A Positron Named Priscilla Scientific Discovery at the Frontier (1994) / Chapter Skim
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3 AIDS: Solving the Molecular Puzzle
3 AIDS: Solving the Molecular Puzzle
Pages 60-97
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From page 60... ...
And so it is that the human immunodeficiency virus (HINI) , the agent that causes AIDS, could first evolve in a remote corner of the world and within little more than a few decades become a dread fear in every corner
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From page 61... ...
The list of opportunistic infections that most frequently affect AIDS patients itself reads like a catalog of plagues. Tuberculosis, recurrent 61
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From page 62... ...
62 But this strategy is not as simple as it sounds. Once the virus infects an individual, the virus and immune system are locked in an intimate and paradoxical relationship.
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From page 63... ...
To do that HIV infections in adults as scientists over the past decade have focused on the complex relationship ow~a,l~ Health O°rganeiz~ between the virus and the cells of the immune system as well as relation- lion 1993 ships of the different immune cells to each other. VIRUSES A famous scientist once defined a virus as "a bit of bad news wrapped in protein." Indeed, while the experimental study of viruses can unlock a wealth of scientific information, viruses offer little else of value to human beings.
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From page 64... ...
The virus takes its form from the protein making up its outer shell, which is sometimes called the capsid. Overlying the outer capsid is a lipid membrane, pilfered from the human host cells that the virus infects.
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From page 65... ...
The viral genes provide the instructions for making more viruses. They are the guidelines for the manufacture of structural proteins that make up the TM gp41 · .
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From page 66... ...
And so it is that newly manufactured viral particles released into the blood must find new host cells to infect, so that they too can start to reproduce. Viruses must spread from cell to cell within the infected individual and to new individuals, in search of new cellular hosts that provide the facilities for them to meet their reproductive needs.
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From page 67... ...
During the course of their life cycles, bacteria can manufacture and secrete biochemicals that are toxic to their hosts. Even though they remain outside host cells, bacteria can still cause disease via their toxins.
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From page 68... ...
The immune system responds to the distress call by deploying another type of white blood cell, a T-cell, which is specially equipped to detect the foreign peptides on the surface of the infected cells. Once the infected host cell has been identified, the T-cell destroys the host cell along with its infectious cargo.
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From page 69... ...
Infected cell and pathogen destroyed by killer T-cell proper chemical signals at the appropriate time, helper T-cells can boost the populations of B-cells that secrete a particular antibody or they can increase the number of killer T-cells that recognize and eliminate virusinfected host cells. As such, helper T-cells are pivotal In plotting, coordinating, and implementing the defense strategy against both contra- and extracellular pathogens.
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From page 70... ...
LIFE CYCLE OF HIV Initial Contact, the Receptor The association between viruses and host cells begins when the virus tries to enter the cell. Because this is a crucial step in viral replication and it starts an infected individual on the road to developing a disease, a great deal of scientific investigation has focused on this process.
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From page 71... ...
Scientists hope to learn more about the way 'HIV spreads in an infected individual by tracing the interactions between CD4-bearing cells. The "pick-up" One of the most common routes of HIV infection is through sexual contact, so one would assume that some receptive cell types are found in the blood going to the skin lnung the vagina, rectum, and other body orifices.
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From page 72... ...
Basically, it is a proteinwrapped package of genes that has no other purpose than to create more packages like itself. The information for this replication is contained entirely within the viral genes, the protein coating being nothing more than protective packaging.
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From page 73... ...
In addition to the shell proteins, many of the viral proteins that will help assemble the new virus particles are also synthesized by the infected host cell. Once all of the viral proteins and genes have been synthesized, the viral shells are assembled, and the viral genes and assembly proteins are packaged inside.
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From page 74... ...
But the cell's genetic material is in the form of DNA, so the viral kNA must be copiec/ into DNA, a task done by the enzyme reverse transcriptase, which is also contained in the viral core. Viral DNA then enters the cell's nucleus and becomes integrates/ into the host cell's chromosomes, where it may sit quietly and undetected for many years.
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From page 75... ...
The very chemical it uses as its genetic material is different from that used by all cells and most viruses. CENTRAL DOGMA The genes of most of the world's creatures are stored in the form of a large molecule called deoxyribonucleic acid, or DNA.
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From page 76... ...
Whenever the cell divides and reproduces its own genes, the viral genes are also reproduced. When host cells pass their own genes on to daughter cells, the viral genes will be passed on too.
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From page 77... ...
THE BIRTH OF NEW PARTICLES Active production of viral particles means that the genes for the viral components are expressed that is, the proteins they encode are manufactured in the cell's cytoplasm. Now that the viral genes have been converted into DNA, the expression of viral genes can be carried out as dictated by the central dogma.
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From page 78... ...
Finally, the pol gene encodes the reverse transcriptase enzyme that converts viral RNA into viral DNA, the integrase enzyme that integrates the viral DNA into the host chromosome, and a third enzyme called a protease. The protease cuts proteins, which is necessary because a single viral gene often encodes more than one protein.
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From page 79... ...
Rather, it is possible that a low level of viral transcription is going on even during the seemingly latent periods. According to this theory, levels of Tat slowly escalate until they reach a critical point where the protein can initiate enough transcription of the viral genes to make detectable amounts of viral protein and from there large numbers of new viral particles.
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From page 80... ...
Not much is known about how viral RNA becomes associated with the shell proteins. The current belief is that the RNA is attached to the segment of the long protein string that will ultimately form the core protein.
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From page 81... ...
The virus that leaves the cell looks pretty much like the one that entered it. The mature virus has an outer protein shell and an inner one that carries viral RNA, integrate, and reverse transcriptase.
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From page 82... ...
Of all body fluids that can support either free virus particles or virally infected cells, blood is the fluid with the highest concentration of both (see Table 3.2~. The blood of an infected individual provides a milieu that supports free virus and infected cells, while the blood of an uninfected individual contains many potentially injectable new cellular hosts.
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From page 83... ...
Cells Peripheral blood 89/92 0.001%-1.0% of mononuclear cells . infected cells Saliva 4/11 <0.01% Bronchial fluid 3/24 Unknown Vaginal or cervical fluid 7/16 Unknown Semen 1 1/28 0.01%-5.0% *
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From page 84... ...
As the virus becomes less detectable in the blood, the protective components of the immune system become more evident, indicating that the immune system may be effectively keeping the virus at bay. Large amounts of antibodies and killer T-cells are specifically deployed to fight free virus and virally infected cells.
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From page 85... ...
Currently, many researchers think that while most virally infected cells may not be actively producing new virus, some proportion of infected cells are. But at this stage an individual's immune system is still strong enough to eliminate a sufficient amount of the free virus and infected cells, so that the individual remains healthy.
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From page 86... ...
Some scientists believe that syncytia may form in people with AIDS as well, but no such syncytium has ever been isolated from an AIDS patient. Other scientists interpret this discrepancy to mean that syncytia are only a test tube phenomenon but that it might hint at some other harmful interaction between infected and uninfected cells in the HIV seropositive individual.
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From page 87... ...
As a consequence, the immune system starts to look like a "Keystone Cops" episode where the perpetrator slips past a frenzied and disorganized immune system. It is important to note that many of these phenomena are studied in the laboratory using viruses and immune cells that have been cultured outside the human hosts from which they were taken.
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From page 88... ...
With vaccines, physicians try to eliminate or at least reduce the lag time so that the immune system is ready to kill an invading pathogen at the moment it enters the body, before it can infect cells, multiply, or cause disease. The vaccine is a device to teach the immune system of an uninfected person the features of a pathogen before that person ever comes in contact with it.
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From page 89... ...
One form of polio vaccine, for example, makes use of viral particles that have been killed. Injecting these killed polio virus particles helps a person's immune system to become familiar with the features of the polio virus and develop immunological memory to it.
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From page 90... ...
Since there is no chance that new viral particles can be generated from peptides, they are deemed safer, at least in that respect, than the classical whole-virus vaccines. Candidate peptides include segments from the surface glycoproteins, but scientists are experimenting with a number of peptides derived from other viral proteins, like the reverse transcriptase and the core proteins.
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From page 91... ...
The virus has a latency period, where the host cell is infected, harbors viral genes and has the potential to reproduce new viral particles at any moment but does not. In this quiescent state the infected cell displays no viral peptides on its surface and has no way of signaling its distress.
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From page 92... ...
In other words, therapeutic approaches of the future may well combine drugs that boost the immune system with ones that inhibit viral replication. A New Generation of Drug Treatments The general hope is that a new generation of drugs may help extend the asymptomatic period from 10 to 30 years or more.
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From page 93... ...
The truncated pieces of viral DNA so produced are virtually useless and cannot direct the synthesis of new viral particles. AZT seems to slow the progression of AIDS once symptoms do appear and may reduce the number of opportunistic infections that 93
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From page 94... ...
Another good target for therapeutic interventions is the integrase that incorporates viral DNA into the host chromosomes, but nothing has yet been developed that can do that. There is now a great deal of interest in agents that can inhibit gene activation by the Tat protein.
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From page 95... ...
As long as a cell remains latently infected, the antisense molecules would serve no purpose, but as soon as a latently infected cell starts expressing viral genes, the antisense molecules would effectively prohibit the manufacture of proteins from those genes. Without viral proteins, new viral particles cannot be made.
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From page 96... ...
+ Burroughs Wellcome PCP treatment trimethoprim and sulfamethoxazole VIDEX~ didanosine Bristol-Myers Squibb Treatment of adult and pediatric (cdl} (New York, N.Y.} patients tover 6 months of age} with advanced HIV infection, who are intolerant or who have demonstrated significant clinical or immunologic deterioration during Retrovir(~) therapy Zovirax(~)
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From page 97... ...
While the world looks to science to end the spread of AIDS, the best solution is also the simplest arid requires absolutely no technology. Scientists stress that no one ever needs to become infected again, if only people would take care not to engage In behaviors that place their tissues In contact with the body fluids of an Infected person.
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