Progress in Human Immunodeficiency Virus Research
For years, doctors, scientists and researchers have been looking for a cure for the devastating retrovirus Human Immunodeficiency Virus (HIV). While pill cocktails have been found to extend the degradation of the virus into AIDS, a successful cure for the virus itself has not been found. However, one child has recently been cured due to a quick diagnosis and fast, aggressive administration of three antiviral drugs. This child is now only the second person to ever be cured, and represents a whole new possibility for treatment of young HIV sufferers. The first cured patient was an adult male, cured through a blood stem cell transplant from someone with a resistance to the virus. This new case provides hope for a new kind of treatment, specific to infants who are infected by their mothers during childbirth. While this is not the ideal form of treatment – the ideal form being treatment of the mother so that the child does not contract HIV at all – it is commonly the only option and could save many lives that would otherwise be taken before they had barely begun.
In March 2013, a child was born in Mississippi to a mother who was positive for the Human Immunodeficiency Virus (HIV). Just before delivery, the child was infected with the virus as it came into contact with the birthing fluid. Within the next 30 hours, doctors were frantically caring for the infant and administering treatment. The specific treatment chosen – referred to ART, or antiretroviral treatment - was a combination of three antiretroviral drugs . The child was kept under close watch, and found to be HIV positive a couple days later: not a good sign for the child or the treatment. However, the treatment was continued daily for fifteen months, at the end of which there were no traces of the virus in the bloodstream. Two years later, there was no change .
While these drugs were eventually successful in eliminating the virus, they are classified as a functional cure rather than a full cure. This label of 'functional' is applied because initial traces of the virus in the child were so small that the drugs are not likely to be as effective in other and older patients. The cure is also considered accidental, meaning that the intention of the doctors at the time of administration was not to cure the child, but rather to simply stall its development. Furthermore, their initial plan was to treat the pregnant mother so that the child would not contract the virus at all, and would not have to spend the first year and a half of its life on daily medication. However, the circumstances changed as delivery neared, and they were forced to adopt a new plan; fortunately, this plan was not only successful, but also an important step in the discovery of a full cure .
Treating pregnant mothers before their child is born has brought the number of babies born with HIV down from 2,000 per year to 200 per year in the US. This process is therefore heavily favored for both its success rate and the fact that it saves the child from complications and a difficult entry into life. Furthermore, the administration of any drug to an infant can have uncertain and unwanted consequences or side effects later in that child's life. This success rate and the Mississippi case indicate that how early treatment is administered is far more important than the actual composition of the drug cocktail. While it has always been know that the earlier the virus is counteracted the better, it has further been learned that the effectiveness of the treatment decreases exponentially the more time passes. Therefore prompt administration is crucial to the cure .
It is even more fortunate and impressive that the treatment was successful because it was administered as a last shot for the child; it had never been used as a treatment before, and was given aggressively for the extremely young age of the child. While this was risky, doctors determined that the potential benefits outweighed the potential risks. Luckily for the child, its mother, and the scientific community, they were correct. However, even as researchers and the community alike rejoice, their joy is premature: it remains unclear whether the success can be replicated, and further testing will be long and difficult .
What is HIV?
In order to better understand what is required by a cure, it is helpful to know how the virus itself came to be and how it functions. HIV originated in West African chimpanzees, and was first contracted by humans when they ate infected chimps. The hunters that consumed the chimps then spread the virus to much of the African population. It was then spread from person to person and to other countries through sexual intercourse or through blood contact with infected blood .
Once the virus became prevalent enough to raise a high level of awareness, research began. The virus was named Human Immunodeficiency Virus (HIV) because it was found to destroy immune system cells – specifically the CD4 cell subgroup of T cells, which are a type of white blood cell. The difference between HIV and many other viruses is therefore that the immune system cannot respond to infection, and so has no natural defenses. The infection process, however, is much the same. When HIV phages infect blood cells, they take over the cell processes so the cell begins replicating the viral DNA. This cell is then destroyed in lysis as the viral DNA is released to infect other neighboring cells .
These HIV phages are about 1/17 the size of the CD4 cells that they infect. The phage is made up of reverse transcriptase that translates their RNA into DNA, integrase that allows the viral genome to become a part of the cell genome, protease to help it replicate, and double stranded RNA. The fact that the genetic material is double stranded complicates replication, and makes the virus more difficult to counteract. This RNA molecule is made up of nine genes: three that code for protein production and six that code for infection and replication. All of these components are contained in a core, which is covered in two different proteins (p24 and p17) as well as 72 spikes of gp120 and gp41 proteins that hide it from the body's immune response . These spikes attach the phage to the membrane of CD4 cells so the viral membrane can fuse with the cell membrane and the core can be deposited into the host cell. The transcription of viral DNA from the RNA that is deposited into the cell, and the incorporation of this DNA into the host genome makes HIV a provirus, meaning it can lie dormant within the host cell for long periods of time before activating and replicating. It is only once the virus enters its replication phase that symptoms are seen .
There are two large categories of the virus: HIV-1 and HIV-2. The two versions differ in the amount of time they remain inactive, with HIV-2 taking longer to begin replication. HIV-2 is therefore less likely to be passed on to someone else; therefore HIV-1 is more common. The transmission process, however, is the same for both: through blood, sex, and childbirth .
How HIV becomes AIDS
HIV becomes AIDS when a patient's T cell count drops below 200. This means that their immune system has been severely weakened by HIV, since a healthy T cell count is between 800 and 1200 cells . This degeneration of the immune system causes many complications, generally involving the contraction of another disease or infection that becomes deadly due to the limited or non-existent response the body can provide. AIDS is therefore also characterized by the development of pnemocystis, pneumonia, cytomegalovirus, tuberculosis, toxoplasmosis, or cryptoporidiosis .
Treatment for Infants
While the Mississippi case may not be effective if it is not administered as quickly after birth as was just seen, it does provide hope for a full cure in infants. Because HIV develops so quickly in children who contracted the virus from their mothers, diagnosis may delay administration too long for the cure to be effective. While it is likely that children born from HIV positive mothers will also have HIV, it is not sure; and administering aggressive treatment to a child only a few hours old for a virus they do not have is not prudent. The steps of treatment – find, test, and treat – must be followed in this order, regardless of the time constraints of the cure.
Most HIV tests are done using PCR, which takes about six weeks to provide conclusive results. PCR is used to separates the genome along an agar plate using electrical charge to pull fragments from one end to the other, distributing each piece by size. This separation allows doctors to identify the provirus within the genome if it is, indeed, present. However, many high-risk areas do not have the money or resources for PCR testing; therefore a simpler test – the antibody test – must be done. This is problematic because results take longer, and even more so for infants because patients must be at least 18 months old for the results to be reliable. In children younger than this, HIV antibodies from the mother can be leftover in their bloodstream and give a false positive. A third method of testing is to take blood samples, dry them out, and send them to a lab where they can be rehydrated and put through a PCR test. However, these samples arrive much less reliable, and the process is time consuming and expensive . Thus diagnosis is a further challenge that infected children face that does not present as much of an issue in older patients. It is, perhaps, the largest challenge facing researchers since prompt treatment is imperative.
The next step is monitoring the progression of HIV in children. This progression is measured by the percentage of white blood cells that are CD4 cells. The CD4 count must be converted to a percentage because the absolute number can vary from child to child, but the percentage generally does not . While diagnosis and monitoring are important, they use up time that could be crucial to saving the child's life. It is therefore commonly decided that the benefits of starting treatment without conclusive results far outweigh the risks of the drugs, especially in children under 2 years of age. Standard procedure for children above the age of 2 is to only begin treatment when the CD4 percentage drops below 25%. The reasoning for this is that less money is spent on patients who are unlikely to survive regardless, given the small level of effectiveness of most current treatment. However, this policy is being contested in light of the Mississippi case because it has shown that treatment given when the cell count is still high is far more effective – enough so to justify earlier administration. This is supported by studies being done in Brazil that have found that about 75% of infants receiving ART drugs (the same given to the Mississippi child) survived for at least four years .
Looking Towards the Future
While the Mississippi case did not provide a full cure, or even a sure functional cure, it represents a huge leap forward in healthcare for HIV patients. It is important in treatment of children in general, and crucial in those with mothers who were undiagnosed or who could not be treated themselves. Looking towards future research, scientists are considering methods of testing that will provide results sooner, as well as even more aggressive combinations of drugs. They are also focusing on eliminating the negative effects of drug treatment, a faster moving process than raising effectiveness of the cocktails. Their goal in this respect of research is to raise the quality of life of those taking the drugs, so that HIV is not only not a death sentence, but also not a guarantee of a life of headaches, nausea, weight loss, dizziness, fatigue, insomnia, and many other side effects that have a large negative impact. These side effects are so bad, in fact, that many people with HIV choose not to take them, and live the rest of their lives out in decidedly less misery .
Research has also shifted to focus more on infants than ever before. This is the new frontier in HIV research because of the greater effects being seen when patients are treated at an early age. Where teenagers and adults had previously been the main focus of research and testing, infants and children have become the greatest hope for curing the virus. The next immediate step is to confirm that the ART drugs administered in Mississippi are as effective in other children in similar situations .
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