User:Erin Bolger/Sandbox 1
From Proteopedia
Contents |
Human Immunodeficiency Virus
Introduction
Human immunodeficiency virus attacks the immune system by destroying CD4+ T cells, white blood cells that protect the body from infection. During HIV’s initial attack, it attaches to CD4 receptor cells injecting its’ RNA genetic material. The enzyme reverse transcriptase converts its’ RNA into DNA allowing HIV to use the CD4 cell’s machinery to replicate itself and travel through the body.As the virus attacks these cells, the immune system becomes weaker causing the body to be unable to fight off infection, leading to the development of AIDS. Although HIV can be treated through the use of antiretroviral therapy there is currently no cure (“The HIV Life Cycle, 2015).HIV’s vast genetic variability makes treatment difficult.This variability is due to the high mutation and recombination rates of the reverse transcriptase enzyme causing HIV viral sequences to differ by up to 10% in each individual (Hemelaar, 2012). An estimated 36.9 million people were suffering from HIV around the world in 2014 (“Global HIV and AIDS Statistics,” 2015).
The Origin of HIV
There are two types of HIV known, HIV-1 and HIV-2 with HIV-1 being by far the most common and most infectious of the two strains. Research has shown that HIV-1 is closely related to the SIV virus (simian immunodeficiency virus) that attacks the immune system of chimpanzees and HIV-2 is closely related to a strain of SIV that infects sooty mangabeys. Chimpanzees became infected with 2 different strains of SIV after eating two smaller species of monkeys (red-capped mangabeys and spot-nosed monkeys). These two strains joined together forming a third strain known as SIVcpz that could be passed on to other chimpanzees as well as to humans. It is believed that this virus was transmitted into humans as a result of them consuming chimpanzee meat or being exposed to their blood. Once inside its new host the virus adapted into what we know as HIV-1. Each time the virus was transferred from chimpanzee to human it developed slightly differently leading to the four strains of HIV-1 (M,N,O, and P). HIV-2 was transferred from sooty mangabeys to humans in a similar way. It is far less infectious and is mainly found among people in a few West African countries (Mali, Mauritania, Nigeria, and Sierra Leone)(“Origin of HIV & AIDS,” 2015) . The first known case of HIV-1 was detected in a man from Kinshasa of the Democratic Republic of the Congo during the 1950’s (“Where Did HIV Come From,” 2011).This area is known to have the most genetic diversity among HIV strains, indicating that there were several different instances of SIV being transferred to humans. People first became aware of HIV and AIDS when it began emerging in the United States and it wasn’t until this time that it became recognized as a medical condition. (“Origin of HIV & AIDS,” 2015).
Life Cycle
During early infection, HIV is macrophage tropic, meaning that it only infects natural killer cells, CD8+ killer T cells, macrophages, cells of the nervous system, and dendritic cells. During that phase, the cells harbor, replicate, and bud HIV without lysis. On the contrary, during later infections, HIV is T-lymphocyte tropic, meaning it infects CD4+ T lymphocytes and will lyse them during production of new viruses, making it a productive infection. HIV enters a cell by interacting its gp120 portion, the head portion of the protruding glycoprotein, with CD4, the major cellular receptor that is abundantly present on T lymphocytes. This interaction causes a conformational change in gp120 and gp41, the spike portion of the protruding glycoprotein, resulting in the exposure of new binding regions on these proteins, thus causing a co-receptor reaction with either CCR5, the macrophages’ co-receptor, or fusin, the T lymphocyte co-receptor. The virus then embeds into the membrane of the CD4+ cell. The gp41 protein changes into a coiled shape that brings the virus and cell membrane close to each other, allowing the fusion of the virus’ membrane and the host cell, resulting in entry and uncoating, which is the release of viral nucleic acids. In the cytoplasm, the viral RNA is converted to DNA by the HIV-encoded reverse transcriptase. The reverse transcriptase binds to the tRNAlys, which is bound to the RNA genome that serves as a primer for the reverse transcriptase, initiating DNA synthesis. When the reverse transcription is completed, it produces a double-stranded DNA (dsDNA) that contains long terminal repeats (LTRs) located at the end of the viral genome. The viral DNA is transported to the nucleus where it may be integrated into the host’s chromosomal DNA, which is catalyzed by integrase protein found on the HIV.
Components
The different components that make up the Human Immunodeficiency Virus include viral enzymes and structural and accessory proteins. There are three viral enzymes: Reverse Transcriptase (RT), Integrase (IN), and HIV Protease (PR). The Reverse Transcriptase builds a new DNA from the viral RNA genome aiding in its replication (Figure 1A). Integrase is responsible for inserting a viral DNA copy into the infected cellular genome (Figure 1B). The HIV protease is needed for maturation (Figure 1C). The structural proteins that make up HIV are matrix, capsid, envelope, and nucleocapsid proteins. The matrix proteins are responsible for forming a coat on the viral inner membrane. The capsid proteins form a cone-shaped coat that aid the virus in being injected into cells. The envelope proteins, SU and TM, binds to the receptors of virally-infected cell to inject it with the HIV’s RNA. The nucleocapsid proteins form a complex to protect the viral RNA. The accessory proteins include viral protein u (Vpu), viral infectivity factor (Vif), viral protein r (Vpr), P6, negative regulatory factor (Nef), regulator of virion (Rev), and trans-activator of transcription (Tat). Vpu aids in the release of virions by allowing the cell envelope to open easier, thereby enhancing the release of the new virions into the host. This is achieved by decreasing the strength of the interactions with the proteins that hold the envelopes to the cell membrane (Guatelli 2009). Viral infectivity factor (Vif) helps with the infection by marking APOBEC3G, a host protein that inhibits the virus’s virulence, to be degraded by the host’s own immune system. This makes the virus more virulent to the host. Vif is mandatory for infection in certain, but not all, types of cells (Rose 2004). Viral protein R is yet another protein that increases the infectivity of HIV. Vpr has several important functions the first of these being its ability to allow viral components to cross the nuclear membrane. Vpr is also capable of preventing host cell division by arresting cell growth in G2 phase. A separate property that this protein has been shown to possess is the ability to cause apoptosis in human cells (Morellet 2003). P6 serves as a docking site for both viral and cellular materials. This protein is also necessary for Vpr to be incorporated into virons, as well as contributing to viral budding (Solbak 2013). Negative regulatory factor (Nef) is important in early development of the virus. It enables T cell activation and causes the endurance of the virus. This protein downregulates the immune response of the host and its production of surface molecules, allowing the infected cells to persist (Das 2005). Regulator of virion (Rev) interacts with viral RNA during a later stage of viral replication. It mainly functions to transport viral, unspliced RNA out of the nucleus and then ensures that these unspliced RNA are assembled into the virion particles (Blissenbach 2010). Trans-activator of transcription (Tat) is an early HIV protein that promotes transcription by interacting with the viral long terminal repeat (LTR) at the transactivator response element (TAR) hairpin. While its major function involves stimulating transcription, Tat regulates gene expression in other significant ways as well, such as recruiting proteins that deal with elongation and the processivity of RNA polymerase II, RNA processing, and chromatin modifications (Das 2011). Viral protein u weakens the interaction between the cell’s receptors and the envelope proteins to help the virus escape. Viral infectivity factor destroys the cell’s defense proteins to aid in destroying the cell. Viral protein r serves a guide for the viral genome into the nucleus. P6 helps in embedding Vpr in virus. Negative regulatory factor inhibits the infected cell from making more defense proteins. Regulator of virion regulates the splicing and transport of viral RNA. The trans-activator of transcription enhances the amount of protein made.
This is a sample scene created with SAT to by Group, and another to make of the protein. You can make your own scenes on SAT starting from scratch or loading and editing one of these sample scenes.
</StructureSection>
References
Blissenbach, M., Grewe, B., Hoffman, B., Brandt, S., Uberla, K. (2010). Nuclear RNA export and packaging functions of HIV-1 Rev revisited. Journal of Virology, 84(13), 6598-604. http://www.ncbi.nlm.nih.gov/pubmed/20427541 Das, A. T., Harwig, A., & Berkhout, B. (2011). The HIV-1 Tat Protein Has a Versatile Role in Activating Viral Transcription. Journal of Virology, 85(18), 9506–9516. http://doi.org/10.1128/JVI.00650-11. Das, S.R., Jameel, S. (2005). Biology of the HIV Nef protein. Indian Journal of Medical Research, 121(4), 315-332. http://www.ncbi.nlm.nih.gov/pubmed/15817946. Daugherty, M.D., Liu, B., Frankel, A.D. (2010). Structural basis for cooperative RNA binding and export complex assembly by HIV Rev. Nat.Struct.Mol.Biol., 17, 1337-1342. http://www.rcsb.org/pdb/explore/explore.do?structureId=3LPH Global HIV and AIDS Statistics. (2015). Retrieved from Averting HIV and AIDS. http://www.avert.org/professionals/hiv-around-world/global-statistics Hemelaar, J. (2012). The Origin and Diversity of the HIV-1 pandemic.In Trends in Molecular Medicine, 18(3):182-192 .http://doi.org/10.1016/j.molmed.2011.12.001 Morellet, N., Bouaziz, S., Petitjean, P., Roques, B. P. (2003). NMR Structure of the HIV-1 Regulatory Protein VPR. J. Mol. Biol, 327, 215-227. http://www.sciencedirect.com/science/article/pii/S0022283603000603 Oie Solbak, Sara Marie, Reksten, Tove Ragna, Hahn, Friedrich, Wray, Victor, Henklein, Petra, Henklein, Peter, Halskau, Oyvind, Schubert, Ulrich, Fossen, Torgils. (2013). HIV-1 p6 - a structured to flexible multifunctional membrane-interacting protein. Biochimica et Biophysica Acta, 1828, 816-823. http://www.ncbi.nlm.nih.gov/pubmed/23174350. Origin of HIV & AIDS. (2015). Retrieved from Averting HIV and AIDS. http://www.avert.org/professionals/history-hiv-aids/origin Rose, Kristine M., Marin, Mariana, Kozak, Susan L., Kabat, David. (2004). The viral infectivity factor (Vif) of HIV-1 unveiled. TRENDS in Molecular Medicine, 10(6), 291-297. http://www.sciencedirect.com/science/article/pii/S1471491404001054 The HIV Life Cycle. (2015). Retrieved from AIDSinfo. https://aidsinfo.nih.gov/education-materials/fact-sheets/19/73/the-hiv-life-cycle Where Did HIV come From? (2011). Retrieved from The AIDS institute http://www.theaidsinstitute.org/education/aids-101/where-did-hiv-come-0
