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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Introduction to Retroviruses

    Basic Biology of HIV-1

    Vivek R. Nerurkar, Ph.D.Professor and Chair

    Department of Tropical Medicine, MedicalMicrobiology and Pharmacology

    John A. Burns School of Medicine

    University of Hawaii at Manoa

    Translational Research in

    NeuroAIDS and Mental Health

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Retroviridae IntroductionFamily/ClassificationStructure/GenomeLifecycle

    HTLVHTLV-1Structure/GenomeLifecycleTransmission

    Learning Objectives

    HIV IntroductionFamily/ClassificationStructure/GenomeLifecycle/BiologyTransmission/

    Pathogenesis

    Diagnosis/Treatment Retroviruses and

    neurological disorders

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Retroviridae: Introduction

    Retro (Latin) = backwards Unique life cycle

    Large and diverse group of viruses found in allvertebrates

    RNA viruses reverse transcribed into DNAintegrate into host chromosomal DNA (provirus)

    template for virus replication and protein expression

    Retroviruses are RNA viruses that copy theirgenome into DNA during their replication.

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Retroviridae: Introduction

    Provirus:PersistenceVertical transmissionMutagenic

    Disease-Immunodeficiency diseases

    Leukemia's

    Solid tumors

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Alpharetrovirus Avian leukosis virus (ALV)

    Rous sarcoma virus (RSV)

    Betaretrovirus Mouse mammary tumor virus (MMTV)Mason-Pfizer monkey virus (MPMV)

    Gammaretrovirus Murine leukemia virus (MuLV)Feline leukemia virus (FeLV)

    Deltaretrovirus Human T-lymphotropic virus (HTLV-1, -2)Simian T-lymphotrophic virus (STLV-1, -2, -3)

    Bovine leukemia virus (BLV)

    Epsilonretrovirus Walleyedermal sarcoma virus

    Lentivirus slow Human immunodeficiency virus (HIV-1, HIV-2)Simian immunodeficiency virus (SIV)

    Equine infectious anemia virus (EIAV)Feline immunodeficiency virus (FIV)

    Caprine arthritis encephalitis virus (CEAV)Visna/maedi virus

    Spumavirus foamy Human foamy virus

    Retroviridae: Family

    Adapted from Fields Virology, 2007

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Genera:

    Simple viruses: encode onlyGag, Pro, Pol, and Env

    Alpha Beta Gamma

    Complex: encode Gag, Pro,Pol, Env, and an array of small

    regulatory proteins

    Delta Epsilon Lentiviruses Spumaviruses

    Retroviridae: Classification

    Fields Virology, 2007

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Simple Retrovirus Retrovirus Genome Organization!

    Complex Retrovirus

    Structural genes: gag, pol, envRegulatory genes: tat, rev

    Accessory genes: vif, vpu, vpr, nef Fields Virology, 2007

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Over 1 million individuals in theUnited States were living with HIV

    infection, with 21% undiagnosedinfections (CDC 2006)

    Nearly 33 million people world-wide were affected by HIV (United

    Nations 2007)

    Human Immunodeficiency Virus

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Milestones in HIV-1 Research

    2009: Thai Phase III HIV vaccine clinical trial, also known as RV144 ends2008: Nobel Prize in Physiology / Medicine-Franoise Barr-Sinoussi, Luc Montagnier, Harald zur Hausen

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Spherical Enveloped 100-120 nm Cone-shaped,cylindrical core

    HIV-1: Structure

    Fields Virology, 2007

    Current Opinion in Microbiology 2006; 4:437-42

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    HIV-1 Biology

    The virus only grows on CD4 cells that are proliferating inresponse to an immune stimulus Therefore it is difficult to growHIV in culture!

    Reverse transcriptase in activated CD4 cells in blood of patientswith AIDS !

    Robert Gallo : HTLV-3!Luc Montagnier and

    Franoise Barr-Sinoussi: !

    Lymphoadenopathy virus (LAV)!

    Human immunodeficiency viral particles areseen at medium magnification in thiselectron micrograph (CDC)

    Human Immunodeficiency

    Virus (HIV)

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    HIV-1 Immunopathogenesis

    Immunol Cell Biol 2007; 1:6-15

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

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    HIV and AIDS: The Cellular and Immunological Picture

    The course of the disease!

    1. Acute Infection!

    High virus titer"Mild symptoms"Fall in CD4+ cells but recovers"Rise in CD8+ cells but recovers

    "A high virus titer (up to 10 million viruses/mL"blood)"Macrophages infected!

    Macrophages bring HIV into the body if sexually transmitted

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    2. A strong immune response!

    Virus almost disappears from circulation! Good cytotoxic T cell response! Soluble antibodies appear later against

    !both surface and internal proteins!

    Most virus at this stage comes from!recently activated (dividing) and

    !infected CD4+ cells ! CD4+ cell production compensates for

    !loss due to lysis of cells by virus!production and destruction of!infected cells by CTLs!

    HIV and AIDS: The Cellular and Immunological Picture

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    3. A latent state" Latency of virus and of symptoms Virus persists in extra-vascular

    tissues

    Lymph node dendritic cells Resting CD4+ memory cells (last a

    very long time - a very stable

    population of cells) carry

    provirus

    HIV and AIDS: The Cellular and Immunological Picture

    10 billion HIV particlesper day!

    Virus half life 5.7 hours!10-100 million virionsper ml blood (set point)

    !

    Small minority of T4cells are infected!

    Virus found in lymphnodes!

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

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    4. The beginning of disease"

    Massive loss of CD4+ cells!

    CD4+ cells are the targets of the virus! Cells that proliferate to respond to the virus are

    !killed by it!

    Dendritic cells present antigen and virus to CD4!cells!

    Epitope variation allows more and more HIV to!escape from immune response just as!response wanes!

    Apoptosis of CD4+ cells!HIV patients with high CD4 cell countsdo not develop AIDS

    HIV and AIDS: The Cellular and Immunological Picture

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    CD4 cell

    count is "not a"good

    predictor of "progressionto disease"

    HIV CD4 Cell Count and AIDS

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    HIV-1: Pathogenesis

    Nat Med 2003; 7:847-52

    HIV primarily infects CD4 T cells andcells of the macrophage lineage (e.g.,

    monocytes, macrophages, alveolarmacrophages of the lung, dendritic

    cells of the skin, and microglial cells ofthe brain).

    Virus causes lytic infection of CD4 Tcells and persistent low-level

    productive infection of macrophage

    lineage cells.

    Virus causes syncytia formation, with

    cells expressing large amounts of CD4antigen (T cells) with subsequent lysis

    of the cells.

    Virus alters T-cell and macrophage cellfunction.

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Positive-sense, single-stranded RNA genome

    HIV-1: Genome

    Fields Virology, 2007

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Positive-sense, single-stranded RNA genome

    HIV-1: Genome Organization

    Main genes gag Group-specific antigen (encodes matrix, capsid, p2,

    nucleocapsid, p1 and p6

    pol polymerase (encodes p6*, protease, RT, Rnase H, integrase

    env envelope

    Auxillary genes nef negative regulatory factor

    rev regulator of expression of virion proteins

    tat transactivator of transcriptionvif virion infectivity factor

    vpr viral protein R

    vpu viral protion U

    Non-coding R repeat sequence

    Sequences U3 unique sequence at the 3 end of the genome

    U5 unique sequence at the 5 end of the genome

    Domains at the TAR trans-acting response element5 end of the Poly-A polyadenylation signal

    genome PBS primer-binding site

    DIS dimerization initiation site

    SD splice donor site

    Psi main part of the packaging signal

    AUG start codon of the gag gene

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    HIV Life History

    A retrovirus"Latency!Specific destruction of

    !CD4+ cells !

    How does the virus!enter the cell?!

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Entry into the cell

    T4 (CD4+) cells are major target

    Human HeLa CellHuman HeLa Cell transfectedwith CD4 antigen

    NOT INFECTED INFECTED

    But NOT the whole answer since this does nothappen if CD4 is transfected into a MOUSE cell"

    HIV Life History

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Co-Receptors!CD8+ Cells"

    "MIP-1 alpha MIP-1 beta RANTES"

    Chemokines""Block HIV infection of macrophages"

    Why do CD4-transfected human cells become infected !but CD4-transfected mouse cells do not?!

    Human cells must possess a co-factor for infection that mouse cells do not!

    HIV Life History

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    HIV-1: Co-receptors

    Tropic and biological properties of HIV-1 isolatesChemokineCoreceptor

    Used

    PBMCReplication

    MacrophageReplication

    T-cell LineReplication

    ReplicativePhenotype

    Syncytium-inducing

    Phenotype

    X4 + _ + Rapid/High ++

    R5 + + _ Slow/Low _

    R5/X4 + + + Rapid/High +

    Adapted from Fields Virology, 2007

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    HIV-1:

    Diagnosis andDisease

    Progression

    Am Fam Physician 2010;10:1239-44

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    HIV-1 Latency and Treatment

    Science 2010; 5988:174-80

    HDAC Histone deacetylases

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    HIV-1: Evolution of Diversity

    N Engl J Med 2008; 18:1965-6

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Features of HIV-1 Pandemic According to

    Subtype or Circulating Recombinant Form

    N Engl J

    Med 2008;18:1965-6!

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Other CD4- cells infected by HIV

    Epithelial cells of!bowel and vagina!

    Brain endothelial!cells!

    Brain macrophage/!microglia,

    !astrocytes and!oligodendroglia!

    !

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Structural: gag, env Functional: pr

    (protease), pol

    (polymerase)

    Regulatory: rex, tax Accessory: p12, p30,

    p13

    Minus strand: HBZ (HTLV-1

    basic zip factor):interact with CREB

    HTLV-1

    transcription

    HTLV-1: Genome

    Lancet Infectious Diseases 2007; 7:266-81

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Unlike HIV, HTLV predominantly remains as cellassociated provirus

    Plasma viral load is very lowDuring early stage cell-to-cell spread throughcontact polyclonal infection of both CD4+ and

    CD8+ cells

    Late stage when equilibrium with immune systemreached: clonal expansion of infected cells

    Hallmark of HTLV-1 infection: spontaneousproliferation of PBMCs in-vitro driven by HTLV-1

    tax

    HTLV-1: Life cycle

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Mother-to-child Rate:15-25% Intrauterine / peripartum:

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    Most common neurological manifestationof HTLV-1

    Chronic inflammation of the white andgrey matter of the spinal cord

    Manifests clinically by slow progressivespastic paraparesis, neurogenic bladder

    disturbances and less conspicuoussensory signs

    HTLV-1: HAM/TSP

    Lancet Neurology 2006; 5:1068

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    Pacific Center for Emerging Infectious Diseases Research, Asia-Pacific Institute of Tropical Medicine & Infectious Diseases

    HIV: HAND

    Ann Neurol 2010; 6:699-714

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