MicroBio 160 1st Edition Lecture 21 Outline of Last Lecture I. Strange DiseasesII. AIDSIII. Does HIV cause AIDS?IV. Peter Duesberg and AIDS DissidentsV. Koch’s PostulateVI. HIV-1 and HIV-2VII. Origins of HIV VIII. How Did HIV Spread into Humans?IX. HIV InfectionX. What Lead to the Current HIV Epidemic?Outline of Current Lecture I. What are VirusesII. Characteristics of HIVIII. Types of HIVIV. Major Viral ComponentsV. HIV binding to CD4+ T-cellVI. Replication of DNAVII. HIV IntegraseVIII. HIV ProteaseIX. HIV PathogenesisX. How does HIV destroy CD4+ cellsXI. SyncytiaCurrent LectureWhat are viruses?:- A virus particle, or virion (virus particle), consists of the following: - Each individual shape are all different types of viruses o Nucleic acid - Genetic instructions, either single-stranded or double-stranded DNA or RNAThese notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.o Coat of protein - Surrounds the DNA or RNA to protect it (Accessory proteins are attachment proteins—how a virus attaches to your cells) o Lipid membrane - Surrounds the protein coat of SOME virions – “stolen” from host cell Called enveloped viruses - Examples: HIV and influenza No lipid membrane = “naked”Characteristics of HIV:- An HIV particle is around 100-150 billionths of a meter in diameter. - That's about the same as:o One seventieth of the diameter of a human CD4+ white blood cell.o 0.1 Micronso 4 millionths of an inchWhat type of virus is HIV?- HIV is a lentivirus (slow) – all attack immune systemo Found in a number of different animals, including cats, sheep, horses and cattle - Most interesting lentivirus is the Simian Immunodeficiency Virus (SIV) that affects monkeys—so far unsuccessful but it is what we use as a model to study primates - Generally accepted that HIV is a descendant of SIV because certain strains of SIVs bear a very close resemblance to HIV-1 and HIV-2 - HIV-2 for example corresponds to SIVsm (sm is the species it is found in), a strain of the SIV found in the sooty mangabey (also known as the green monkey), indigenous to western Africa.Major Viral Components: structure - Gp120 and Gp41 are two separate proteins that combine together - Viral Envelopeo P17 P24- Protease- Reverse transcriptase - RNAHIV binding to CD4+ T-cell- Gp120-CD4 binding- Conformation change which pulls the virus closer- Gp120-CD4 BIND (CCR5/cCXCR4)- GP41 membrane: penetration—inserts itself into your membrane - Membrane fusionEnvelope virus: when two plasma membranes meet together, they fuseReplication of HIV:1. HIV attaches to host cell at membrane protein CD42. Viral envelope fuses with plasma membrane, capsid breaks down, and RNA is released3. Viral RNA uses reverse transcriptase to make complementary DNA (cDNA)4. Viral RNA degrades5. Reverse transcriptase synthesizes the second DNA strand6. cDNA enters the nucleus and is integrated into the host chromosome via HIV protein integrase, forming a provirus (it doesn’t realize that it may be infected with HIV—RNA polymerase doesn’t know it isn’t normal so it makes a copy of it)7. Upon activation, proviral DNA is transcribed to viral RNA, which is exported to the cytoplasm8. In the cytoplasm, the viral RNA is translated into proteins using host ribosomes (RNA goes into the capsid, proteins get inserted through the membrane, the virus will butt off)9. Viral protein matures via HIV protease (fully capable of infecting another cell) 10. Viral glycoproteins, new capsids, RNA, and viral envelopes are assembled11. An assembled virus buds from the plasma membraneHIV Integrase: - HIV integrase is responsible for integrating HIV DNA into host cell DNAo It is an attractive target for anti-HIV drugs- On October 12, 2007, the Food and Drug Administration (U.S.) approved the integrase inhibitor Raltegravir (MK-0518, brand name Isentress TM).- The second integrase inhibitor, elvitegravir, was approved in the U.S. in August 2012HIV Protease:- HIV PR cleaves newly synthesized polyproteins (made by our proteins—has to be cut up so we have infectious particles—it can’t spread to further cells) to create the mature protein components of an infectious HIV virion. - Without active HIV PR, HIV virions remain uninfectious.- Thus, HIV PR inhibition is the subject of much research.- Protease inhibitors such as Atazanavir, Lopinavir, and Ritonavir are available for HIV therapyWhy do they make good drug targets? Because it is specific to HIVCell Types Infected by HIV:- Innate immune system recognizes a pathogen and turns on a pathogen: If it doesn’t haveCD-4+ marker on the outside, it can’t infect ito Can also be CCR5, CXCR4- These cells have 3 receptors in common (CD4, CCR5, and CXCR4). HIV uses these 3 receptors to enter hosts, therefore HIV can infect all 4 of these cell typesHIV Pathogenesis: like to alert the body that there is an invader—HIV infects your immune cells so it helps establish an infection inside of the lymphatic tissue due to the alert signal - If you are infected with the virus, your immune system has an immune response—body responds to the HIV and starts killing it- Your body has a hard time clearing HIV—not easy to destroy immune cells, not HPVo Destruction of the immune system occursHow does HIV destroy CD4+ cells?- If hundreds of virus particles are living at the same time, it cant survive- Immune system cells take a piece of HIV and put it on the outside—if the protein on the outside is gp120 then it is expressing the same thingo One cell infected with HIV and one that isn’t—fuse then they are both infecto As HIV comes in contact with new cells they become infected (can happen to hundreds of cells)o Nuclei begins to be knocked out- Anytime a cell says their infected, the cytotoxic t-cells tell it to go through apoptosisHIV induced syncytia:Syncytia: can go into your brain and disrupt brain
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