Antigens are objects such as bacteria, viruses, proteins, chemicals, etc that stimulate an immune response. Antibodies interact with the antigens and try to facilitate removal of antigens from the body.
Antibodies interact with the surface of antigens by forming a tight match with the surface contours. The antigenic structure might be the surface of a cell or a virus, but could also be a particular region of a protein surface. Once the antibody interacts with the particular antigne structure, it forms a complex with the antigen and that complex is recognized by other componenets in the bloodstream and removed from the body. Thus, the ability to form an antigen-antibody complex is central to removing antigens.
Some viruses, like HIV, can evade the immune system. They do this by constantly changing the proteins that reside on the surface of the virurs. By the time the body creates antibodies to the viral surface, the virus has changed its surface proteins so that it is no longer recognized by the antibodies.
Antibodies are composed of a number of 4 polypeptide chains. They consist of two heavy chains and two light chains. Each type of polypeptide has a variable region and a constant region. The variable regions are different in each antibody and represents the ability of the particular antibody molecule to bind to a discrete set of antigenic strutures. The constant region does not vary between individual antibodies and is how the organism can recognize a protein molecule as being a particular kind of antibody and can therefore be treated appropriately. The variable regions of the light and heavy chains are adjacent to each other in the intact antibody molecule and together comprise the variable site on the antibody which provides the antibody with specificity. The specificy allows the antibody to interact only with specific antigenic structures and not with others.
One problem posed by the enormous number of possible antibody specificities was how the genome could code for so much diversity. If each antibody were encoded as a specific gene, then the antibody genes would require over half of the human genomic DNA - obviously things don't work this way. How then can we manufacture so many different kinds of specificities?
Antibody diversity is accomplished primarily by DNA rearrangement. B-cells are the kind of white blood cell that produces antibodies. During differentiation of the B-cell, several kinds of DNA segments are reorganized to produce the final antibody gene that specifies the particular antibody this B-cell can produce.
Light chain genes are composed of a variable segment (V) connected to a junction segment (J) which is connected to a constant segment (C). In humans there are about 300 different Vsegments, 5 different Jsegments, and a single Csegment for the type of light chain called a kappa light chain.
The Jsegments are directly connected to the single Csegment. The V, J, and Csegments of the gene are spread out over a large region of DNA
in the undifferentiated cell. During B-cell differentiation, however,
a rearrangement occurs that brings together one of the Vsegments and one of the Jsegments. Each Vsegment contains a promoter which is inactive until the DNA is rearranged. The presence of
an enhancer which lies between the Jand Csegments is what stimulates transcription from the promoter adjacent
to the Vsegment in the rearragned and intact V-J-C light chain gene. Thus, only the rearranged gene is transcribed;
the promoters adjacent to all the other non-rearranged Vsegments will not be active because they are not near the enhancer.
The DNA that originally existed between the "chosen" Vsegment and the "chosen" Jsegment is actually deleted from the cell - it is lost forever
from the particular differentiated B-cell.
Each B cell rearranges its DNA in different ways to produce different
antibody specificities. The DNA segments called Vand Jcombine to code form the variable region of the light chain on the antibody protein itself. There are
1, 500 different ways in which the Vand Jsegments can recombine (300 x 5). However, because the recombination
of the Vand Jsegments can happen at a number of different positions along the
DNA sequence, there are actually 15,000 different ways for light
chain protein variable regions to be generated.
In heavy chains, a Dsegment is also used but the principle is the same. Recombination
events take place to link a V, D, J, and Csegment to produce the final heavy chain V-D-J-C combination. Each of the heavy chain Vsegments (which are different from the light chain variable segments)
has a promoter which is not active until it is brought into proximity
with the enhancer near the Csegment. The variable region on the heavy chain protein is the
result of information coded for by the V-D-J heavy chain DNA segment.
A virus may be recognized by an antibody on the surface of the B-cell. This triggers the B-cell to start multiplying to mount an immune response. As the B-cells differentiate, they start to secrete the antibodies into the blood stream. These secreted antibodies have the same specificity as the original antibodies on the cell surface and can interact with the invading virus (or whatever antigen it reacts with). The secreted antibodies form large complexes with the antigens and these large complexes are removed from the bloodstream by other types of white blood cells. Some B-cells may differentiate into a memory cell which is a specially programmed cell to metabolize slowly so that it can live for up to 30 years. Memory cells are what allow immunizations to work. If the memory cell runs into the antigen that it is coded to recognize, it acts immediately.
Typically, when a virus or other antigenic particle triggers an immune response, it generates a polyclonal response. This means that a number of different antibodies interact with different antigenic sites on the antigen. For example, there may be 10 different structures on the surface of a virus that interact with 10 different antibodies. There could also be a polyclonal response to different sites on the surface of a protein. The polyclonal response means that there will be a number of different kinds of antibodies released into the bloodstream that can each interact with a site on the antigen. This provides the immune system with a better chance of actually removing the antigen.
It has been possible to generate a monoclonal antibody response artificially in the lab. A B-cell that makes the particular antibody of interest can be fused with a myeloma cell which is a cancer cell of lymphocytes. These two cells together create the hybridoma cell which is capable of constantly secreting an antibody with a single specificity.
The global total of people infected with HIV is 16 million. The Sub-Sahara African total is 10 million. This figure consists mostly of heterosexual individuals. The United States has a total of 1 million people infected with HIV, most of these cases are homosexual males. In the United States one out of every seventy-five males has HIV with only one out of every 700 females infected. In Africa one out of every forty males and females has the HIV infection. As these statistics indicate, the major burden of the HIV virus is in the developing world.
At Dartmouth-Hitchcock, there are 100 active AIDS patients. Twenty percent of these are female and eighty percent male.
AIDS is the leading cause of death in males in the United States. In women, cancer is the leading cause of death with AIDS coming in third.
There are three modes of transmission for the virus: sexual, blood, and mother/fetus. The virus is usually transported through HIV infected white blood cells.
In heterosexual individuals, the semen of infected men showed HIV in their semen seventy-four percent of the time. In women the cervix showed the virus thirty-four percent of the time. The rate of transmission is higher from man to woman. Transmission rates of long term heterosexual partners is fifteen to twenty percent. One out of every one thousand is the overall transmission rate sexually, but biological circumstances can alter this. In one study, even when one of the partners was HIV positive, only forty-eight percent of the couples used condoms every time. There was about a two percent transmission rate for people who did not use condoms. There was no transmission by people who used condoms.
Blood transfusion transmissions have become increasingly less frequent now that hospitals and doctors have become more careful about disposing of bloodied needles and products and more sensitive tests have been developed to screen blood.
A needle exchange program can lower transmission by blood. A needle exchange program hands out clean needles to drug users who bring in used ones. This policy has proven effective in foreign countries but has met with considerable resistance in this country.
About one third of infants born to a mother with the disease will be infected.
A gp120 protein on the outside of the virus binds to the human white blood cell and then the genetic material from the virus enters the host cell. The genetic information for the virus is stored in two single stranded RNAs. Gp120 binds to CD4 receptors on white blood cell (which is also called a CD4 cell). Reverse transcription produces DNA from the viral RNA genomes and that DNA is inserted into the host's DNA as a provirus. The fidelity of the reverse transcriptase system to make DNA from RNA is not very good, and each copy has at least one new error introduced. These errors explain the evolution of HIV.
HIV turns into full blown AIDS when the CD4 cell count has fallen down to about 200.
ABT-538 treatment drops the virus two logs which is a dramatic drop and may be a step in the right direction of controlling the disease.
Another type of therapy is the antiviral therapy which can be administered through reverse transcriptase inhibitors,, but this works only in the early viral infection when DNA is being made from RNA. Some protease inhibitors can prevent infected cells from making more viruses once the provirus has been formed.
HIV-I can divide into different clades (or strains of HIV-1). These clades are labeled A through H. Almost all of the subtypes in the United States are subtype B. Africa boasts more diversity because the virus has been there longer. Tracking trends in the different subtypes furthers knowledge and might aid in immunity development. It is important to also know how long the virus has been in the individual when trying to track transmission and evolution patterns.