The content of this paper is whether or not mutations undergone by the Human Immunodeficiency Virus and allow it to survive in the immune system. The cost of treating all persons with AIDS in 1993 in the United States was $7. 8 billion, and it is estimated that 20,000 new cases of AIDS are reported every 3 months to the CDC. The question dealing with how HIV survives in the immune system is important, not only in the search for a cure for the virus and its inescapable syndrome, AIDS (Acquired Immunodeficiency Syndrome), but also so that over 500,000 Americans already infected with the virus could be saved.
This is possible because if we know that HIV can survive through mutations then we might be able to come up with a type of drug to confuse these mutations allowing the immune system time to erase it before the onset of AIDS. In order to be able to fully comprehend and analyze this question we must first prove what HIV is, how the body attempts to counter the effects of viruses in general, and how HIV infects HIV is the virus that causes AIDS. HIV is classified as a RNA Retrovirus. A retrovirus uses RNA templates to produce DNA. For example, within the core of HIV is a double molecule of ribonucleic acid, RNA.
When the virus invades a cell, this genetic material is replicated in the form of DNA . But, in order to do so, HIV must first be able to produce a special enzyme that can construct a DNA molecule using an RNA template. This enzyme, called RNA-directed DNA polymerase, is also known as reverse transcriptase because it reverses the normal cellular process of transcription. The DNA molecules produced by reverse transcription are then inserted into the genetic material of the host cell, where they are co-replicated with the host’s chromosomes; they are then distributed to all daughter cells during later cell divisions.
Then in one or more of these daughter cells, the virus produces RNA copies of its genetic material. These new HIV clones become covered with protein coats and leave the cell to find other host cells where As viruses begin to invade the body, a few are consumed by macrophages, which catch their antigens and display them on their own surfaces. Among millions of helper T cells circulating in the bloodstream, a selected few are programmed to read that antigen Binding the macrophage, the T cell then becomes activated. Once activated, helper T cells begin to multiply.
They then stimulate the multiplication of those few killer T cells and B ells that are sensitive to the invading viruses. As the number of B cells increases, helper T cells tell them to start producing antibodies. Meanwhile, some of the viruses have entered cells of the body – the only place they are able to replicate. Killer T cells will sacrifice these cells by chemically puncturing their membranes, letting the contents spill out, thus disrupting the viral replication cycle. Antibodies then offset the viruses by binding directly to their surfaces, preventing them from attacking other cells.
Also, they precipitate chemical reactions that actually destroy the infected cells. As the infection is contained, suppresser T cells halt the entire range of immune responses, preventing them from spiraling out of control. Memory T and B cells are left in the blood and lymphatic system, ready to move quickly should the same virus once again invade the body. In the first stage of the HIV infection, the virus colonizes helper T cells, specifically CD4+ cells, and macrophages, while replicating itself relatively unnoticed. As the amount of the virus soars, the number of helper cells falls; macrophages die as well.
The infected T cells perish as thousands of new viral particles burst from the cell membrane. Soon, though, cytotoxic T and B lymphocytes kill many virus-infected cells and viral particles. These effects limit viral growth and allow the body an opportunity to temporarily restore its supply of helper cells to almost normal concentrations. It is at this time the virus enters its second stage. Throughout this second stage the immune system functions well, and the net concentration of measurable virus remains relatively low.
But after a period of time, the viral level rises constantly, in parallel with a decline in the helper population. These helper T and B lymphocytes are not lost because the bodys ability to produce new helper cells is efective, but because the virus and cytotoxic cells are destroying them. This idea that HIV is not just evading the immune system but attacking and disabling it is what distinguishes HIV from other retroviruses. The hypothesis in question is whether or not the mutations undergone by HIV allow it to survive in the immune system.
This idea was conceived by Martin A. Nowak, an immunologist at the University of Oxford, and his coworkers when they considered how HIV is able to avoid being detected by the immune system after it has infected CD4+ cells. The basis for this hypothesis was excogitated rom the evolutionary theory and Nowaks own theory on HIV survival. The evolutionary theory states that chance mutation in the genetic material of an individual organism sometimes yields a trait that gives the organism a survival advantage. That is, the affected individual is better able than its peers to overcome obstacles to survival and is also better able to reproduce prolifically.
As time goes by, offspring that share the same trait become most generous in the population, outcompeting other members until another individual acquires a more adaptive trait or until environmental onditions change in a way that favors different characteristics. The pressures exerted by the environment, then, determine which traits are selected for spread in a population. When Nowak considered HIVs life cycle it seemed evident that the microbe was particularly well suited to evolve away from any pressures it confronted (this idea being derived from the evolutionary theory).
For example, its genetic makeup changes constantly; a high mutation rate increases the probability that some genetic change will give rise to an helpful trait. This great genetic variability stems from a property of the viral enzyme reverse transcriptase. As stated above, in a cell, HIV uses reverse transcriptase to copy its RNA genome into double-strand DNA. The virus mutates rapidly during this process because reverse transcriptase is rather error prone. It has been estimated that each time the enzyme copies RNA into DNA, the new DNA on average differs from that of the previous generation in one site.
This pattern makes HIV one of HIVs high response rate further increases the odds that a mutation useful to the virus will arise. To fully appreciate the extent of HIV multiplication, look at the numbers published on it; a billion new viral particles are produced in an infected patient each day, nd in the absence of immune activity, the viral population would on average double With the knowledge of HIVs great evolutionary capable in mind, Nowak and his colleagues conceived a plot they thought could explain how the virus resists complete extermination and thus causes AIDS, usually after a long time span.
Their proposal assumed that constant mutation in viral genes would lead to continuous production of viral variants able to evade the immune defenses operating at any given time. Those variants would come out when genetic mutations led to changes in the structure of viral eptides recognized by the immune system. Frequently such changes put out no effect on immune activities, but sometimes they can cause a peptide to become invisible to the bodys defenses. The affected viral particles, bearing fewer recognizable peptides, would then become more difficult for the immune system to detect.
Using the theory that he had developed on the survival of HIV, along with the evolutionary theory, Nowak devised a model to simulate the dynamics and growth of the virus. The equations that formed the heart of the model reflected features that Nowak and is colleagues thought were important in the advance of HIV infection: the virus impairs immune function mainly by causing the death of CD4+ helper T cells, and higher levels of virus result in more T cell death. Also, the virus continuously produces escape mutants that avoid to some degree the current immunologic attack, and these mutants spread in the viral population.
After awhile, the immune system finds the mutants efficiently, causing The simulation manged to reproduce the typically long delay between infection by HIV and the eventual sharp rise in viral levels in the body. It also provided an explanation or why the cycle of escape and pressure does not go on indefinitely but culminates in uncontrolled viral replication, the almost complete loss of the helper T cell population and After the immune system becomes more active, survival becomes more complicated for HIV.
It is no longer enough to replicate freely; the virus also has to be able to ward off immune attacks. Now is when Nowak predicts that selection pressure will produce increasing change in peptides recognized by immune forces. Once the defensive system has collapsed and is no longer an obstacle to viral survival, the pressure to change evaporates. In patients with AIDS, we would again predict selection for the fastest-growing variants and a decrease in viral diversity.
Long-term studies involving a small number of patients have confirmed some of the modeling predictions. These investigations, conducted by several researchers- including Andrew J. Leigh Brown of the University of Edinburgh, He tracked the evolution of the so-called V3 segment of a protein in the outer cover of HIV for several years. V3 is a major target for antibodies and is highly variable. As the computer simulation predicted, viral samples obtained within a few weeks after patients become nfected were alike in the V3 region.
But during subsequent years, the region changed, thus causing a rapid increase in the amount of V3 variants and a progressive decrease in The model presented by Nowak is greatly difficult to resolve with clinical tests alone, largely because the changed interactions between the virus and the immune system are impossible to monitor in detail. Nowak turned to a computer simulation in which an initially homogeneous viral population evolved in response to immunologic pressure. He reasoned that if the mathematical model produced the known patterns of HIV progression, e could conclude the evolutionary scenario had some merit.
To verify his model, he turned to the experiments done on the V3 protein segment in HIV. These experiments demonstrated that the peptides were mutating and that these mutations were leading to a Now since all of these tests were performed other questions have risen. Does the virus mutate at random or is it systematic? And how does the virus know where to mutate in order to continue surviving undetected? These are all questions that must first be answered before we even begin to try to determine if viral mutations are what allows HIV to survive in the immune system.
