and Antibodies 22
2.11 Hydrophobic Chromatography of Cells 24
2.12 Recent Works on HIV-Blood Interactions 25
2.13 Conclusion 26
CHAPTER THREE 27
THEORETICAL CONSIDERATIONS 28
3.1 Concept of Interfacial Free Energy 28
3.2 The Thermodynamic Approach to Particle-Particle Interaction 28
3.3 Relationship between Hamaker Coefficients and Free Energy of Adhesion ΔFadh 35
3.4 Experimental Evidence for van der Waals Repulsion 36
3.5 Conclusion 37
CHAPTER FOUR 38
RESEARCH METHODOLOGY 39
4.1 Introduction 39
4.2 Sample Collection 39
4.3 Sample Preparation 39
4.4 Measurements 39
ix
4.5 Conclusion 40
CHAPTER FIVE 41
DATA ANALYSIS 42
5.1 Introduction 42
5.2 Relevant Mathematical Applications 42
5.3 Comparison between the Peak Absorbance Values of HIV Positive and Negative
Blood Components 50
5.4 Computation of the Hamaker Coefficients 50
5.5 Mathematical Model for the Interactions between the Lymphocyte and the Virus 57
5.6 Deductions for the Absolute Combined Hamaker Coefficient A132abs 59
5.7 Deductions for the Absolute Combined Negative Hamaker Coefficient 59
CHAPTER SIX 62
CONCLUSION AND RECOMMENDATION 63
6.1 Conclusion 63
6.2 Recommendation 63
REFERENCES 65
APPENDICES Appendices 1-70
x
LIST OF FIGURES
Page
Fig.1.1: Human Immunodeficiency Virus (HIV) Anatomy 4
Fig.1.2: Interaction of a Dendritic Cell having HIV bound to its surface
With a Lymphocyte 5
Fig. 2.1: Process of Platelet Adhesion to a Surface 13
Fig. 2.2: Dependence of ΔFadh on γsv (A: γlv > γpv, B: γlv < γpv) 14
Fig. 3.1: Schematic Diagram Showing Application of a Force on a Surface 28
Fig. 3.2: Attraction of Surface Molecules by Bulk Molecules in a Container of Volume V 29
Fig. 3.3: Interaction of Two Identical Molecules of Materials 1 and Polarizability
α, at a Separation, H 30
Fig. 3.4: Interaction of Two Semi-infinite Solid Bodies, 1 at a Separation, d in Vacuum 31
Fig. 3.5: Interaction of a Sphere of Radius, R at a Separation, d from a Solid Surface
of the same Material, 1 in Vacuum 31
Fig. 3.6: Schematic Demonstration of the Screening Effect for the Interaction of Two
Solid Bodies, 1, at a Separation, d, in Vacuum 33
Fig. 3.7: Plot of ln{[ε (iζ) – 1]/[ε (iζ) + 1]} as a function of (iζ) for various materials 34
Fig. 5.1: Plot of Absorbance, ā versus Wavelength, λ for Twenty Samples of HIV
Infected Red Blood Cells 44
Fig.5.2: Plot of Absorbance, ā versus Wavelength, λ for Twenty Samples of HIV
Positive Lymphocytes (White Blood Cells) 45
Fig.5.3: Plot of Absorbance, ā versus Wavelength, λ for Twenty Samples of HIV
Positive Plasma (Serum) 46
Fig.5.4: Plot of Absorbance, ā versus Wavelength, λ for Twenty Samples of HIV
xi
Negative Red Blood Cells (RBC) 47
Fig.5.5: Plot of Absorbance, ā versus Wavelength, λ for Twenty Samples of HIV
Negative Lymphocytes or White Blood Cells (WBC) 48
Fig.5.6: Plot of Absorbance, ā versus Wavelength, λ for Twenty Samples of HIV
Negative Plasma (Serum) 49
Fig.5.7: Plot of Combined Hamaker Coefficient, A132 Versus Wavelength, λ (Hz)
For the HIV Infected Blood Samples 52
Fig.5.8: A Comparison between the Plots of Maxima/Minima and the Harmonized
Values of the Hamaker Coefficient 53
Fig.5.9: Plot of Harmonized Combined Hamaker Coefficients, A132har Vs Sample
Number, #, for the Infected Blood Samples 55
Fig.5.10: Plot of Harmonized Combined Hamaker Coefficients, A132har Vs CD4+
Count for the Infected Blood Samples 56
Fig.5.11: Interaction of Two Un-identical Molecules of Lymphocyte, 1 and Virus
(HIV), 2, at a Separation, d 57
xii
LIST OF TABLES
Page
Table 1.1: Cell Surface Receptors Implicated in Binding HIV Virions: Receptors
Other than CD4 or Coreceptors that attach HIV Virions to Cell Surfaces 6
Table 1.2: Human Polymorphisms in Chemokine and Coreceptor Receptor Genes
That influence HIV Infection and Disease Progression 8
Table 2.1: Surface Tensions of Biological Entities in ergs/cm2/T=22oC 17
Table 2.2: Hydrophobic Chromatography on Phenyl-Sepharose of Whole Human Serum 21
Table 2.3: Comparison of Surface Tension Data of Biological Cells obtained from some
Techniques 25
Table 3.1: Combinations of Materials for which Negative Lifshitz-van der Waals
Constant A132 is found 34
Table 5.1: Comparison between Peak Absorbance Values of HIV Positive and Negative
Blood Components Respectively 50
Table 5.2: Comparison of the Values of the Hamaker Constants A11, A22, A33 and Hamaker
Coefficients A132 and A131 for the Infected and Uninfected Blood Samples 61
Table 5.3: Values of Absorbance, ā Measured over a Range of Wavelengths,
λ and their Corresponding CD4+ Counts for Twenty HIV Positive Red
Blood Samples Appendix 1
Table 5.4: Transmittance Values, T for Twenty Samples of HIV Positive Red Blood
Cells, over a Range of 23 Wavelengths Appendix 3
Table 5.5: Reflectance Values, R for Twenty Samples of HIV Positive Red Blood
Cells, over a Range of 23 Wavelengths Appendix 4
Table 5.6: Refractive Index Values, n for Twenty Samples of HIV Positive Red
xiii
Blood Cells, over a Range of 23 Wavelengths Appendix 5
Table 5.7: Real Part Values of Refractive Index, n1 for Twenty Samples of HIV
Positive Red Blood Cells, over a Range of 23 Wavelengths Appendix 7
Table 5.8: Imaginary Part Values of Refractive Index, n2 for Twenty Samples of
HIV Positive Red Blood Cells, over a Range of 23 Wavelengths Appendix 8
Table 5.9: Extinction Coefficient Values, K for Twenty Samples of HIV Positive
Red Blood Cells, over a Range of 23 Wavelengths Appendix 9
Table 5.10: Real Part Values for Dielectric Constant, ε1 for Twenty Samples of
HIV Positive Red Blood Cells, over a Range of 23 Wavelengths Appendix 10
Table 5.11: Imaginary Part Values for Dielectric Constant, ε2 for Twenty Samples
of HIV Positive Red Blood Cells, over a Range of 23 Wavelengths Appendix 11
Table 5.12: Hamaker Constant, A11 (x10-21Joule) for Twenty Samples of HIV
Positive Red Blood Cells, over a Range of 23 Wavelengths Appendix 12
Table 5.13: Absorbance Values, ā for Twenty Samples of HIV Positive White
Blood Cells, over a Range of 23 Wavelengths Appendix 13
Table 5.14: Transmittance Values, T for Twenty Samples of HIV Positive White
Blood Cells, over a Range of 23 Wavelengths Appendix 14
Table 5.15: Reflectance Values, R for Twenty Samples of HIV Positive White
Blood Cells, over a Range of 23 Wavelengths Appendix 15
Table 5.16: Refractive Index Values, n for Twenty Samples of HIV Positive
White Blood Cells, over a Range of 23 Wavelengths Appendix 16
Table 5.17: Real Part Values of Refractive Index, n1 for Twenty Samples of
HIV Positive White Blood Cells, over a Range of 23 Wavelengths Appendix 18
Table 5.18: Imaginary Part Values of Refractive Index, n2 for Twenty Samples
of HIV Positive White Blood Cells, over a Range of 23 Wavelengths Appendix 19
xiv
Table 5.19: Extinction Coefficient Values, K for Twenty Samples of HIV Positive
White Blood Cells, over a Range of 23 Wavelengths Appendix 20
Table 5.20: Real Part Values for Dielectric Constant, ε1 for Twenty Samples of
HIV Positive White Blood Cells, over a Range of 23 Wavelengths Appendix 21
Table 5.21: Imaginary Part Values for Dielectric Constant, ε2 for Twenty Samples
of HIV Positive White Blood Cells, over a Range of 23 Wavelengths Appendix 22
Table 5.22: Hamaker Constant, A11 (x10-21Joule) for Twenty Samples of HIV
Positive White Blood Cells, over a Range of 23 Wavelengths Appendix 23
Table 5.23: Absorbance Values, ā for Twenty Samples of HIV Positive Plasma
(Serum), over a Range of 23 Wavelengths Appendix 24
Table 5.24: Transmittance Values, T for Twenty Samples of HIV Positive Plasma
(Serum), over a Range of 23 Wavelengths Appendix 25
Table 5.25: Reflectance Values, R for Twenty Samples of HIV Positive Plasma
(Serum), over a Range of 23 Wavelengths Appendix 26
Table 5.26: Refractive Index Values, n for Twenty Samples of HIV Positive
Plasma (Serum), over a Range of 23 Wavelengths Appendix 27
Table 5.27: Real Part Values of Refractive Index, n1 for Twenty Samples of
HIV Positive Plasma (Serum), over a Range of 23 Wavelengths Appendix 29
Table 5.28: Imaginary Part Values of Refractive Index, n2 for Twenty Samples
of HIV Positive Plasma (Serum), over a Range of 23 Wavelengths Appendix 30
Table 5.29: Extinction Coefficient Values, K for Twenty Samples of HIV Positive
Plasma (Serum), over a Range of 23 Wavelengths Appendix 31
Table 5.30: Real Part Values for Dielectric Constant, ε1 for Twenty Samples of
HIV Positive Plasma (Serum), over a Range of 23 Wavelengths Appendix 32
Table 5.31: Imaginary Part Values for Dielectric Constant, ε2 for Twenty Samples
xv
of HIV Positive Plasma (Serum), over a Range of 23 Wavelengths Appendix 33
Table 5.32: Hamaker Constant, A11 (x10-21Joule) for Twenty Samples of HIV
Positive Plasma (Serum), over a Range of 23 Wavelengths Appendix 34
Table 5.33: Absorbance Values, ā for Twenty Samples of HIV Negative Red
Blood Cells, over a Range of 23 Wavelengths Appendix 35
Table 5.34: Transmittance Values, T for Twenty Samples of HIV Negative Red
Blood Cells, over a Range of 23 Wavelengths Appendix 36
Table 5.35: Reflectance Values, R for Twenty Samples of HIV Negative Red
Blood Cells, over a Range of 23 Wavelengths Appendix 37
Table 5.36: Refractive Index Values, n for Twenty Samples of HIV Negative
Red Blood Cells, over a Range of 23 Wavelengths Appendix 38
Table 5.37: Real Part Values of Refractive Index, n1 for Twenty Samples of HIV
Negative Red Blood Cells, over a Range of 23 Wavelengths Appendix 40
Table 5.38: Imaginary Part Values of Refractive Index, n2 for Twenty Samples
of HIV Negative Red Blood Cells, over a Range of 23 Wavelengths Appendix 41
Table 5.39: Extinction Coefficient, K for Twenty Samples of HIV Negative Red
Blood Cells, over a Range of 23 Wavelengths Appendix 42
Table 5.40: Real Part Values for Dielectric Constant, ε1 for Twenty Samples of
HIV Negative Red Blood Cells, over a Range of 23 Wavelengths Appendix 43
Table 5.41: Imaginary Part Values for Dielectric Constant, ε2 for Twenty Samples
of HIV Negative Red Blood Cells, over a Range of 23 Wavelengths Appendix 44
Table 5.42: Hamaker Constant, A11 (x10-21Joule) for Twenty Samples of HIV
Negative Red Blood Cells, over a Range of 23 Wavelengths Appendix 45
Table 5.43: Absorbance Values, ā for Twenty Samples of HIV Negative White
Blood Cells, over a Range of 23 Wavelengths Appendix 46
xvi
Table 5.44: Transmittance Values, T for Twenty Samples of HIV Negative White
Blood Cells, over a Range of 23 Wavelengths Appendix 47
Table 5.45: Reflectance Values, R for Twenty Samples of HIV Negative White
Blood Cells, over a Range of 23 Wavelengths Appendix 48
Table 5.46: Refractive Index, n for Twenty Samples of HIV Negative White
Blood Cells, over a Range of 23 Wavelengths Appendix 49
Table 5.47: Real Part Values of Refractive Index, n1 for Twenty Samples of HIV
Negative White Blood Cells, over a Range of 23 Wavelengths Appendix 51
Table 5.48: Imaginary Part Values of Refractive Index, n2 for Twenty Samples of
HIV Negative White Blood Cells, over a Range of 23 Wavelengths Appendix 52
Table 5.49: Extinction Coefficient Value, K for Twenty Samples of HIV Negative
White Blood Cells, over a Range of 23 Wavelengths Appendix 53
Table 5.50: Real Part Values for Dielectric Constant, ε1 for Twenty Samples of
HIV Negative White Blood Cells, over a Range of 23 Wavelengths Appendix 54
Table 5.51: Imaginary Part Values for Dielectric Constant, ε2 for Twenty Samples
of HIV Negative White Blood Cells, over a Range of 23 Wavelengths Appendix 55
Table 5.52: Hamaker Constant, A11 (x10-21Joule) for Twenty Samples of HIV
Negative White Blood Cells, over a Range of 23 Wavelengths Appendix 56
Table 5.53: Absorbance Values, ā for Twenty Samples of HIV Negative Plasma
(Serum), over a Range of 23 Wavelengths Appendix 57
Table 5.54: Transmittance Values, T for Twenty Samples of HIV Negative
Plasma (Serum), over a Range of 23 Wavelengths Appendix 58
Table 5.55: Reflectance Values, R for Twenty Samples of HIV Negative
Plasma (Serum), over a Range of 23 Wavelengths Appendix 59
Table 5.56: Refractive Index Values, n for Twenty Samples of HIV Negative
xvii
Plasma (Serum), over a Range of 23 Wavelengths Appendix 60
Table 5.57: Real Part Values of Refractive Index, n1 for Twenty Samples of
HIV Negative Plasma (Serum), over a Range of 23 Wavelengths Appendix 62
Table 5.58: Refractive Index Values, n2 for Twenty Samples of HIV Negative
Plasma (Serum), over a Range of 23 Wavelengths Appendix 63
Table 5.59: Extinction Coefficient, K for Twenty Samples of HIV Negative
Plasma (Serum), over a Range of 23 Wavelengths Appendix 64
Table 5.60: Real Part Values for Dielectric Constant, ε1 for Twenty Samples of
HIV Negative Plasma (Serum), over a Range of 23 Wavelengths Appendix 65
Table 5.61: Imaginary Part Values for Dielectric Constant, ε2 for Twenty Samples
of HIV Negative Plasma (Serum), over a Range of 23 Wavelengths Appendix 66
Table 5.62: Hamaker Constant, A11 (x10-21Joule) for Twenty Samples of HIV
Negative Plasma (Serum), over a Range of 23 Wavelengths Appendix 67
Table 5.63: Combined Hamaker Coefficient, A132 (x10-21Joule) Values for the
Twenty HIV Infected Blood Samples over a range of 23 Wavelengths Appendix 68
Table 3.64: Combined Hamaker Coefficients A131 (x10-21Joule) for the Uninfected
Twenty Blood Samples over a Range of 23 Wavelengths Appendix 69
Table 3.65: Combined Hamaker Coefficients A232 (x10-21Joule) for the Infected
Twenty Blood Samples over a Range of 23 Wavelengths Appendix 70
xviii
SYMBOLS
Α Polarizability dimensionless
ā Absorbance dimensionless
Aij Hamaker Constants Joules (J)
Aikj Hamaker Coefficients Joules (J)
Cp Heat capacity kJ/kg.K
D Separation distance μm
Di Particle diameter μm
DL Self-diffusion coefficient cm2s-1
Feng Free energy of engulfing Joules (ergs)
Fvdw van der Waals force J/m2
H Planck’s constant dimensionless
Hs Separation distance Å
K Thermal conductivity kW/m.K
k Reciprocal of the Debye length m-1
k Extinction coefficient dimensionless
Kd Affinity dimensionless
Le Lewis number dimensionless
N Refractive index dimensionless
N0 Critical concentration cells/ml
P Pressure Pa (Nm-2, bar)
Pvdw van der Waals pressure Pa (Nm-2, bar)
q Number of atoms dimensionless
xix
R Ideal gas constant kJ/kg.K
r Radius m
R Reflectance dimensionless
Re Reynolds number dimensionless
t Temperature K (oC)
T Transmittance dimensionless
u Electrophoretic mobility μm/s.v.cm
V Volume m3
VA Mutual attraction energy Joules (J)
Vc Rate of engulfment μms-1
Vc Critical velocity ms-1
Z Distance m
Absorption coefficient dimensionless
αL Thermal diffusivity kW/m.K
β London/van der Waals constant dimensionless
γij Interfacial tension Jm-2(ergscm-2)
ΔFadh Free energy of adhesion J (ergs)
ΔFcoh Force of cohesion J (ergs)
ΔFe Electrostatic interaction energy J (ergs)
Lifshitz correction factor dimensionless
ℓ Density Kgm-3
ε Dielectric constant dimensionless
εr Relative permittivity dimensionless
η or μ Fluid viscosity Nsm-2
λ Wavelength Hertz (H)
xx
ρl Liquid metric density kgm-3
ρp Particle density kgm-3
υo Characteristic frequency Hz
π Pi dimensionless
ψo Surface potential dimensionless
Фt Proportionality constant dimensionless
ӨY Young contact angle degree
Zeta potential millivolts
2
CHAPTER ONE
INTRODUCTION
1.1 Rationale:
At the 2001 Special Session of the UN General Assembly on AIDS, 189 nations
agreed that AIDS was a national and international development issue of the highest
priority [1]. Between December 2005 and March 2006, UNAIDS compiled data from
reports obtained from 126 countries on HIV/AIDS prevalence. In sub-Saharan Africa
a mature epidemic continues to ravage beyond limits that many experts believed
impossible. Also, relatively new but rapidly growing epidemics in regions such as
Eastern Europe and South-East Asia that may come to rival that of sub-Saharan
Africa in scope, had erupted [2].
Over time diverse clinical approaches to the issue of HIV/AIDS have been employed
to seek to proffer possible solutions to the threat. Progress in this regard has been slow
and far in between but has given birth to some palliative measures which include the
introduction of the Highly Active Anti-retroviral Therapy (HAART). However, the
results have not actually shown an easy and comprehensive solution due to the rapid
mutative genetic nature of the virus [3].
Much research has been and is still on, on this subject with a cure not yet in view. The
choice to approach it via the vehicle of surface thermodynamics against the
conventional clinical methods is a novel one. The optimism stems from the great
successes recorded with this approach in related areas of biology and medicine. The
role of surface properties in various biological processes is now well established. In
particular, interfacial tensions have been shown to play an important, if not crucial
role in phenomena as diverse as the critical closing and opening of vessels in the
microcirculation, cell adhesion, protein adsorption, antigen-antibody interactions, and
phagocytosis [4].
1.2 Background to Study:
The HIV is assumed to be a particle which is dispersed in a liquid (the serum) and
attacks another particle (the lymphocytes). The virus attaches itself on the surface of
the blood cell before penetrating it to attack the RNA. If the surface of the blood cell
is such that it will repel the virus, access to the virus into the interior of the cell would
have been denied. Thus, the initial actions take place on the surfaces of the cell and of
the virus (assumed to be particles). This interaction which involves two surfaces
coming together in the first instance can be viewed as a surface effect.
It therefore stands to reason that, if it is possible to determine the surface properties of
the interacting particles, then one can predict the mechanisms of their interactions.
4
When two particles make contact, they establish a common area of contact. Some
original area of the surface of each particle has been displaced, and the work done to
displace a unit area of the surface is referred to as the surface free energy. The actions
therefore that take place on the surfaces are termed surface thermodynamic effects.
These actions are assumed to occur slowly so that thermodynamic equilibrium is
assured. This concept will be employed in this research work to characterize the HIVblood
interactions with the serum as the intervening medium.
The clinicians have analyzed the surfaces of blood cells on which the virus binds.
There are receptors and coreceptors on these cells and suggested types and their roles
in the attachment processes are given in tables 1.1 and 1.2. Figures 1.1 and 1.2 show
the nature and the interactions of these cells.
Fig.1.1: Human Immunodeficiency Virus (HIV) Anatomy [5]
HIV infects immune cells by interacting with proteins on the cells’ surfaces. The
CCR5 is the preferred co-receptor for HIV in the human immune system. Immune
cells that express CCR5 respond to sites of injury or inflammation. In order to
respond effectively, they must go to the site of action. When a tissue experiences
trauma or inflammation, nearby cells secret signal molecules called chemokines. The
chemokines diffuse out from the site of the trauma through the blood stream where
they come in contact with cells expressing the appropriate receptor. Each cell
expresses several different receptors so they can respond to different immune signals.
5
Figure 15b
The
Fig.1.2: Interaction of a Dendritic Cell (right) having HIV bound to its surface
(arrow) with a Lymphocyte (left) [6]
CCR5 is a seven trans-membrane protein or 7TM which means that it crosses the
plasma membrane of the cell seven times. 7TM proteins are sensors for the cell. They
communicate what happens outside the cell to the inside of the cell through a process
called alosterism. The Chemokines bind to CCR5 which causes the CCR5 to change
shape both outside and inside of the cell. The altered shape of CCR5 changes the
interactions with G-proteins inside the cell initiating a signal transduction cascade that
activates the cell to go to the site of injury.
The redundancy inherent in the immune system allows many Chemokines to signal
for multiple coreceptors. CCR5 binds the Chemokine’s RANTES, MIP-1α and
MIP-1β. It is important to note that these Chemokines also bind to other receptors.
Both RANTES and MIP-1α can bind to CCR1 and RANTES can also bind to CCR3.
This is an example of redundancy which is common in the immune system. In this
way, if one pathway is blocked, the immune response can be achieved through
another. Thus, as these receptors interact with the stream of Chemokines they direct
the cell to the site of injury or inflammation. In summary, CCR5 plays an important
role in the movement of immune cells to the site of action. The key points include;
CCR5 is a censor protein on certain immune cells.
CCR5 binds to selected Chemokines like MIP-1α, MIP-1β and RANTES.
CCR5 transduces signals inside the immune cell.
These signals result in chemotaxis or movement of the cell to the site of
injury.
6
Table 1.1: Cell Surface Receptors Implicated in Binding HIV Virions: Receptors
other than CD4 or Coreceptors that attach HIV Virions to Cell Surfaces [7]
Receptor Affinity
(Kd)
Expression Role in attachment and
infection
Reference
Gal-C High
(11.6 nM)
Neuronal and
glial cells
Confers inefficient
infection presumably by
aiding attachment
Harouse et al. (1991)
Sulphatide (sulphate
derivative of Gal-C)
Colorectal
epithelial cells
and primary
macrophages
Confers efficient CD4-
independent infection by
NDK, a TCLA HIV-1
strain Requires CXCR4
coreceptor
Fantini et al. (1993);
Seddiki et al. (1994);
Delezay et al. (1997)
Placental
membrane-binding
protein
High
(1.3–0.6
nM)
Cloned from a
placental
cDNA library
Binds virus particles to
the cell surface and thus
enhances infectivity via
CD4 and coreceptors.
May trap HIV in the
periphery and carry to
T-cells in lymph nodes
Curtis et al. (1992);
Geijtenbeek et al.
(2000)
DC-SIGN On dendritic
cells
DC-SIGNR
Endothelial
cells, such as
liver,sinusoidal
and lymph
node sinus
endothelial
cells
Acts in the same way as
DC-SIGN
Pohlmann et al.
(2001)
Mannose-specific Macrophages Binds gp120 Larkin et al. (1989)
7
macrophage
endocytosis receptor
Heparans
Many cell
types
Attaches virus particles
to cell surfaces via an
interaction with the V3
loop thus enhancing
infectivity via CD4 and
coreceptors. Acts
predominantly for
CXCR4-using viruses
Mondor et al. (1998)
LFA-1/ICAM-1
LFA-1 is
expressed on
haematopoietic
cells, ICAM-1
is on a wide
variety of cell
types
ICAM-1 encorporated
onto virions enhances
attachment and infection
of LFA-1+ cells
Fortin et al. (1999);
Paquette et al.
(1998)
8
Table 1.2: Human Polymorphisms in Chemokine and Coreceptor Receptor
Genes that influence HIV Infection and Disease Progression [7]
Genotype
Frequency
Effect
CCR5 32/wild-type Up to 18 % in
Caucasians
Slows disease progression
CCR5 32/ 32 Up to 1 % in
Caucasians
Protects against infection
CCR5 m303 leads to premature stop
codon and CCR5 truncated in E1
3/209 healthy
donors
In combination with a 32 CCR5 allele confers
T-cells with resistance to R5 viruses
CCR5 P1 allele, characterized by a pattern
of 10 specific bases at different sites,
including A at –2459
43–68 % Accelerates disease progression
CCR5 A/G at –2459 43–68 % Slows disease progression
CCR2 V64I is linked to a point mutation in
the promoter region of CCR5
10–15 % in
Caucasians and
US Africans
Slows disease progression
SDF-1 in 3´ untranslated region of mRNA.
In SDF-1 but not SDF-1 mRNA
16–25 % Homozygotes have slower disease progression,
even slower if 32/wild-type CCR5 or V64I
CCR2 also
RANTES promoter AC, GC and AG at
sites –471, –96 (sites equivalent to –403
and –28 as described by Liu et al., 1999)
Variable
depending on
population
Faster/slower disease progression depending on
genotype and population (Gonzalez et al., 2001).
Some protection from transmission if –471A
present
MIP-1 intron +113, +459 Variable
depending on
population
Faster/slower disease progression depending on
genotype and population (Gonzalez et al., 2001)
9
1.3 Statement of Problem:
The discovery and application of highly active anti-retroviral therapy (HAART) to
suppress HIV has revolutionized the clinical management of HIV/AIDS cases. The
HIV however, has the capacity to develop resistance to the antiretroviral drugs and
this phenomenon has turned out to be a significant cause of failure of HAART. HIV,
being an RNA-based rapidly mutating virus, (unlike the DNA-based counterparts)
lacks the ability to check for and correct genetic mutations that can occur during
replication. In chronic HIV cases, about ten billion new viral species can be generated
daily. This rapid genetic variation has made it rather very difficult to proffer a clinical
solution to the problem [3] and the worldwide picture is one of increasing rates of
infection [8].
It is against this backdrop that this study explores a novel and rare approach using
surface thermodynamics to seek a way forward in the research on the topic of
HIV-blood interactions. The successes recorded in the use of this approach in finding
solutions that have brought about many scientific applications cannot be
overemphasized [4].
1.4 Objective of the Study:
This research work is aimed at employing the concept of surface thermodynamics to
study the interaction between the virus and the blood cells with a view to proffering a
solution to the HIV/AIDS pandemic. The following tasks therefore, must be kept in
view;
(i) Determine the mechanism of interaction of HIV with white blood cells.
(ii) Seek a thermodynamic interpretation of such interactions through van
der Waals attraction mechanism.
(iii) Quantify such interactions through actual measurements.
(iv) Recommend possible approach to eliminating the HIV-blood
interactions.
Thus, the main thrust of this research work is the use of surface thermodynamics in
explaining the HIV/AIDS jinx.
1.5 Scope and Limits of the Study:
The scope of this research is limited to specifying the relevance of van der Waals
forces to the fusion of the HIV with the receptor cells and how such fusion process
could be quantified and prevented. This is intended to be achieved by the application
of surface thermodynamics using the concept of Hamaker coefficients derived from
absorbance data required for the computation of the Lifshitz formula. The sign of the
10
combined Hamaker coefficient will suggest whether there is attraction or repulsion
between the virus and the blood cells.
The next approach would be to suggest a formulation that would aid in preventing
contact between the virus and the blood cell, and hence prevent their interactions.
This entails the development a model that would render the absolute combined
Hamaker coefficient, A132abs negative thus causing the virus and the lymphocytes to
repel each other [9].
Sourcing for additives to achieve this aim is beyond the scope of this work. Other
approach for the determination of Hamaker coefficients, e.g. by contact angle data,
will not be considered. These will serve as suggested areas for further research.
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