THE DISEASE IMAGERY GALLERY

Bio Chemical Treatment Overview

Interferon acts synergistically with Ribavirin. This combination seems to enhance the immune system, facilitating destruction of infected cells before viral replication and budding occurs. The immune response to virus infections is predominately mediated by T-cells, which eliminate virus-infected cells from the body.  The T-cell response is regulated by certain proteins called cytokines.

The immune system has developed two mechanisms; The natural (innate) immune system, composed of various white blood cells and natural killer cells that non-specifically ingest microbes, tumor cells and virus-infected cells. Second is the acquired (specific) immune system, which is characterized by learning, adaptability and memory. It's major components are two subsets of lymphocytes: T-cells that are primarily thymus-derived and B-cells that are bone marrow-derived. The goal of treatment is to enhance (via temporary supplementation) this second mechanism, teaching the infected host's immune system to specifically, and perpetually, target HCV infected cells via an antibody communication process driven by cytokines. 

Ribavirin enhances the ability of human immune system cells to make cytokines which help enhance this T-cell response, while other, different cytokines enhance the production of antibodies that help protect against a repeat infection.1  Ribavirin may also act to lower genetic nucleoside guanosine triphosphate (GTP) pools, which inhibits RNA capping and gene chain elongation. Because GTP is necessary for genetic transcription, lack of it inhibits the ability of the virus to properly replicate. Together, this combination disrupts, and challenges on two different fronts, the replication scheme of HCV.2    It is reported HCV virion have short lives of only a day or so. Therefore, rather than direct viral destruction, viral elimination as a result of combination therapy probably occurs by attrition. The virion simply die a natural death from old age, unable to find a suitable cell to replicate in. The enhanced immune system continues to target any infected cells via the "learned" antibody communication process, which keeps the viral load below detectable levels, and eliminates or reduces infectivity.

 Scroll down to view images and read narratives.

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smkang2A.JPG (13015 bytes)
"The Virus"
(click on the virus to see all the parts labeled)

The HCV virus has not been photographed for a number of technical, and biologically driven reasons. These images are simply depictions based on science, and what is known about the virus architecture. Above, a close up of a single HCV virus. As perspective, if this virion was the size of a basketball, a single liver cell would be the size of a football field.

Taxonomy: Synonym(s): Flavivirus group. Description is on the taxonomic level of family. Taxon contains the following Genera: Flavivirus, Pestivirus, "hepatitis C-like viruses".
Host: Taxon infects vertebrates.
Genome: Linear; single stranded; RNA. Genome monopartite. Genomic nucleic acid positive sense; infectious. Total genome 10000-11000 nucleotides long. 3' terminus has no poly (A) tract. 5' terminus has a methylated nucleotide cap, or a genome-linked protein (VPg).
Morphology: Virions uniform in shape; spheroidal; enveloped; 40-60 nm in diameter. Surface projections of envelope small (surface appears rough), or distinct (and are obvious fringes in negative stains). Nucleocapsids isometric; 25-30 nm in diameter. Symmetry polyhedral. 7

This image reveals specific internal elements such as the centralized icosahedral shaped nucleocapsid with internal gene chains, and chemokine peptide nodules on the outer caspid. An outer lipid envelope provides a protein coating for the capsid, and support chemokine peptide molecules (depicted as spherical nodules) that attach to and allow entry into hepatocyte host cells (liver cells). Inside of the glycoprotein capsid is the isosahedral shaped nucleocaspid containing HCV genomic (gene) chains. 

After the chemokine peptide molecules attach to host cell receptor sites, HCV virion gain entry via outer cytoplasmic membrane fusion and release RNA gene chains into the cytoplasm of the host cell. The virion gene chains migrate towards hepatocyte gene chains, and absorb specific nucleotides in order to replicate (transcription). This leaves the host cell deficient.

"Each viral genotype encodes different RNA segments that can affect the body's tissues directly or indirectly on a basal level.  The core of the hepatitis C virus is where the viral blue print is stored for replication and evolutionary survival.  The RNA virus is much like a carpenter's flexible ruler that coils within its case upon retraction except viruses work in the opposite manner.  Capsid viruses are extracted from their 'containers' once inside the target cell.  The virus encodes the polyprotein as it unfolds and exposes a continuous string of RNA sequences from its viral envelope until the core has been completely extricated.  Once outside of its protein capsule and protective envelope the core looks to replicate itself."10

HCV replication and viral protein production occurs. The virion migrate back through the liver cell's cytoplasm to the cell surface, forming the structural nucleocaspid, capsid and outer lipid envelope. Finally, the assembled virus particals are released from the host cell by a process called budding. This complete cycle interferes with proper function of the liver cell and results in cell death. It can also transform cells, leading to malignancies such as hepatocelluar carcinoma.

Some of the literature indicates the outer protein envelopes actually have spikes for breaking into and out of host cells. My "mind's eye" sees these spikes as peptide nodules which support a chemo-molecular membrane fusion at specific chemokine peptide receptor sites on the outer surface of the host cell. This fusion results in erosion of virion outer lipid envelope, capsid, and host cell cytoplasmic membrane. The erosion allows entry of genetic material through resulting fissures in the envelope, capsid, and cytoplasmic cell wall.3



virusantigen.JPG (4931 bytes)
"Antibody"

Those little greenish globs are HCV histocompatibility molecules, or antibodies, attaching to the outer lipid envelope of the virus. An antigen is any foreign protein substance that stimulates the body to produce antibodies, which attempt to counteract that foreign substance. This may be a glycoprotein sluffing process. Histocompatibility molecules of one organism act as antigens when introduced into a different organism. The antigen protein is absorbed by immune system cells like T Cells and Lymphocytes, which produce virus specific antibodies. Once released, antibodies attach to circulating virus, as well as infected cells. A peptide driven communication process provides clues to the immune system, which attempts to destroy the virus or infected cell.9 Sometimes the immune system gets confused, and targets healthy organic cells. This is an auto immune response and results in disorders like thyroiditis, arthrititis, lupus and diabetes. Also, studies suggest that the emergence of neutralizing anti-interferon antibodies (auto immune markers) during treatment may contribute to breakthrough, or re-emergence of viral load. This happens in about one third of these breakthrough cases. It is also suspected that breakthrough relates to nonspecific ALT fluctuation in some patients and to emergence of resistant hepatitis C virus strains (mutant or wild type quasi species) in others. 8



smkang2wbc.JPG (15105 bytes)
"HCV Encounter with
Leukocytes"

Leukocytes, or white blood cells are one of the body's main immune defense mechanisms. The monocyte is the largest of the white blood cell group, with a nucleus that sometimes takes up the entire cell cytoplasm.. Leukocytes non-specifically destroy HCV infected cells, but the mechanism is not very efficient, and not the primary way HCV is cleared from the body. White blood cells main function is the first line of defense against infection, defending the body by phagocytosis (eating cells) invaded by foreign organisms. This process leads to the development of specific antibodies which are involved in activating the second, and more efficient immune response which can result in treatment success. There are a number of types of leukocytes and each has a different job in the body.4, 5

Granulocytes

Nongranulocytes

Band Neutrophiles

Lymphocytes

Neutrophils

Monocytes

Eosinophils

 

Basophils

 

The image depicts HCV virion encountering several leukocytes, which have been activated by circulating HCV antigens.  Leukocytes don't directly ingest these virion, but engage in wholesale ingestion of infected (and some un infected) cells. They then produce specific antibodies, which are released into the blood stream. These HCV specific antibodies will seek out circulating HCV virion and infected liver cells, attach themselves and activate nearby leukocytes to attack.


smhcv.JPG (9852 bytes)
"Visualize the Battle"

Monocytes and lymphocytes are common leukocytes, or white blood cells. HCV virion being challenged by a lymphocyte. Notice the antibodies attached to the outer HCV virion envelope. Typically, leukocytes do not destroy circulating virus, but ingest only infected cells.



smbloodvirus.JPG (13953 bytes)
"Virion"

Circulating Hepatitis C virion with small surface antigens in a field of active red blood cells. Larger antibodies in hot pursuit. An antigen is any foreign protein substance that stimulates the body to produce antibodies, which attempt to counteract that foreign substance. Bacteria, viruses, and such physical agents as pollen may act as antigens. The amount of virus circulating in the blood is measured by a Polymerase Chain Reaction (PCR), and is referred to as viral load.6 The virus cannot infect red blood cells as it is specifically interested in hepatocytes (liver cells). However, recent evidence suggests HCV can replicate (probably less efficiently) in other body cells in such organs as the kidney, pancreas and brain. The Hepatitis C Virus (HCV) is not a single virus but rather a family of 'like' viruses.  HCV is more analogous to the leaves of a tree rather than the trunk of that tree.  The virus is really a community of 'like' viruses that are constantly sliding down the evolutionary trail of life mutating ever so slightly over the years as they evolve.

"Within twenty years of being in a host the virus may have mutated to sub-quasi type genotypes of the virus.  The changing genetic nature of the virus over time is thought to play a major part in its ability to elude the host's immune system for decades and in the development of an effective cure.  The body is actually simultaneously defending itself from many similar HCV viruses after years of assault resulting in chronic liver disease.

There are six major genotypes of HCV categorized today and it is estimated that there are more than eighty subtypes already known to exist.  Almost one thousand quasi subtypes of HCV genotypes have been theorized to exist.  Each individual HCV virus encodes a large polyprotein structure that cleaves into seven separate RNA viral proteins.  Some are structural and can be utilized in a protein synthesis reaction by the body or blocks a protein synthesis reaction.   The non-structural proteins are either utilized or can be mis-utilized as enzymes to facilitate reactions."10


References
1. ICN discovers what makes Ribavirin good for treating Hep C , See Journal of Hepatology, March 1999, ICN Pharmaceuticals.
2. Virology 2 - Virus Replication and Antivirals, See Antiviral Drugs, by Steve Dewhurst, University of Rochester.
3. Virology 1 - Introduction to Biology of Viruses, by Steve Dewhurst, University of Rochester.
4. Blood Chemistry Definitions, See W.B.C. (White Blood Cell Count),
5. White Blood Cells in Action!, Leukocyte Adhesion Deficiency
6. What is a PCR?, See Lab Tests, A Hepatitis C Resource
7.
The Big Picture Book of Viruses: Flaviviridae, D. Sander 1995-1999
8.
Role of anti-interferon antibodies in breakthrough occurrence during therapy
9.
Histocompatibility Molecules , Kimball's Biology Pages, John W. Kimball
10. HCV: A genetic tree of encoded viral proteins, why no two cases are similar , Excerpts from Kevin Donnelly document, May 1999

Copyright 1999
Zebographix
04/15/2001

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