Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Lecture 12: HIV Infection Questions to Consider How does HIV-1 use the efficiency of the immune system to efficiently infect and destroy the immune system? What features of HIV-1 replication permit it to evade the immune system as well as to become resistant to antiretrovirals? How is HIV-1 replication regulated to synchronize its replication to that of its host cell? What molecular mechanisms are used by HIV-1 to evade innate anti-viral cellular responses? Mode of HIV Transmission Flint, Principles of Virology, 2nd Ed. Infectivity of Body Fluids and Cells Flint, Principles of Virology, 2nd Ed. Initiation of HIV-1 Infection Initiation of HIV-1 Infection Abbas- Cellular and Molecular Immunology M Cells May Provide a Portal for HIV-1 Entry Rapid Depletion of Intestinal CD4+ T Cells After HIV Infection JEM, 2004;200:6:749 HIV Uses the Mucosal Immune System to Disseminate Overview of the Course of HIV-1 Infection Abbas- Cellular and Molecular Immunology Clinical Course of HIV-1 Infection Is Associated With Depletion of CD4+ T Cells Course of HIV Infection and Onset of Immunodeficiency Flint, Principles of Virology, 2nd Ed. HIV Infection Causes Destruction of Lymphoid Tissue Architecture Flint, Principles of Virology, 2nd Ed. HIV Infection Causes Destruction of Lymphoid Tissue Architecture Flint, Principles of Virology, 2nd Ed. Structure of HIV-1 The HIV-1 Genome Encodes Structural and Regulatory Proteins HIV Transcription Involves Multiple Reading Frames and RNA Splicing HIV-1 Entry, Transcription and Integration Entry of HIV-1 Requires Interaction of gp120 With CD4 and a Chemokine Receptor Abbas- Cellular and Molecular Immunology Divergent Behavior of HIV Isolates: M-tropic and T-tropic Isolates M-tropic HIV isolates infect monocytes, primary T lymphocytes and NOT T cell lines. M-tropic isolates initiate infection after transmission and are the predominant isolate until late in the disease course. T-tropic HIV isolates infect, T cell lines, primary T lymphocytes and NOT monocytes T-tropic isolates are the predominant isolate in later stages of the disease course. M-tropic and T-tropic HIV Isolates are Defined by Their Use of Coreceptors Flint, Principles of Virology, 2nd Ed. A Broad Range of Chemokines Selectively Induce the Migration of Different Inflammatory Cells CXC Motif Chemokines CC Motif Chemokines Reverse Transcription is Critical for Translation of HIV-1 RNA Genome Into DNA Activated T Cells are The Primary Source of HIV-1 but Memory Cells are the Primary Reservoir Abbas- Cellular and Molecular Immunology Rapid Kinetics of HIV-1 Replication and High Error Rate of RT Contribute to the Emergence of Mutants Rapid HIV-1 infectious cycle- ~109 HIV particles produced daily. HIV-1 life span free virions- 8 hrs HIV-1-infected cells- 2.2 days ~ 300 replication cycles/year Because RT does not proof-read, one mutation/104 bases occurs. With a genome of 104 bases, a mutation occurs at each position HIV-1 over 10,000 times every day. This generates resistant mutants that will selectively become the predominant population. Rapid Emergence of HIV-1 Drug Resistant Mutants Immune Response Directed Against HIV-1 Controls but Does Not Eradicate Infection The CTL Response is Critical to Control Viral Infections There Are Two Different Types of MHC Molecules Capable of Presenting Peptides to T Cells Virally Encoded Proteins Are Presented by MHC Class I Molecules Presentation of Peptide to CD8 by Class I MHC Molecules T cell epitopes Peptide MHC Class I From Dr. Stanley Nathenson Anchor Residues Possible Strategies Used by HIV to Evade the CTL Response Generation of immune epitope escape mutants Reduction in the level of HLA class I molecule surface expression Decreasing the qualitative activity of HIV-specific CTLs suppressing their function by chronic antigenic exposure decreasing their perforin production shortening their telomere length increasing their susceptibility to apoptotic death. Reduction in available CD4+ T lymphocyte help Anchor Residue Motifs Determine Binding of Peptides to MHC Molecules HIV Mutates Anchor Residue of Immunogenic Epitope to Evade CTL Response Nature 2001;412:334 HIV Mutates Anchor Residue of Immunogenic Epitope to Evade CTL Response Nature 2001;412:334 Nef Downregulates Surface Expression of CD4 and MHC Class I Molecules Flint, Principles of Virology, 2nd Ed. Nef Downregulates MHC Class I Expression Protecting HIV-infected Cells From CTLs Nature. 1998;391:397 HIV-specific CTL Immunity May Be Compromised by Expression of Immunoinhibitory PD-1 J Exp Med. 2006;203:2223. Using Lentiviral Vectors To Reprogram CD8 CTLs To Be HIV-specific Neutralizing Antibodies Can Prevent Viral Infection Differential Effect of Antibodies on HIV Infection Flint, Principles of Virology, 2nd Ed. Neutralizing Antibodies Bind Sites on gp41 Nabel, Science 308 (5730), 1878. Neutralizing Antibodies Bind Sites on gp120 Nature Immunology 5, 233 - 236 (2004) Escape of HIV From Passsive anti-HIV Antibody Therapy (2F5, 4E10, 2G12) Nature Medicine 2005;11:593 The Capacity of Each Antibody to Recognize HIV is Conferred by a Small Highly Unique Region Generated by Genetic Shuffling Using Gene Therapy To Educate B Cells to Make Broadly Neutralizing HIV-specific Antibodies Clone out the antiHIV antibody genes into a lentivector B cell making neutralizing Antibodies to HIV Genetically educated B cell from an HIV-infected patient now makes broadly neutralizing antibodies to HIV Uneducated B cell from an HIV-infected patient Lentivirus antibody gene therapy vector Activated T Cells are The Primary Source of HIV-1 but Memory Cells are the Primary Reservoir Abbas- Cellular and Molecular Immunology Differential HIV-1 Replication Rates in Different Cells Can Result in Latent Infection or Lysis Scientific American October 1988 TCR Signal Transduction Uses Nuclear Binding Proteins Abbas- Cellular and Molecular Immunology HIV-1 LTR is Regulated by Cellular Nuclear Binding Proteins The HIV-1 Proteins Tat and Rev are Critical for HIV-1 Virion Production Secondary Structure of TAR and Rev-Responsive Element (RRE) HIV Transcription Involves Multiple Reading Frames and RNA Splicing Rev Protein is Required for Transport of Unspliced HIV mRNA Rev Protein is Required for Transport of Unspliced HIV-1 Structural RNAs CRS- cis restrictive sequence CAR- cis acting region No Rev + Rev Scientific American October 1988 Vif Vif = viral infectivity factor A basic ~23,000 kD phosphoprotein Required for efficient HIV-replication in primary T cells Differential Infection of Permissive and Nonpermissive Cells by Vif HIV-1 2004;10:391 Expression of CEM15 in CEM-SS Cells Selectively Inhibits HIV-1 vif Replication From Sheehey et al. Nature 2002; 418, 646 - 650 Vif Sequesters APOBEC3G Permitting Production of Infectious HIV Questions to Consider How does HIV-1 use the efficiency of the immune system to efficiently infect and destroy the immune system? What features of HIV-1 replication permit it to evade the immune system as well as to become resistant to antiretrovirals? How is HIV-1 replication regulated to synchronize its replication to that of its host cell? What molecular mechanisms are used by HIV-1 to evade innate anti-viral cellular responses?