The Problem
Human Immunodeficiency Virus (HIV) is the causative virus of Acquired Immunodeficiency Syndrome (AIDS), a disease that is a global pandemic.
HIV/AIDS has infected well over 34 million people globally, and results in over 1.7 million deaths per year. Another 2.5 million people are infected annually.
HIV is spread through infected bodily fluids. There are two types of HIV, HIV-1 and HIV-2. The virus afflicts the host by destroying vital diseases-fighting blood cells called T cells.
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Human Immunodeficiency Virus (HIV)
Aptamer Applications:
Image Citation 5: Artist's rendering of a HIV viroid
Image Citation 5: Artist's rendering of a HIV viroid
Text Citation 18: HIV in bloodstream with T cell (green molecule, right)
Text Citation 18: HIV in bloodstream with T cell (green molecule, right)
Although some patients develop flu-like symptoms, others do not and are completely unaware of their infection.
AIDS is the late stage of the infection, in which the body's immune system is destroyed to the point that it has difficulty fighting diseases and cancers.
There is currently no cure for HIV/AIDS. Treatment consists of a containment strategy, in which existing virus is prevented from spreading further throughout the body. This is accomplished through combination therapy involving several retroviral drugs that inhibit virus reproduction through various methods. This treatment has been deemed the "drug cocktail," that allows a patient to continue to live for decades.
However, this treatment's success is limited by high cost, unknown side effects of long-term treatment, and a lifelong commitment to precise and strict dosage times that can dominate a patient's life. Additionally, drug resistance and toxicity remain pressing issues.
There is a pressing need for a cheaper, more effective containment treatment. High cost retards effective treatment in poorer countries.
Superseding a need for a more effective containment treatment is the end goal for all HIV/AIDS research: a cure. Otherwise, this uncertain stalemate with the virus will continue indefinitely - we will be able to keep HIV/AIDS at bay in an uneasy and costly ceasefire.
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Image Citation 12
Image Citation 12
Aptamers as a Solution
The enzyme Reverse Transcriptase (RT),
relatively large with around 1,000 amino acids, is the
virus's tool for this conversion. RT's name is directly
relevant to its function - the enzyme is responsible for
carrying out the Reverse Transcription process.
RT has a unique structure, in which it operates as a
sort of "hand" (diagram at right). The "thumb"
section of the enzyme closes over the genetic
material when transcription is underway.
The enzyme translates the virus's RNA base-for-
base to its complementary DNA version, and then creates a mirror strand that forms DNA's double helix structure.
Several existing AIDS drugs use this approach by binding to RT and inhibiting transcription. Stop transcription, and viral replication is stopped dead in its tracks. Stop viral replication, and the virus cannot spread.
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" What's clear is if you find a foolproof way to stop RT from doing its job you will have cured AIDS "
To find the "foolproof way to stop RT" is a thousand times easier said then done. HIV translation is notoriously imperfect, resulting in many mutations that change the virus's genome - allowing HIV to elude drugs that target it based on genetic information. HIV is estimated to be capable of evolving 10 million year's worth of human evolution in just 10 years.
Researchers are exploring effective ways to cut off viral genetic information's access to the RT enzyme - this had been conducted in a combination of experiments and computer simulations, as scientists want to learn the actual mechanisms in which drugs, DNA, and aptamers all bind to RT to inhibit its process. There is a need for new treatment methods as the virus develops drug resistance.
Aptamers are an attractive solution because of their unique methodology.
One school of thought is that aptamers selected for
HIV/AIDS could perform a process called
"Competitive Inhibition." Aptamers
compete with viral RNA/DNA for the area of the
"palm" region of the RT enzyme that reverse
transcription occurs at. The aptamer binds into the
enzyme, preventing its use by the virus - therefore
inhibiting viral replication.
In order for this process to occur correctly, aptamers
have to be able to distinguish between the many HIV
subtypes within both type HIV-1 and HIV-2. The main challenge has been to develop these so-called broad spectrum aptamers that have highly adaptable structures. This high adaptability capability is critical, as it allows the aptamers to target the many HIV subtypes and prevent RT from structurally evading the aptamer.
Research to develop a broad-spectrum aptamer is ongoing. Research is focused primarily on structural and functional details of aptamer-RT interactions. Once scientists better understand these interactions, it will help them develop and discover functional broad-spectrum RT inhibitor aptamers.
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Text Citation 15: Competitive inhibition conceptualized: Aptamer blocks HIV access to reverse transcriptase by taking its place
Text Citation 15: Competitive inhibition conceptualized: Aptamer blocks HIV access to reverse transcriptase by taking its place
Text Citation 22: Reverse transcriptase (RT) structure, showing allegorization of the concept as a hand - Blue for the "fingers," red for the "palm," green for the "thumb"
Text Citation 22: Reverse transcriptase (RT) structure, showing allegorization of the concept as a hand - Blue for the "fingers," red for the "palm," green for the "thumb"
- Madrid & Lukin (Text Citation 22)
Text Citation 21: Computer simulated model of Aptamer T1.1 (purple) binding with RT enzyme. Fingers and thumb are labeled to approximate position.
Text Citation 21: Computer simulated model of Aptamer T1.1 (purple) binding with RT enzyme. Fingers and thumb are labeled to approximate position.
An explored approach to HIV/AIDS treatment is to inhibit the Reverse Transcription phase of the HIV virus's life cycle, in which the virus replicates itself. This step in the virus's life cycle is indispensable. Transcription is process in which DNA is translated into RNA. The "reverse" part of the process refers to the opposite function, as RNA is translated into DNA.
HIV carries its genetic information as single-stranded RNA, which must be converted into double-stranded DNA for viral reproduction.
Video Citation 3: Animation of HIV Life Cycle, showing RT in action (approx. around 0:40-1:00)
On this page, a look at aptamers as a future solution to an unsolved, global problem will be reviewed.