* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download HIVART_4 - I-Tech
Survey
Document related concepts
Immune system wikipedia , lookup
DNA vaccination wikipedia , lookup
Hygiene hypothesis wikipedia , lookup
Globalization and disease wikipedia , lookup
Molecular mimicry wikipedia , lookup
Adoptive cell transfer wikipedia , lookup
Cancer immunotherapy wikipedia , lookup
Adaptive immune system wikipedia , lookup
Innate immune system wikipedia , lookup
Polyclonal B cell response wikipedia , lookup
Psychoneuroimmunology wikipedia , lookup
Transcript
HIV Pathogenesis and Natural Course of the Disease Unit 4 HIV Care and ART: A Course for Physicians Learning Objectives Describe the origin and basic virology of HIV-1 Describe the normal immunological response to HIV-1 List the mechanisms used by HIV-1 to evade the normal immune responses Explain the principles of HIV-1 pathogenesis Describe the natural course of HIV-1 2 HIV-1 Virology Transfer of SIV to Humans “Natural transfer” theory (Science 2000) SIV was transferred to humans through hunting and handling of chimpanzees The epidemic required urbanization and increased population mobility Most scientific-based theory 4 Transfer of SIV to Humans (2) “Human error” theory (Edward Hooper,“The River” 2000) Oral polio vaccine used in West Africa during the late 1950s may have been contaminated with SIV SIV has not been recovered from this vaccine in subsequent studies 5 Spread of HIV in Africa, 1990-2005 Source: UNAIDS, 2006 6 The HIV Epidemic Unfolds Sudden outbreak in USA of opportunistic infections and cancers in homosexual men in 1981 Pneumocystis carinii pneumonia (PCP), Kaposi’s sarcoma, and non-Hodkins lymphoma HIV isolated in 1984 - Luc Montanier (Pasteur Institute, Paris) and Robert Gallo (NIH, Bethesda, USA) HIV diagnostic tests developed in 1985 First antiretroviral drug, zidovudine, developed in 1986 Exploding pandemic Has infected more than 50 million people around the world Has killed over 22 million people 7 Classification of HIV HIV class: Lentivirus Retrovirus: single stranded RNA transcribed to double stranded DNA by reverse transcriptase Integrates into host genome High potential for genetic diversity Can lie dormant within a cell for many years, especially in resting (memory) CD4+ T4 lymphocytes HIV type (distinguished genetically) HIV-1 -> worldwide pandemic (current ~ 40 M people) HIV-2 -> isolated in West Africa; causes AIDS much more slowly than HIV-1 but otherwise clinically similar 8 Classification of HIV-1 HIV-1 groups M (major): cause of current worldwide epidemic O (outlier) and N (Cameroon): rare HIV-1 groups that arose separately HIV-1 M subgroups (clades) >10 identified (named with letters A to K) Descended from common HIV ancestor One clade tends to dominate in a geographic region Clades differ from each other genetically Different clades have different clinical and biologic behavior 9 Origin and Distribution of HIV-1 Clades HIV-1 rapidly evolves by two mechanisms: Mutation: changes in single nucleosides of the RNA Recombination: combinations of RNA sequences from two distinct HIV strains Several common clades (e.g., A/G ad A/E) are recombinants Geographic distribution of HIV group M clades A in Central Africa B in North American, Australia, and Europe C in Southern and Eastern Africa (Ethiopia) 10 11 12 HIV at Surface of CD4 Lymphocyte 13 Courtesy of CDC How HIV Enters Cells gp120 env protein binds to CD4 molecule CD4 found on T-cells macrophages, and microglial cells Binding to CD4 is not sufficient for entry V3 loop of gp120 env protein binds to co-receptor CCR5 receptor - used by macrophage-tropic HIV variants CXCR4 receptor - used by lymphocyte-tropic HIV variants Binding of virus to cell surface results in fusion of viral envelope with cell membrane Viral core is released into cell cytoplasm 14 HIV HIVReceptors Receptors HIV and Cellular Receptors Copyright © 1996 Massachusetts Medical Society. All rights reserved. 15 Viral-host Dynamics About 1010 (10 billion) virions are produced daily Average life-span of an HIV virion in plasma is ~6 hours Average life-span of an HIV-infected CD4 lymphocytes is ~1.6 days HIV can lie dormant within a cell for many years, especially in resting (memory) CD4 cells, unlike other retroviruses 16 HIV Immunology Overview of Adaptive Immune Response Extracellular infection APC Intracellular infection MHC I presentation of endogenous antigen Free antigen MHC II presentation of exogenous antigen Naïve T8 cell Naïve B-Cell Naïve T4 helper cell Cell-mediated (CTLs) Th1 Th2 Humoral (plasma cells / antibodies) 18 Diagram courtesy of Dr. Samuel Anderson General Principles of Viral-host Interactions: Host: mounts HIV-specific immune responses Cellular (cell-mediated) - most important Humoral (antibody-mediated) Virus: subverts the immune system Infects CD4 cells that control normal immune responses Integrates into host DNA High rate of mutation Hides in tissue not readily accessible to immune system Induces a cytokine environment that the virus uses to its own replicative advantage • Achieved by “activation” of the immune system 19 Cellular Immune Responses to HIV CD8 Cytotoxic T lymphocyte (CTL) Critical for containment of HIV Derived from naïve T8 cells, which recognize viral antigens in context of MHC class I presentation Directly destroy infected cell Activity augmented by Th1 response 20 Cellular Immune Responses to HIV CD4 Helper T Lymphocyte (Th) Plays an important role in cell-mediated response Recognizes viral antigens by an antigen presenting cell (APC) • Utilizes major histocompatibility complex (MHC) class II Differentiated according to the type of “help” • Th1 - activate Tc (CD8) lymphocytes, promoting cellmediated immunity • Th2 - activate B lymphocytes, promoting antibody mediated immunity 21 Humoral Immune Response to HIV Neutralization Antibodies bind to surface of virus to prevent attachment to target cell Antibody-dependent cell-mediated cytotoxicity (ADCC) Fc portion of antibody binds to NK cell Stimulates NK cell to destroy infected cell 22 HIV Evasion Methods Makes 10 billion copies/day -> rapid mutation of HIV antigens Integrates into host DNA Depletes CD4 lymphocytes Down-regulation of MHC-I process Impairs Th1 response of CD4 helper T lymphocyte Infects cells in regions of the body where antibodies penetrate poorly, e.g., the central nervous system 23 Pathogenesis of HIV Cells Infected by HIV Numerous organ systems are infected by HIV: Brain: macrophages and glial cells Lymph nodes and thymus: lymphocytes and dendritic cells Blood, semen, vaginal fluids: macrophages Bone marrow: lymphocytes Skin: langerhans cells Colon, duodenum, rectum: chromaffin cells Lung: alveolar macriphages 25 General Mechanisms of HIV Pathogenesis Direct injury Nervous (encephalopathy and peripheral neuropathy) Kidney (HIVAN = HIV-associated nephropathy) Cardiac (HIV cardiomyopathy) Endocrine (hypogonadism in both sexes) GI tract (dysmotility and malabsorption) Indirect injury Opportunistic infections and tumors as a consequence of immunosuppression 26 General Principles of Immune Dysfunction in HIV All elements of immune system are affected Advanced stages of HIV are associated with substantial disruption of lymphoid tissue Impaired ability to mount immune response to new antigen Impaired ability to maintain memory responses Loss of containment of HIV replication Susceptibility to opportunistic infections 27 Mechanisms of CD4 Depletion and Dysfunction Direct Elimination of HIV-infected cells by virus-specific immune responses Loss of plasma membrane integrity because of viral budding Interference with cellular RNA processing Indirect Syncytium formation Apoptosis Autoimmunity 28 Syncytium Formation Observed in HIV infection, most commonly in the brain Uninfected cells may then bind to infected cells due to viral gp 120 This results in fusion of the cell membranes and subsequent syncytium formation. These syncytium are highly unstable, and die quickly. 29 Apoptosis 30 Courtesy of CDC Role of Cellular Activation in Pathogenesis of HIV HIV induces immune activation Which may seem paradoxical because HIV ultimately results in severe immunosuppression Activated T-cells support HIV replication Intercurrent infections are associated with transient increases in viremia The magnitude of this increase correlates inversely with stage of HIV disease Accounts for why TB worsens underlying HIV disease 31 Role of Cytokine Dysregulation in Pathogenesis of HIV HIV is associated with increased expression of pro-inflammatory cytokines TNF-alpha, IL-1,IL-6, IL-10, IFN-gamma Associated with up-regulation of HIV replication HIV results in disruption and loss of immunoregulatory cytokines IL-2, IL-12 Necessary for modulating effective cell-mediated immune responses (CTLs and NK cells) 32 Consequence of Cell-mediated Immune Dysfunction Inability to respond to intracellular infections and malignancy Mycobacteria, Salmonella, Legionella Leishmania, Toxoplama, Cryptosporidium, Microsporidium PCP, Histoplamosis HSV, VZV, JC virus, pox viruses EBV-related lymphomas 33 Natural History of HIV Infection Transmission Modes of infection Sexual transmission at genital or colonic mucosa Blood transfusion Mother to infant Accidental occupational exposure Viral tropism Transmitted viruses is usually macrophage-tropic Typically utilizes the chemokine receptor CCR5 to gain cell entry Patients homozygous for the CCR5 mutation are relatively resistant to transmission 35 Early Phases of HIV Infection of Mucosal Surfaces Cell free HIV T-cell Immature Dendritic cell Skin or mucosa HIV co-receptors, CD4 + chemokine receptor CC5 Burst of HIV replication Via lymphatics or circulation 24 hours 1. PEP 2. 48 hours Selective of macrophagetropic HIV 3. Mature Dendritic cell in regional LN undergoes a single replication, which transfers HIV to 36 T-cell Laboratory Markers of HIV Infection Viral load Marker of HIV replication rate Number of HIV RNA copies/mm3 plasma CD4 count Marker of immunologic damage Number of CD4 T-lymphocytes cells/mm3 plasma Median CD4 count in HIV negative Ethiopians is significantly lower than that seen in Dutch controls • Female 762 cells/mm3 (IQR 604-908) • Male 684 cells/mm3 (IQR 588-832) 37 Spread of HIV in Host Tissues Copyright © 1998 Massachusetts Medical Society. All rights reserved. 38 Primary HIV Infection The period immediately after infection characterized by high level of viremia (>1 million) for a duration of a few weeks Associated with a transient fall in CD4 Nearly half of patients experience some mononucleosislike symptoms (fever, rash, swollen lymph glands) Primary infection resolves as body mounts HIV-specific adaptive immune response Cell-mediated response (CTL) followed by humoral Patient enters “clinical latency” 39 Window Period: Untreated Clinical Course Acute HIV syndrome Primary HIV infection Asymptomatic antibody viremia --------------------------------------------PCR P24 ELISA a 0 2 3 b Time from a to b is the window period 4 years Weeks since infection Source: S Conway and J.G Bartlett, 2003 40 Natural History of HIV-1 Fauci As, 1996 41 HIV RNA Set Point Predicts Progression to AIDS HIV RNA viral loads after infection can be used in the following ways: To assess the viral set point To predict the likelihood of progression to AIDS in the next 5 years The higher the viral set point: The more rapid the CD4 count fall The more rapid the disease progression to AIDS 42 CD4 T-cell Count and Progression to AIDS In contrast to VL, baseline CD4 is not a good predictor of time to progression to AIDS Unless CD4<321 cells/ml However, as the CD4 count declines over time, patients will develop opportunistic infections Develop in a sequence predictable according to CD4 count WHO Staging system 43 Key Points HIV is a retrovirus, capable of integrating into host genome and establishing chronic infection HIV can be classified into subgroups (clades) which have characteristic geographic distribution The important steps in the lifecycle of HIV include cell entry, reverse transcription, integration, and maturation/assembly Cell-mediated immunity is critical for containment of HIV infection and other intracellular infections HIV evades host immunity by a variety of mechanisms 44 Key Points (2) HIV activates the immune system to increase its own replication CD4 count declines by both direct and indirect mechanisms HIV RNA set point predicts rate of progression to AIDS CD4 count decline is associated with a predictable sequence of opportunistic infections 45