32 the normal ligands for this receptor rantes mip 1

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32 The normal ligands for this receptor, RANTES , MIP-1 β , and MIP-1 α , are able to suppress HIV-1 infection in vitro . HIV uses the CCR5 co-receptor A number of new experimental HIV drugs, called entry inhibitors , have been designed to interfere with the interaction between CCR5 and HIV PRO140 ( Progenics ) = McAb, injected every other week Vicriviroc ( Schering Plough ) = noncompetitive allosteric antagonist of CCR5. Late stage clinical trials did not meet their primary efficacy endpoints = not pursue regulatory approval Aplaviroc (GW-873140) ( GlaxoSmithKline ) = Development of Aplaviroc has been terminated due potential liver toxicity. Maraviroc (UK-427857) ( Pfizer ) = full FDA approval on August 6, 2007. Industry experts forecast annual Maraviroc sales of $500 million by 2011.
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33 Under selective pressure HIV will evolve to use another co-receptor Binding to alternative domains of CCR5, or • By binding to the receptor at a higher affinity. Concerns surrounding CCR5 antagonists Maraviroc-resistant variants of HIV-1 have already been generated in vitro by mutating residues in the V3 loop of gp120
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34 HIV is a Retrovirus HIV RNA DNA Copy Transcriptase Reverse HIV RNA provirus Normally : DNA RNA Protein
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35 HIV Structure
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36 Steps in general viral replication 1. Union of virus and host cell (adsorption) 2. Penetration and uncoating 3. Nucleic acid synthesis 4. Viral protein synthesis 5. Assembly of new viruses 6. Release of new viruses Capsid Genome Nucleus Genome Capsid Fig 2.13
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37 Replication Cycle of HIV (Fig 2.14) reverse transcriptase Replicating host cells Virus is ready to “bud” out of infected cell provirus (a) (f) (e) (d) (c) (b) HIV RNA RNA provirus host DNA cell nucleus capsid provirus New viral capsids and RNA host DNA cell nucleus New spikes inserted in cell membrane reverse transcriptase host DNA HIV DNA
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38 Movie of HIV replication cycle http://www.youtube.com/watch?v=1P0VVPU5j6E
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39 Life cycle of HIV
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40 Provirus = lysogeny = latent infection
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