Lecture 27 The Biology of HIV Questions Why is president Mbeki responsible for approximately 300 000 deaths that occurred in his country What person s theory did he buy into He delayed access to health care and medications because he believed an online article that said there was no correlation between HIV and AIDS Peter Duesberg Regarding HIV 1 and HIV 2 which of these statements are true HIV 2 causes a more serious infection than HIV 1 HIV 2 has been cured and HIV 1 has not been cured Immunodeficiency progresses more slowly in HIV 2 patients HIV 1 is more infectious The modes of transmission for HIV 1 and HIV 2 are very different What factors contributed to the massive spread of HIV 1 and still contributes to the epidemic Drug abuse mother to child transmission international travel or just travel interaction with chimpanzees unprotected sex What are some of the strange diseases that showed up in young otherwise healthy gay men at the time HIV was being discovered phenomena Karopsi s Sarcoma yeast infection of the mouth or other orifices Where geographically did HIV 1 come from and how did it originate Central Africa What are Viruses DNA or RNA A virus particle or virion consists of the following o Nucleic acid Genetic instructions either single stranded or double stranded o Coat of protein Surrounds the DNA or RNA to protect it capsid o Lipid membrane Surrounds the protein coat of SOME virions lipid bilayer stolen from host cell o Called enveloped viruses o Examples HIV and influenza How Small is HIV An HIV particle is around 100 150 billions of a meter in diameter That s about the same as One seventieth of the diameter of a human CD4 white blood cell 0 1 microns 4 millions of an inch What Type of Virus is HIV HIV is a lentivirus all attack the immune system Lentiviruses are a type of retrovirus Transmitted as enveloped RNA virus Upon target cell entry viral RNA is converted to dsDNA by reverse transcriptase present in the virus particle The Simian Immunodeficiency Virus SIV affects monkeys Generally accepted that HIV is a descendent of SIV because certain strains of SIVs bear a very close resemblance to HIV 1 and HIV 2 Major Viral Components Has 72 spikes that go across the membrane Spikes are made up of the protein GT120 Underneath in the membrane is gp41 Spikes allow to interact with target cell Capsid inside is reverse transcriptase GP120 and gp41 need to know How Does HIV Bind to Target Cells Integrase CD4 binding Coreceptor binding Virus cell fusion CD4 means that the CD4 receptor exists on the cell surface Going to interact with the gp120 CD4 will bring that HIV particle down and will interact with CCR5 Starts to penetrate the membrane gp41 membrane penetration Whole population of people who have mutated CCR5 receptors so they are not susceptible to HIV Descendants of black plague survivors Binding of HIV to CD4 T cell Movie on moodle that will walk you through this process Replication of HIV released 1 HIV attaches to host cell at membrane protein CD4 2 Viral envelopre fuses with plasma membrane capsid break down and RNA is 3 Viral RNA uses reverse transcriptase to make complementary DNA cDNA 4 Viral RNA degrades 5 Reverse transcriptase synthesizes the second DNA strand 6 cDNA enters the nucleus and is integrated into the host chromosome via HIV protein integrase forming a provirus 7 Upon activation proviral DNA is transcribed to viral RNA which is exported to the cytoplasm In the cytoplasm the viral RNA is translated into proteins using host ribosomes 8 9 Viral protein matures via HIV protease 10 Viral glycoproteins new capsids RNA and viral envelopes are assembled 11 An assembled virus buds from the plasma membrane HIV integrase is responsible for integrating HIV DNA into host cell DNA Thus an attractive target for anti HIV drugs HIV Integrase HIV Protease PR HIV PR cleaves newly synthesized polyproteins 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 therapy Questions Two single of RNA What type of genetic material is enclosed in the HIV capsid What is the first step in HIV binding to a target cell Looks for cells with CD4 receptors and uses GP120 will interact with CD4 Which protein inserts into the target cell membrane GP41 protein Patients infected with HIV most often take a combination cocktail of drugs The treatment is called HAART or Highly Active Antiretroviral Therapy Targeting multiple different aspects of the HIV s life cycle from binding to target cells to budding impedes the virus gaining drug resistance The goal is to lower viral load in the body or slow down the production of infectious virions What type of drugs would you include in a cocktail What part of the lfie cycle would they target or inhibit Inhibiting binding protease integrase reverse transcriptase Cell Types Infected by HIV Helper T Cells Natural Killer T Cell Macrophage Natural Killer T Cell CD4 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 types HIV S Path to Immune System Destruction Establishment of infection in lymphoid tissue Massive amount of HIV in bloodstream Wide dissemination to lymphoid organs Trapping of virus and establishment of chronic persistent infection Inflammation occurs and CD4 cells are called in via signaling for an immune response leading to more infection Accelerated virus replication destruction of immune system How Does HIV Destroy CD4 Cells Lysis of budding virus particles Mutations occur Cell undergoes programmed cell death 95 CD4 cells in lymphoid tissue HIV Induced Syncytia on plasma membrane The fusion of CD4 cells target cells due to some cells expressing gp120 protein
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