The topic of this paper is the human immunodeficiency virus, HIV, andwhether or not mutations undergone by the virus allow it to survive in theimmune system. The cost of treating all persons with AIDS in 1993 in theUnited States was $7.
8 billion, and it is estimated that 20,000 new cases ofAIDS are reported every 3 months to the CDC. This question dealing with howHIV survives in the immune system is of critical importance, not only in thesearch for a cure for the virus and its inevitable syndrome, AIDS (AcquiredImmunodeficiency Syndrome), but also so that over 500,000 Americans alreadyinfected with the virus could be saved. This is possible because if we knowthat HIV survives through mutations then we might be able to come up with atype of drug to retard these mutations allowing the immune system time toexpunge it before the onset of AIDS. In order to be able to fully comprehend and analyze this question we mustfirst ascertain what HIV is, how the body attempts to counter the effects ofviruses in general, and how HIV infects the body. DefinitionHIV is the virus that causes AIDS. HIV is classified as a RNA Retrovirus.
A retrovirus uses RNA templates to produce DNA. For example, within thecore of HIV is a double molecule of ribonucleic acid, RNA. When the virusinvades 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 particularenzyme that can construct a DNA molecule using an RNA template.
This enzyme,called RNA-directed DNA polymerase, is also referred to as reversetranscriptase because it reverses the normal cellular process oftranscription. The DNA molecules produced by reverse transcription are theninserted into the genetic material of the host cell, where they areco-replicated with the host’s chromosomes; they are thereby distributed toall daughter cells during subsequent cell divisions. Then in one or more ofthese daughter cells, the virus produces RNA copies of its genetic material. These new HIV clones become covered with protein coats and leave the cell tofind other host cells where they can repeat the life cycle. As viruses begin to invade the body, a few are consumed by macrophages,which seize their antigens and display them on their own surfaces. Amongmillions of helper T cells circulating in the bloodstream, a select few areprogrammed to read that antigen.
Binding the macrophage, the T cellbecomes activated. Once activated, helper T cells begin to multiply. Theythen stimulate the multiplication of those few killer T cells and B cellsthat are sensitive to the invading viruses. As the number of B cellsincreases, helper T cells signal them to start producing antibodies. Meanwhile, some of the viruses have entered cells of the body – the onlyplace they are able to replicate.
Killer T cells will sacrifice these cellsby chemically puncturing their membranes, letting the contents spill out,thus disrupting the viral replication cycle. Antibodies then neutralize theviruses by binding directly to their surfaces, preventing them from attackingother cells. Additionally, they precipitate chemical reactions that actuallydestroy the infected cells. As the infection is contained, suppresser Tcells halt the entire range of immune responses, preventing them fromspiraling out of control.
Memory T and B cells are left in the blood andlymphatic system, ready to move quickly should the same virus once againinvade the body. In the initial stage of HIV infection, the virus colonizes helper T cells,specifically CD4+ cells, and macrophages, while replicating itself relativelyunnoticed. As the amount of the virus soars, the number of helper cellsfalls; macrophages die as well. The infected T cells perish as thousands ofnew viral particles erupt from the cell membrane. Soon, though, cytotoxic Tand B lymphocytes kill many virus-infected cells and viral particles. Theseeffects limit viral growth and allow the body an opportunity to temporarilyrestore its supply of helper cells to almost normal concentrations.
It is atthis time the virus enters its second stage. Throughout this second phase the immune system functions well, and the netconcentration of measurable virus remains relatively low. But after a periodof time, the viral level rises gradually, in parallel with a decline in thehelper population. These helper T and B lymphocytes are not lost because thebodys ability to produce new helper cells is impaired, but because the virusand cytotoxic cells are destroying them. This idea that HIV is not justevading the immune system but attacking and disabling it is whatdistinguishes HIV from other retroviruses. The hypothesis in question is whether or not the mutations undergone by HIVallow it to survive in the immune system.
This idea was conceived by MartinA. Nowak, an immunologist at the University of Oxford, and his coworkers whenthey considered how HIV is able to avoid being detected by the immune systemafter it has infected CD4+ cells. The basis for this hypothesis wasexcogitated from the evolutionary theory and Nowaks own theory on HIVsurvival. The evolutionary theory states that chance mutation in the genetic materialof an individual organism sometimes yields a trait that gives the organism asurvival advantage. That is, the affected individual is better able than itspeers to overcome obstacles to survival and is also better able to reproduceprolifically.
As time goes by, offspring that share the same trait becomemost abundant in the population, outcompeting other members until anotherindividual acquires a more adaptive trait or until environmental conditionschange in a way that favors different characteristics. The pressures exertedby the environment, then, determine which traits are selected for spread in apopulation. When Nowak considered HIVs life cycle it seemed evident that the microbewas particularly well suited to evolve away from any pressures it confronted(this idea being derived from the evolutionary theory). For example, itsgenetic makeup changes constantly; a high mutation rate increases theprobability that some genetic change will give rise to an advantageous trait.
This great genetic variability stems from a property of the viral enzymereverse transcriptase. As stated above, in a cell, HIV uses reversetranscriptase to copy its RNA genome into double-strand DNA. The virusmutates rapidly during this process because reverse transcriptase is rathererror prone. It has been estimated that each time the enzyme copies RNA intoDNA, the new DNA on average differs from that of the previous generation inone site.
This pattern makes HIV one of the most variable viruses known. HIVs high replication rate further increases the odds that a mutationuseful to the virus will arise. To fully appreciate the extent of HIVmultiplication, look at the numbers published on it; a billion new viralparticles are produced in an infected patient each day, and in the absence ofimmune activity, the viral population would on average double every twodays. With the knowledge of HIVs great evolutionary potential in mind, Nowak andhis colleagues conceived a scenario they thought could explain how the virusresists complete eradication and thus causes AIDS, usually after a long timespan.
Their proposal assumed that constant mutation in viral genes wouldlead to continuous production of viral variants able to evade the immunedefenses operating at any given time. Those variants would emerge whengenetic mutations led to changes in the structure of viral peptidesrecognized by the immune system. Frequently such changes exert no effect onimmune activities, but sometimes they can cause a peptide to become invisibleto the bodys defenses. The affected viral particles, bearing fewerrecognizable peptides, would then become more difficult for the immune systemto detect.
Using the theory that he had developed on the survival of HIV, along withthe evolutionary theory, Nowak devised a model to simulate the dynamics andgrowth of the virus. The equations that formed the heart of the modelreflected features that Nowak and his colleagues thought were important inthe progression of HIV infection: the virus impairs immune function mainlyby causing the death of CD4+ helper T cells, and higher levels of virusresult in more T cell death. Also, the virus continuously produces escapemutants that avoid to some degree the current immunologic attack, and thesemutants spread in the viral population. After awhile, the immune systemfinds the mutants efficiently, causing their population to shrink. The simulation managed to reproduce the typically long delay betweeninfection by HIV and the eventual sharp rise in viral levels in the body. Italso provided an explanation for why the cycle of escape and repression doesnot go on indefinitely but culminates in uncontrolled viral replication, thealmost complete loss of the helper T cell population and the onset of AIDS.
After the immune system becomes more active, survival becomes morecomplicated for HIV. It is no longer enough to replicate freely; the virusalso has to be able to ward off immune attacks. Now is when Nowak predictsthat selection pressure will produce increasing diversity in peptidesrecognized by immune forces. Once the defensive system has collapsed and isno longer an obstacle to viral survival, the pressure to diversifyevaporates. In patients with AIDS, we would again anticipate selection forthe fastest-growing variants and a decrease in viral diversity. Long-term studies involving a small number of patients have confirmed someof the modeling predictions.
These investigations, conducted by severalresearchers–including Andrew J. Leigh Brown of the University of Edinburgh,et al. –tracked the evolution of the so-called V3 segment of a protein in theouter envelop of HIV for several years. V3 is a major target for antibodiesand is highly variable. As the computer simulation predicted, viral samplesobtained within a few weeks after patients become infected were alike in theV3 region.
But during subsequent years, the region diversified, thus causinga rapid increase in the amount of V3 variants and a progressive decrease inthe CD4+ cell count. The model presented by Nowak is extremely difficult to verify with clinicaltests alone, largely because the diversified interactions between the virusand the immune system are impossible to monitor in detail. Consequently,Nowak turned to a computer simulation in which an initially homogeneous viralpopulation evolved in response to immunologic pressure. He reasoned that ifthe mathematical model produced the known patterns of HIV progression, hecould conclude the evolutionary scenario had some merit.
To verify hismodel, he turned to the experiments done on the V3 protein segment in HIV. These experiments demonstrated that the peptides were mutating and thatthese mutations were leading to a decline in helper lymphocytes. Before we begin to answer the question that this paper is investigating, anevaluation of our primary experiment source is necessary, this being apublication of Nowaks model. Upon evaluation of this source, a problem isexposed, this being that because there was no experiment performed tosubstantiate this model, we have no idea if the modeling predictions aretrue. Although there were previous non-directly related experiments ( i. e.
,V3 experiment) that Nowak referred to to rationalize his model there wasnever an experiment done solely based on the model. Because the V3 findingswere in accord with the findings of Nowaks model, we can assume that themodel has some merit. This absence of an experiment is what leads to the boundaries that oneencounters when experimenting with HIV mutations. These boundaries beingthat because HIV replicates and mutates non-linearly, it is impossible tochronicle all its viral dynamics scrupulously. The lack of experimental data based on Nowaks model along with theinadequacy of experiments dealing with HIV mutations leads to the conclusionthat at present, there is no answer to this question.
Although, otherquestions have been exposed, including: does the virus mutate at random oris it systematic? And how does the virus know where to mutate in order tocontinue surviving undetected?These are all questions that must first be answered before we even begin totry to determine if viral mutations are what allows HIV to survive in theimmune system.
