Running Head: AN UNDERSTANDING OF HIV- 1, SYMPTOMS, AND TREATMENTS. An Understanding of HIV- 1, Symptoms, and Treatments.

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1 Running Head: AN UNDERSTANDING OF HIV- 1, SYMPTOMS, AND TREATMENTS An Understanding of HIV- 1, Symptoms, and Treatments Benjamin Mills

2 Abstract HIV- 1 is a virus that has had major impacts worldwide. Numerous people have died due to infection caused by HIV. Around the world, HIV is contracted in areas that are full of infection and disease. Without a cure, it is impossible to get rid of HIV once a person has been infected. Many treatments exist to counteract symptoms of HIV, but a cure has yet to be found. One reason that scientists have not discovered a cure yet is that we do not entirely understand how HIV works. In order to effectively create a vaccine, it is crucial that we understand how the virus works. This paper creates a very simply, light- hearted approach into the molecular biology of HIV.

3 Introduction By 2008, twenty- five million people had died of a similar, unnatural cause: the human immunodeficiency virus type- 1. At that point, forty million people were living under the effects of HIV- 1. With no easy, quick treatment in the near future, the prospects were drab. However, scientists were quickly discovering the method with which HIV attacked one s immune system. This report gives a basic understanding of what HIV RNA codes for, how it attacks the body, and some treatments. Cell Entry HIV- 1 is a virus. It is shaped like a mushroom, complete with a capsid and an envelope glycoprotein. The capsid contains the viral RNA. The envelope glycoprotein recognizes a surface glycoprotein. These surface glycoproteins can be found in abundance in the phospholipid bilayer of T- lymphocytes and lymphocytes of helper- T cells (Haseltine). In this way, developing cells of the immune system are targeted. Because these cells traverse all the pathways of the body, HIV- 1 is carried throughout the entire body. The two glycoproteins fuse together. Once the glycoproteins fuse, the viral RNA is inserted past the phospholipid bilayer and into the cell. Once in the cytosol, the viral RNA is transported to the nucleus. Genetic Code HIV- 1 is a retrovirus. A retrovirus is a virus that contains RNA rather than viral DNA. This viral RNA is reverse- transcribed into the DNA in the infected cell.

4 This process is carried out using the reverse transcriptase enzyme carried in the capsid. The reverse transcriptase will use the viral RNA as a template, and synthesize an entirely new DNA strand. Once the new viral DNA has successfully been synthesized, it is integrated into a host chromosome using the integrase enzyme. The viral DNA in the chromosomes is now known as pro- viral DNA or a provirus (Ward). At this point, the viral DNA goes through normal cell processes in order to create proteins. The proteins created by the viral DNA go on to perform specific functions. Proteins made by the viral DNA are used to make the budding viruses. In order to understand the way that a virus infects a cell, one must understand the genes in a virus and for what they code. HIV- 1 has 9 genes in all. However, it codes for 17 proteins. This is possible through a unique process in which the viral mrna codes for several proteins that are bonded together to form a polyprotein. Three of HIV s genes code for polyproteins: Gag, Pol, and Env(Ward). The Gag gene codes for four different proteins. After reverse- transcription, transcription, and translation, a polyprotein is produced. The polyprotein is then cleaved by HIV s protease enzyme. The resultant proteins are a matrix protein, a major capsid protein, a nucleic acid- binding protein, and a small proline- rich protein that helps with virion assembly. The next gene is called the Pol gene. It is reverse transcribed into a cell s DNA and then transcribed into viral mrna. The mrna exits the nucleus without any post- transcriptional modifications. When being translated in a ribosome, the

5 viral mrna experiences a process called frame shifting. While the enzyme is reading the viral mrna,it will stop at a certain base and jump back one base. Then the enzyme will continue reading the viral RNA from that point on. Frame shifting creates a whole new sequence of proteins for which the viral mrna codes. Not only does frame shifting create a whole new sequence of proteins, but it also creates a point at which the Gag polyprotein can fuse to the Pol polyprotein(ward). Pol codes for 3 major enzymes. The three enzymes it codes for are a viral protease, reverse transcriptase, and integrase. These enzymes are then released into the cytoplasm for virion assembly. When the budding virus, or the second generation, infects a different cell, protease, reverse transcriptase, and integrase will be used to create the third generation of HIV viruses. However, when these enzymes are made, they are bound together to form a polyprotein. The Pol polyprotein is fused to the Gag polyprotein, and will remained fused until it is cleaved by an enzyme(ward). The last gene that codes for a polyprotein is called Env. Env is responsible for two major proteins. Like all the other genes in the HIV genome, Env goes through reverse- transcription, transcription, and translation without any post- transcriptional modifications. When translation is finished, the final product is a polyprotein called gp160. gp160 is cleaved by a natural protease enzyme created by the cell. gp160 then becomes two glycoproteins, gp120 and gp41(ward). The gp120 glycoprotein becomes the viral envelope of the budding HIV virus. This envelope is what fuses to the CD4 receptor in the first stage of infection. The gp41 glycoprotein is stem- shaped. It joins with gp120 to form the

6 mushroom shape of the HIV virion. These two structures are what make up the exterior of the HIV virion. The term virion refers to the completed, mature virus as it is outside of the host cell (Ward). The HIV genome also contains a section called Tat. This gene codes for the Tat protein, the ref protein, and the nef protein. The Tat protein is also known as the transactivator, and is used for increasing the rate of viral RNA translation. Tat does this by moving to the nucleus and nucleolus of the cell. It then binds to the new viral RNA being formed. The transactivator allows an entire sequence of RNA to be translated at once. This is how polyproteins are made. The transactivator also increases the frequency of RNA initiation. The other two proteins created by Tat, ref and nef, are both regulatory and regulate infection of a cell(haseltine). Also important to the replication process, the Rev gene codes for one Rev protein. The Rev protein can be found primarily in the cytosol. In the cytosol, Rev gathers spliced transcripts and moves them to ribosomes, where the transcripts can be translated into capsid and envelope glycoproteins. Without the RNA transcripts being gathered together by the Rev protein, only regulatory proteins could be made through translation (Kula). The Rev protein is able to transport spliced transcripts by interacting with an export receptor called Crm- 1. The Rev protein and spliced viral mrna transcripts will bind together via the Crm- 1. This occurs in the nucleus. Once the binding occurs, Crm- 1 can interact with the nuclear pores in the nuclear membrane, allowing the Crm- 1, Rev protein, and mrna transcripts to enter the cytosol. Once in

7 the cytosol, the Rev proteins drop the transcripts to be translated and then return to the nucleus (Kula). Effects of HIV on the Body and the Cell HIV- 1 does not directly kill a cell. It has adverse effects on the cell, which may lead to cell death, but the actual virus does not attack a cell with malicious intentions. Instead, the intention of a virus is to replicate itself. All of the coding genetic material is meant to create proteins that are used for creating new viruses. However, there are still ways in which viruses can cause cell death. When HIV- 1 virion enters the body, it seeks a certain type of cell that has the cell membrane protein receptor CD4. These CD4 receptors can be found in abundance in the phospholipid bilayers of T lymphocytes and lymphocytes of helper T cells. In this way, the immune system of an HIV- positive person is targeted upon infection. Because T- lymphocytes are responsible for triggering the production of antibodies, disabling these cells effectively halts the body s attempt to fight the virus. Without antibodies to recognize the envelope glycoprotein responsible for cell fusion on an HIV virion, macrophages will not destroy infected cells and HIV can continue replication in the body undisturbed (Haseltine). HIV- 1 virions fuse with the CD4 receptors in order to inject the genetic material into a cell. After the cell has created budding viruses inside itself, the new viruses can leave the cell. However, the first generation of budding viruses will often fuse directly with the cell that it just left. The fusion between HIV virions and a

8 cell will quickly deteriorate a cell membrane, resulting in death of the cell. In this way the first generation of budding HIV viruses can kill a cell (Haseltine). A second way that HIV- 1 virions can kill a cell is very dramatic and rapid. When a virus fuses with the CD4 receptor on a cell membrane, this can trigger other CD4 receptors along the cell membrane to fuse with other cells that have the CD4 receptor along their cell membrane. One HIV- infected cell can fuse with up to 500 uninfected T- cells. The result of this reaction is one giant multinucleated cell. The half- life of this multinucleated cell is very short. This means that individual cells inside the multinucleated cell can die very quickly because of cell membrane deterioration (Haseltine). Many diseases are associated with HIV- 1. When HIV- infected cells get into the bloodstream, they can travel around the entire body. HIV- infected cells can have the most damage on the brain. HIV- infected cells will travel via the bloodstream, where they can be dropped off into vascular tissue. Once in these capillaries, these cells diffuse across the selectively permeable blood- brain barrier (BBB). Scientists are unclear of how the HIV virus crosses the BBB, but several theories exist. One such theory is the Trojan Horse theory- that HIV can hide its receptors in order to be disguised as something else and cross the BBB (Ghafouri). Once the virus is inside the brain, the infected human can acquire many diseases. One of the most general and prominent diseases is HIV- associated dementia. Dementia is described as damages and disorders to the brain and has a wide variety of symptoms. Dementia can be expressed in many different ways, including cognition, behavior, affection, motor skills, and psychiatric disorders. In

9 humans under 60 years, HIV is the most common cause of dementia worldwide (Ghafouri). Many STD s can result from HIV infection as well. Herpes is a virus that can be very easily acquired once HIV has infected a person. HIVE stands for HIV- related Encephalitis, and is a common disease in HIV- positive patients. Encephalitis is described as an inflammation of the brain, and has many serious symptoms. HIVE occurs when the aforementioned large, multinucleated cells enter the brain. These giant structures act, virtually, as tumors in the brain. This is how the swelling results (Ghafouri). Treatment Unfortunately, HIV has no direct cure. Because HIV targets T- cells and prevents the production of antibodies, the body has no way to stimulate the production of antibodies. The job of antibodies is to find and recognize a virus. Once it has found and recognized a virus, it can kill it and recognize it in the future. However, because HIV stops the production of these antibodies, the body cannot recognize HIV upon entry of the body. This is why there is no vaccination to encourage immunity to HIV in the body. One way to treat HIV symptoms is through inhibitors. Inhibitors are drugs that inhibit the reacting of certain processes. For example, the most common inhibitors are protease inhibitors. Each HIV virion has a protease enzyme. This enzyme is coded for in the Gag polyprotein and is necessary for the virion to become mature and have the ability to harm cells. A protease inhibitor will prevent protease

10 enzymes from being active. This treatment can help slow down or stop HIV, but it cannot cure a person of the virus (Ghafouri, Jr., J.E.). Other such inhibitors work as well. There are 5 FDA- approved inhibitors on the market today. All of these can help, but none can cure a person of HIV. There are also drugs to help treat the symptoms of HIV. These drugs may relieve HIVE symptoms, or help boost the immune system. However, none of these deal directly with the HIV virus (Jr, J.E.). Conclusion Although there is no immediate cure for HIV, scientists are researching and growing closer to a cure. Some scientists believe that a cure will be found within the decade, while others believe that it may be farther away. What we do know is that the more research that is conducted, the closer we are to finding a cure. And as 2.6 million people are being diagnosed as HIV- positive each year, the need to find a cure is very real. Understanding HIV is a great way to begin people along the path of contributing to finding a cure for the human immunodeficiency virus- type 1.

11 References Barnabas, R., & Celum, C. (2013). Infectious Co-factors in HIV-1 transmission Herpes Simplex Virus type-2 and HIV-1: New Insights and Interventions. NIHPA Author Manuscripts, 10(3), Retrieved April 9, 2013, from Chugh, P., Bradel-Tretheway, B., Monteiro-Filho, C., Planelles, V., Maggirwar, S., Dewhurst, S., et al. (2008). Akt inhibitors as an HIV-1 infected macrophaphagespecific anti-viral therapy. Retrovirology, 5(11). Retrieved April 9, 2013, from Ghafouri, M., Amini, S., Khalili, K., & Sawaya, B. (2006). HIV-1 associated dementia: symptoms and causes. Retrovirology, 3(28). Retrieved April 9, 2013, from Haseltine, W. (1991). Molecular biology of the human immunodeficiency virus type. The FASEB Journal, 5(10), Retrieved April 9, 2013, from Jr., J. E. (2000). HIV-1 Protease Inhibitors. Journals of the Royal Society of Tropical Medicine and Hygiene, 30(2), Retrieved April 9, 2013, from Kula, A., & Marcello, A. (2012). Dynamic Post-Transcriptional Regulation of HIV-1 Gene Expression. Structural and Molecular Biology of HIV, 1(2), Retrieved April 9, 2013, from

12 Sampey, G., Guendel, I., Das, R., Jaworski, E., Klase, Z., Narayanan, A., et al. (2012). Transcriptional Gene Silencing (TGS) via the RNAi Machinery in HIV-1 Infections. Structural and Molecular Biology of HIV, 1(2), Retrieved April 9, 2013, from Simon, V., Ho, D., & Karim, Q. (2006). HIV/AIDS Epidemiology, pathogenesis, prevention, and treatment. The Lancet, 368(9534), Retrieved April 9, 2013, from Ward, D. (1999). The AmFAR AIDS Handbook. New York: W.W. Norton & Company. Zeinalipour-Loizidou, E., Nicolaou, C., Nicolaides, A., & Kostrikis, L. (2007). HIV-1 Integrase: From Biology to Chemotherapeutics. Current HIV Research, 5, Retrieved April 9, 2013, from Current_HIV_Research_2007. pdf

MedChem 401~ Retroviridae. Retroviridae

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