The AIDS Virus:
Its Origins, Effects, Transmission and Genetics
1994 Woodrow Wilson Collection
Immune System Effects
"A number of obstacles thwart effective education to prevent AIDS in the United States. These include the biological basis and social complexity of the behaviors that must be AIDS changed, disagreement about the propriety of educational messages to prevent AIDS, uncertainty about the degree of risk to the majority of Americans, and the dual messages of reassurance and alarm from responsible officials."
Editorial from Science
February 5, 1988
The Normal Helper T Cell
When bodily injury occurs of a type where the skin is penetrated, macrophages will rush to the penetration site and begin ingesting all foreign substances. Foreign cells will be destroyed, but antigens from these cells will be presented on the surface of the macrophage.
The presenting macrophage will then release Interleukin-I (IL-1). This substance activates the Helper T Cells (HTC). If there is enough of it in circulation, the substance also stimulates the brain to increase the body temperature and produce a fever to help combat the invasion.
The HTC will remove the presented antigen from the surface of the macrophage and become activated. It will then release Interleukin-2 (IL-2). This chemical will stimulate other HTC's and killer T Cells (KTC) to grow and divide. The HTC's also release B Cell Growth Factor (BCGF) which stimulates the B cells to multiply. As the number of B cells increase, the HTC's will release B Cell Differentiation Factor (BCDF). This chemical will cause the B cells to produce antibodies specific to the antigen the HTC's took in.
HTC's also release gamma-interferon (IF). This material activates the KTC's, helps the B cells to produce their antibodies, causes the macrophages to congregate and remain at the infection site, and helps the macrophages digest the materials they have already engulfed.
This lymphokine cascade continues to amplify the immune response until sheer numbers overwhelm the invader. It is then the job of the HTC's to send out chemical messages to shut down the immune response. Thus the HTC's are the field generals of the immune system who command and coordinate the attack of their army. Without their guidance, the immune system would not function.
HTLV-III Immune System Effects
The HTLV-III virus usually comes concealed inside a foreign macrophage or HTC that is introduced in serum or blood. These foreign cells are correctly recognized as such by the body's macrophages which then engulf and kill the foreign macrophage or HTC. Being inside these engulfed cells, the HTLV-III virus is unaffected. The HTLV-III virus will then pierce the membrane of the body macrophage and wait for the foreign HTC antigen to be presented on the macrophage surface. When the body HTC arrives to pick up the antigen, the HTLV-III virus will infect the body HTC. This cell-type specific attack is unique among retroviri.
The HTLV-III virus may also stay inside the original body macrophage. Here it may reproduce and bud into vacuoles which are kept within the cell membrane of the macrophage. In this manner, the virus will not be seen or recognized by the body defense mechanisms as it is still contained within a body cell. This allows amplification of the virus without the body becoming aware of its presence.
Normally, IL-I is released by a macrophage which has picked up a foreign particle. An HTLV-III infected macrophage demonstrates a reduction in chemotaxis and releases a substance that prevents the activation message from getting to the HTC's. This prevents the HTC from beginning the immune response cascade.
Infected monocytes fail to kill foreign organisms that they normally would be capable of killing. This failure seems to be a failure associated with the message received by the CD4 receptor. Infected monocytes also leak Interferon-2 (IF-2) and necrosis factor (NF). This leakage is uncontrolled and causes the fever and wasting disease that often is seen in AIDS patients.
The body macrophage or HTC containing the HTLV-III virus eventually lodges in a lymph node. Here the virus will proliferate, transfer and infect other macrophages and/or HTC, and eventually collapse the lymph node. This damage leads to a body-wide decrease in the number of circulating lymphocytes.
The normal route of infection involves the HTLV-III virus cycling through the macrophage, positioning itself on the macrophage surface and infecting the HTC. The HTC is entered by endocytosis, release of lysosome and injection of the HTLV-III capsid. The viral RNA is turned into DNA which then inserts itself into the DNA of the host HTC. Here it may remain dormant for several years, or become partially or totally active.
When the body releases granulocyte-macrophage colony stimulating factor (GM-CSF), the incorporated HTLV-III DNA becomes activated. This reaction is particularly intense in the promonocytes of bone marrow. As these promonocytes mature, they release IL-1 to help activate T4 cells. This activation makes the T4 cells extremely susceptible to HTLV-III attack.
Cells infected with the HTLV-III virus may recognize the virus as foreign and present the viral coat on their cell surface so that the HTC will come and begin the immune system cascade. Unfortunately, the viral protein coat, specifically the gp-120 component, in conjunction with the CD4 antigen-antibody binding site on the surface of the HTC will mediate syncytia formation. Thus, large single cells with multiple nuclei will be formed. Obviously, when HTC's are captured in this manner, they are deactivated and removed from circulation.
The HTLV-III virus also effects the B cells of the body by 1) causing polyclonal activation, 2) reducing the circulating immune complex level, 3) causing hypergammaglobulinemia, 4) causing the creation of autoantibodies, and 5) reducing the immunoglobulin-M (Ig-M) level.
The HTLV-III infection reduces the killing capacity of the natural KTC's. This reaction is probably due to the deactivation of the HTC's which would normally begin KTC production and activation.
For several reasons the HTLV-III virus is especially difficult for the body to attack: 1) The virus undergoes rapid protein coat changes. This means that the body produces antibodies to counter the "old" form of the virus which no longer exists. The HTLV-III virus has the highest antigenic drift of any known organism; 5 times that of the influenza virus family, the previous record holder. 2) The virus will incorporate into its own protein coat part of the host cell membrane as it ruptures and kills its host cell. This membrane coating makes it nearly impossible for the body defenses to recognize this HTLV-III virus as "foreign." 3) The gp-120 protein component of the outer coat of the HTLV-III virus is very similar to part of the neuroleukin protein that our body normally makes. 4) The virus blocks the binding of Class-II major histocompatibility complexes (MHC's) at the CD4 binding site. They do this by not allowing an infected cell to display the CD4 antigen on its cell membrane. The Class-II MHC's will not bind, immunoreactions will decline and the level of IL-2 will fall, shutting down the immune response. 5) The damage done to the immune system is permanent and irreversible. 6) Several different strains of the virus exist at a single time within the body. (Ex: From one individual, 17 different strains were isolated from 27 samples. A second individual had 9 strains isolated from 17 samples.) This variability increases with time. (In the second individual, after an additional 6 months, 13 strains were isolated from 18 samples.) Each strain also seems to have a different biological activity and seems to have a different cellular affinity. 7) As the disease progresses, the virus becomes more efficient at replication and these replicants are more cytopathic in nature.
Questions always arise as to why there seems to be no natural immunity to the HTLV-III virus. The best answer to this questions seems to be that it binds to the CD4 antigen/antibody site of the HTC's. Normal Class-II MHC antigens react at this site as a function of self-recognition. Thus, to make an antibody against this site would be to make an antibody against self as well as the virus. The body will not do this under normal circumstances.
Also remember that the naturally occurring virus exists in many, many different strains. Each of these strains differs in biological activity, affinity and protein coat. A single amino acid change in the enveloping protein coat renders the virus immune to the original antibody. This variability seems to come about as a natural result of the way the virus reproduces itself. During normal DNA translation there exists a "proofreading" enzyme which recognizes, removes and corrects mistakes. With the HTLV-III virus, the RNA is used to make DNA. There is no "proofreader" for this reverse transcription and hence mistakes that are made are directly encoded.
It should be pointed out that in all cases the immune system will mount an immune system response. It usually even goes so far as to produce antibodies against the virus. Unfortunately, this is a case of too little, too late.
Latest information suggests that the HTLV-III virus binds to the "-saramide" site of any cell if that site is present. The virus prefers that galactosaramide site with decreasing preferences for the lactosaramide and glucosaramide sites. These sites are especially prevalent HTC's, macrophages, endothelial tissue and nerve tissue. It should be noted that some -saramide sites cannot be attached to. More information on this preferential binding is just beginning to emerge.
HTLV-III Effect on the HTC's
The HTLV-III attack is specific to the HTC's and related inducer cells and is an extremely deadly one. These cells normally make up 60-80% of the circulating T cells. HTLV-III infection can reduce this number to such a degree that it is impossible to detect their presence.
As the virus multiplies, it punches holes in the membrane of the HTC's killing them. Infected HTC's also secrete a toxin which is fatal to other non-infected HTC's, but does not kill already infected HTC's.
The virus specifically targets the CD4 molecule on the outer membrane of cells. This site is present mainly on the HTC's, but is also found on lymphocytes, monocytes and macrophages. The HTLV-III virus will not only reduces the cell population, but also alters their function. Each T4 cell normally produces about 1,000 copies of itself when stimulated to divide. The HTLV-III reduces this number to about 10. This loss of reproductive ability eventually wipes out the T4 cell population except for the few infected and HTLV-III reproducing cells.
The CD4 site of the HTC is not an absolute requirement but rather a preference. The virus will also infect macrophages, blood platelets and B cells. Once these cells incorporate the virus, it is spread to the endothelial lining of the blood and lymph vessels, the general epithelium, the glial cells of the nervous system, and finally the nerve cells.
With HTLV-III infection, the CD4 site of the HTC is deactivated and altered in such a way that the site will not accept the macrophage presentation of the antigen. This means that the HTC is not going to be activated against an antigen, which in turn stops the HTC immune system coordinator response. No HTC, KTC, or B cell multiplication and no antibody production.
To add insult to injury, HTLV-III infection causes the HTC's to initiate a B cell antibody production to a protein (p18) which all HTC's normally carry. Thus, the antibody will attack the HTC's and precipitate them from the blood.
The HTLV-III virus triggers the release of a suppressor factor which turns off the immune system response before it has a chance to start. The net effect of all this havoc is to remove all immune system protection from the body. Hence, any foreign invasion normally present in the body is no longer held in check. The body is wide open to any opportunistic attack.
The HTLV-III Virus
"In some ways, the purely scientific issues pale in comparison to the highly sensitive issues of law, ethics, economics, morality and social cohesion that are beginning to surface."
C. Everett Koop
Former Surgeon General of the U. S.
The HTLV-III virus has been assigned many names through its short history. They include: 1) Human T-Lymphotropic Virus-III (HTLV-III), one of two proper names to which it is referred in the literature. 2) Human Immunodeficiency Virus (HIV-I), the second proper literature name. 3) Lymphadenopathy-associated virus (LAV). 4) AIDS-related virus (ARV).
The virus itself is extremely small. 230,000,000 will fit on the period at the end of this sentence. It is also a retrovirus so it uses RNA as its genetic material. This use of RNA, and thus the enzyme reverse transcriptase to turn the RNA into DNA, lie at the heart of the variability problem of the virus.
The reverse transcriptase produces a corresponding complementary DNA copy (Proviral DNA). This DNA molecule usually inserts itself into the host cell DNA and provides the basis for further viral replication. Remember that the DNA may incorporate and remain dormant for several years, or may immediately start to produce new viri.
The structure of the HTLV-III follows along the lines of the standard virus; a protein coat surrounding an internal capsid of hereditary material. Around the outside of the virus is usually a dual protein layer that is separated by a lipid membrane layer. This membrane comes from the host cells that the newly-created viri poke holes in.
HTLV-III Viron, or virus particle, is a sphere that is roughly 1,000 Angstrom units or 1/10,000 of a millimeter across. The particle is covered by a bilipid membrane that is derived from the outer membrane of the host cell. Studding the membrane are glycoproteins. Each glycoprotein has two components: gp41 spans the membrane and gp120 extends between it. The membrane-and-protein envelope covers a core made up of proteins designated p24 and p18. The viral RNA is carried in the core, along with several copies of the enzyme reverse transcriptase, which catalyzes the assembly of the viral DNA.
At present, the HTLV-III virus is composed of 9 recognized genes. The layout of the genome can be shown in a diagram
The viral genome is about 9.8 kilobases in length. The plus strand of the RNA codes for a minus strand of DNA. This negative strand of DNA contains only 9 genes which code for 13 proteins: 1) gag codes for a protein of 55,000 Dalton units in size which is further processed into a p25 (capsid coat), p17 (matrix protein, a mRNA binding protein ?) and p6 (mRNA binding protein and virus budding gene). 2) pol precursor which eventually is processed into three proteins: p55, the RT protein which is the reverse polymerase protein, p15, the PR protein, which processes the gag and pol proteins, and p11, the IN protein which helps in viral cDNA integration. 3) env, which codes for the enveloping proteins, in the form of a gp160 precursor which is processed into both the glycoprotein (gp) 120 and the gp 41. 4) tat, the transactivation of transcription gene. This gene regulates the transcription of mRNA from the viral gene. It helps the mRNA-making-viral protein process. It does so by making a protein that activates the long terminal redundancies (LTR's) that the virus carries. These LTR's are multiple copies of the gag, pol and env genes. 5) rev or the regulator of expression gene. It produces a protein of 19,000 Daltons in size which controls the relative amounts of unspliced and singly or multiply spliced mRNA's in production. It also facilitates viral mRNA entrance into cellular cytoplasm from the cell nucleus and allows the creation of full length viral proteins. Together the tat and rev genes make RNA binding proteins that interact with cellular factors to create conditions for optimum viral activity. 6) nef (Negative Factor) creates a p27 protein which is a down regulator of viral expression. 7) vif makes a p23 protein which increases viral efficiency and cell-to-cell transmission. This viral protein may also be a cysteine protease. 8) vpr is a p18 protein that helps viral replication and possibly transactivation. 9) vpu makes a p15 protein which causes the release of the virus from its host cell.
The gp 120 is the major enveloping protein gene of the virus. It is also responsible for the CD4 interactions, viral binding, cell penetration and inactivation. It is about 120,000 Daltons in size. Small parts of this gene are constant while major parts are extremely variable. It seems that only a 12 amino acid sequence is necessary to bind to the CD4 site; the rest of the glycoprotein may vary as it pleases. Of course this variability makes it very difficult for the body to build up a specific antibody reaction.
The gp 41 is responsible for the incorporation of part of the host bilipid membrane onto the outside envelope of the virus. This membrane is taken from the host as it is killed and ruptured. It is also responsible for anchoring the gp 120 to the virus particle.
The LTR (Long Terminal Redundancy) region of the genome is simply a series of multiple copy of the gag, pol and env genes. This allows for rapid viral replication of the structural components. This area may also contain a cis activator for these same regions.
The tat gene, which is unique to the HTLV-III virus, codes for a protein that is about 14,000 Daltons in size. Sometimes this protein is designated as p40 xI. Tat alone causes a 15-20 fold increase in the expressivity of the env gene. When combined with the expression of the rev gene, the expression rate increases 45-60 fold. (The rev gene by itself has no increasing effect.) It also seems that the tat and rev genes must function in combination to synthesize the gp 120 from the env gene.
It should be noted that two other proteins are coded for, though their location on the viral genome is not exactly known. The vpx protein, p15, is a protein which helps determine the infectivity of the virus. The Teu p26 protein seems to help in the tat and rev activation process.