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Merissa Chiu

Evolution of Treatment and Prevention of HIV-1

The researchers from the University of North Carolina at Chapel Hill sought out to discover the effectiveness of antiretroviral therapy, or ART, on preventing HIV transmission. They hypothesize that ART reduces the rate of transmission by reducing the concentration of HIV in blood and genital secretions, both of which are common modes of transmission. The researchers analyzed data associated with ART and its effects on the blood and genital tract, on transmission, and looked at the HIV Prevention Trials Network 052 (HPTN052) that is supported by National Institues of Health. The researchers took a closer look at the impact that ART may have on sexual behavior and the implications for public health. They found that ART has the ability to not only be a treatment for the HIV infection but can also serve as a preventative factor as well.

The researchers hypothesize that antiretroviiral pre-exposure prophylaxis, or PrEP, for mucosal and intravenous HIV-1 transmission can reduce transmission to high-risk populations. They believe this treatment could be effective if it is able to broadly protect the routes of transmission, thus leading to the slower spread of HIV-1. They designed an experiment involving an in vivo preclinical study where antiretrovirals were given before HIV-1 exposure. The test subjects in this experiment were mice that had human-like characteristics. The experiment showed that pre-exposure to PrEP was able to prevent both rectal and intravenous HIV-1 transmission. This study has great implications for high-risk populations because if they are able to be pre-exposed to PrEP early on, it could help with the spread and transmission of HIV/AIDS.

The researchers hypothesize that a better understanding of the relationship between plasma HIV-1 RNA and HIV-1 transmission risk may help in understanding the impact of drug therapies and vaccinations on the plasma HIV-1 levels. They bring this hypothesis to light because they believe that there is a strong link between the sexual transmission of HIV-1 with the levels of HIV-1 RNA in plasma. To test their hypothesis, they analyzed data collected from 2004 to 2008 in East and Southern Africa from HIV-1 couples. They looked at the data with the intention of finding a quantitative relationship between the plasma and the transmission risk. . Their model assumed a linear relationship between the logarithm of risk of transmission to the log of plasma. They then extrapolated their data to understand the impact their findings have on therapies used now. They found that ART is the only therapy that consistently reduces plasma HIV-1 RNA.

The researchers hypothesize that antiretroviral therapy, or ART, that is active in blood HIV RNA viral load, or bVL, may reduce HIV transmission. They acknowledge the controversy over the effectiveness and impact of ART but perform a longitudinal study to better understand the effects of ART. The participants were HIV-infected men and started ART. Their blood and semen were collected every two weeks for 24 weeks and HIV RNA was taken from each sample. After analyzing their data, the researchers concluded that effective ART is able to reduce HIV transmission on a population level but further studies need to be done to conclude whether or not isolated semen HIV RNA shedding can lead to sexual transmission.

The researchers identified that the HIV-1 virus is unable to replicate on its own but instead, needs to itself within a host cell to replicate. With this knowledge, researchers ran a genome-scale siRNA screen in HeLa P4/R5 cells that was able to pick out over three hundred host factors, a majority of which were not linked to HIV before. They found that the overlapping host factors had common pathways or protein complexes even though there was little commonality between the genes and the HIV dependency on the host cell. They were also able to pinpoint six specific genes that are host factors for HIV which include: SERPINB6, PRKAA1, NEIL3, CD97, BMP2K, and AKT1.

List of symptoms
It might be useful to add the symptoms associated with HIV/AIDs when talking about the treatment associated with the disease especially since the article primarily talks about managing the disease and not just about finding a cure. (http://www.aids.gov/hiv-aids-basics/hiv-aids-101/signs-and-symptoms/)

New perspective on treatment on prevention
There might be research out there that indicates that the use of antiretroviral treatment on people that might be at high risk but do not yet have the disease can actually help to reduce their risk of contracting the disease from their sexual partner. While patients with HIV/AIDs using antiretroviral treatment may be helpful to reduce risk, the use of ART on patients without HIV could also help to reduce the risk and prevent the transmission of the disease. (http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0008829)

Difference or transition from HIV to AIDS
It might be helpful to provide the reader with an understanding of how the virus transitions from HIV to AIDS and how they are different. It may help to understand how the specific treatments listed affect the HIV virus but not the AIDs. (http://www.aids.gov/hiv-aids-basics/hiv-aids-101/what-is-hiv-aids/)

Explanation of HIV-1
It might be helpful to explain why there is a distinction between HIV and HIV-1 and explain what HIV-1 is.

Addition to Article
In another study on mice, it was proposed that the antiretroviral therapy might reduce the risk of contracting HIV when administered to high-risk individuals who did not have the disease but could easily be exposed to it by others.

Link to Article
https://en.wikipedia.org/wiki/Management_of_HIV/AIDS

Final Draft of Paper
In the United States alone, 1.1 million people are living with the human immunodeficiency virus and on a global level, over 33 million people are affected by this disease (Global statistics). The human immunodeficiency virus, also known as HIV, is one of the fastest evolving viruses and scientists are constantly working to provide new treatments and drugs to control the affects and prevent the spread of the disease. To develop new vaccines and treatment plans, scientists have studied the evolutionary origins of HIV and discovered that HIV is closely related to other immunodeficiency viruses found in primates and wild cats. They use the evolutionary origins of HIV to learn how to better treat HIV and prevent the spread of the disease especially since the immunodeficiency viruses found in other animals do not harm the animals, even if they carry the virus. When analyzing the research done in combating this constantly evolving disease, it is seen that scientists rely heavily on evolutionary techniques. Researchers often base their hypotheses of future and effective treatments on the analyses of the ways that HIV strains have evolved over time and on a worldwide level. Human intervention has now become a significant evolutionary force as scientists rely on artificial selection of extreme strains of HIV to slow the spread of the disease (Palumbi). Researchers are employing the Red Queen hypothesis in that they are simply trying to keep up with the evolutionary changes that HIV is making and trying to slow the spread of the disease instead of making huge efforts to cure the disease on a whole. In an effort to stay ahead of the rapidly evolving HIV virus, researchers from the University of North Carolina at Chapel Hill sought out to discover the effectiveness of antiretroviral therapy, or ART, in preventing HIV transmission. Antiretroviral therapy is the combination of three antiretroviral drugs that are used specifically to suppress and stop the progression of the HIV virus. They hypothesized that ART reduces the rate of transmission by reducing the concentration of HIV in blood and genital secretions, both of which are common modes of transmission. The researchers analyzed data associated with ART and its effects on the blood and genital tract, on transmission, and looked at the HIV Prevention Trials Network 052 (HPTN052) that is supported by National Institutes of Health. The researchers took a closer look at the impact that ART may have on sexual behavior and the implications for public health overall. They found that ART has the ability to not only be a treatment for the HIV infection but can also serve as a preventative factor as well. They drew this conclusion based on the analysis of a series of studies that showed that the antiviral agents could concentrate in areas in which transmission could easily occur, such as the genitals, and the agents were able to reduce the resurgence of HIV in those areas for high risk individuals (Cohen et al).

As scientists gain more knowledge about the HIV virus, they are artificially selecting against a common strand of HIV, HIV-1, in targeted high-risk populations. Scientists are now relying on human intervention to prevent the spread of HIV and preemptively stop the transmission in its tracks. The researchers hypothesize that antiretroviral pre-exposure prophylaxis, or PrEP, for mucosal and intravenous HIV-1 transmission can reduce transmission to drug users, and men and women at high-risk based on their sexual partner. They believe this treatment could be effective if it is able to broadly protect the routes of transmission, thus leading to the slower spread of HIV-1. The researchers specifically wanted to identify whether or not systematic administration of PrEP was able to efficiently reduce HIV-1 transmission in the rectal area as it does in the vaginal area, and protect against intravenous HIV-1 infection. They designed an experiment involving an in vivo preclinical study where antiretrovirals were administered before HIV-1 exposure. The test subjects in this experiment were mice that had human-like characteristics. The experiment showed that pre-exposure to PrEP was able to prevent both rectal and intravenous HIV-1 transmission. This study has great implications for high-risk populations because if they are able to be pre-exposed to PrEP early on, it could help with the spread and transmission of HIV/AIDS (Denton et al).

To once again adapt to the quickly evolving HIV virus and prevent the spread of this uncontrollable disease, scientists approached the issue by observing the correlation between the level of HIV-1 RNA in plasma and the risk of sexual transmission. The researchers hypothesized that a better understanding of the relationship between plasma HIV-1 RNA and HIV-1 transmission risk may help in understanding the impact and compare the effectiveness of drug therapies and vaccinations on the plasma HIV-1 levels. To test their hypothesis, they analyzed data collected from 2004 to 2008 in East and Southern Africa from HIV-1 couples, and artificially selected couples that were at high risk of transmission of the HIV-1 strain. They looked at the data with the intention of finding a quantitative relationship between the plasma and the transmission risk. Their model assumed a linear relationship between the logarithm of risk of transmission to the log of plasma. While this model calculated the relationship between HIV-1 transmission risk and the reduction of plasma HIV-1 RNA as proportional to each other and independent of the initial plasma HIV-1 level, the absolute reduction of plasma HIV-1 RNA was found to be greater at high plasma HIV-1 RNA levels. They then extrapolated their data to understand the impact their findings have on therapies used now. They found that ART is the only therapy that consistently reduces plasma HIV-1 RNA. This is a significant evolutionary finding because ART can also be described as a drug cocktail in which multiple drugs are used simultaneously to slow evolutionary forces (Lingappa et al).

Even with antiretroviral therapy and its ability to lower genital HIV levels which in turn reduces the risk of HIV transmission, scientists still seek to understand the persistence of HIV RNA shedding in semen. The researchers hypothesize that ART, that is active in blood HIV RNA viral load, or bVL, may reduce HIV transmission. They acknowledge the controversy over the effectiveness and impact of ART but perform a longitudinal study to better understand the effects of ART. The participants were HIV-infected men and started ART. Their blood and semen were collected every two weeks for 24 weeks and HIV RNA was taken from each sample. After analyzing their data, the researchers concluded that effective ART is able to reduce HIV transmission on a population level but further studies need to be done to conclude whether or not isolated semen HIV RNA shedding can lead to sexual transmission. This study is evolutionarily significant because it shows that while scientists are working hard to come up with new treatment plans and preventative regiments, evolution is taking its course in the HIV virus and evolving quicker than scientists can develop new drugs. Thus, researchers are at a point where they are simply trying to maintain and aim to reduce the number of patients with HIV instead of placing all of their effort in finding a cure of the disease (Sheth et al).

Scientists are seeking new ways to target the HIV-1 virus and are now looking into the replication pattern of the disease. The researchers identified that the HIV-1 virus is unable to replicate on its own but instead, needs to bind itself within a host cell to replicate. With this knowledge, researchers ran a genome-scale siRNA screen in HeLa P4/R5 cells that was able to pick out over three hundred host factors, a majority of which were not linked to HIV before. They found that the overlapping host factors had common pathways or protein complexes even though there was little commonality between the genes and the HIV dependency on the host cell. They were also able to pinpoint six specific genes that are host factors for HIV which include: SERPINB6, PRKAA1, NEIL3, CD97, BMP2K, and AKT1. They looked for common pathways and components of these host factors to evaluate their results. The researchers recognize that the RNAi-based screens that were used provide an initial starting point in understand the potential genetic elements of HIV but that more tests are needed to confirm their results (Zhou et al).

To understand and develop effective and dependable HIV vaccines, the genetic diversity of HIV-1 must be understood because it creates a significant obstacle in providing successful vaccines. Scientists analyze the virology of the HIV-1 infection at its earliest stages to shed light on the mechanisms that propagate viral replication and immune control. By studying the virology of acute HIV-1, scientists are gaining new insights on the lineages that are critical in launching the infection, the adaptive changes that are made early on that allow HIV-1 to go unnoticed and bypass any immune responses from the host, and the viral replication process as it is impacted by the mutations of HIV-1. An evolutionary analysis of HIV-1 and its ability to constantly mutate has been the basis of much of the treatments that have been developed to combat the problem of HIV in patients with the disease and in people who are at high risk of contracting the disease (Boutwell et al).

Another method of approaching the disease is through phylogenetic analyses. Scientists posit that these analyses show the diversity of HIV-1 strains circulating in the world. In this study, they picked a specific HIV-1 strain that was recognized as a distinct subcluster in subtype A radiation because it was found that this strain was particularly prevalent in dually infected individuals when compared to women who had been singly infected by HIV-1. The researchers used phylogenetic analyses to show that while some of the viruses were closely related and clustered within the HIV-1 subtype A radiation, they were also distinct. They made distance calculations between the distinct viruses and termed them A3. Their data showed that women that were classified as having been infected by HIV-1 subtype A under a specific subcluster could also be classified as being infected with HIV-1 sub-subtype A3. While the classification of the different strains and the phylogenetic analyses of the virus may seem cumbersome, it has revealed the sequence divergence within subtypes and helps in identifying the most effective treatment for each patient. This use of an evolutionary technique helps to better combat the constantly changing disease (Meloni et. al.).

Through the analysis of different studies, it is clear that evolutionary factors and techniques are vital in combating HIV. Without an evolutionary basis, scientists would have trouble developing drugs and treatment plans that are specifically effective in slowing the spread of the disease.

Edit to an Existing Article
Evolutionary Origins of HIV and Evolutionary Methods Used

In the United States alone, 1.1 million people are living with the human immunodeficiency virus and on a global level, over 33 million people are affected by this disease. The human immunodeficiency virus, also known as HIV, is one of the fastest evolving viruses and scientists are constantly working to provide new treatments and drugs to control the affects and prevent the spread of the disease. HIV is spread through the passing of bodily fluids and it is a virus that destroys the body’s CD4 cells which is a specific type of white blood cell that aids in helping the body to fight disease. Without these cells, the body becomes highly susceptible to disease and the immune system is weakened and compromised. HIV can eventually lead to AIDS when the CD4 cell count becomes too low. Scientists have seen that HIV is closely related to other immunodeficiency viruses such as simian immunodeficiency virus (SIV) and feline immunodeficiency virus (FIV). By studying these viral lineages and the evolutionary origins of HIV, scientists have observed that even when primates and wild cats are found to carry these viruses, they do not harm the animal which is surprising since HIV very much affects its human carrier. Researchers are using this information to develop new vaccines and treatment plans and to learn how to prevent the spread of HIV among high-risk populations. When analyzing the research done in combating this constantly evolving disease, it is seen that scientists rely heavily on evolutionary techniques such as the creation and analysis of phylogenetic trees. Researchers often base their hypotheses of future and effective treatments on the analyses of the ways that HIV strains have evolved over time and on a worldwide level. One of the leading and most effective treatment plans the use of antiretroviral therapy or ART. Antiretroviral therapy is the combination of three antiretroviral drugs that are used specifically to suppress and stop the progression of the HIV virus. This is evolutionarily significant because ART can be described as a drug cocktail in which multiple drugs are used simultaneously to slow evolutionary forces. Human intervention has now become a significant evolutionary force as scientists rely on artificial selection of extreme strains of HIV to slow the spread of the disease. Researchers are employing the Red Queen hypothesis in that they are simply trying to keep up with the evolutionary changes that HIV is making and trying to slow the spread of the disease instead of making huge efforts to cure the disease on a whole.

Link to page: https://en.wikipedia.org/wiki/Talk:HIV_drug_resistance#Evolutionary_Origins_of_HIV_and_Evolutionary_Methods_Used

I added to this to the talk page because it discusses HIV drug resistance but does not address the issue of how evolution is involved in developing the drugs and on the evolution of the virus. It left out a lot of background information but I was not sure if the author meant to do that because it is addressed in other Wikipedia articles so I added the information to the talk page.