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.
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.
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.
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.
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.
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.
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.
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.
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 CD4independent 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) | |
| macrophage endocytosis receptor | ||||
| Heparans |