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HIV INFECTION AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)

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Title: HIV INFECTION AND THE ACQUIRED IMMUNODEFICIENCY SYNDROME (AIDS)


1
HIV INFECTIONAND THE ACQUIRED IMMUNODEFICIENCY
SYNDROME (AIDS)
2
HISTORICAL PERSPECTIVES OF AIDS
  • 1981
  • 1982
  • 1983
  • 1984
  • 1986
  • Recognition of Pneumocystis carinii pneumonia
    (PCP) and Kaposis sarcoma (KS) in young healthy
    men in NYC and Los Angeles
  • GRID to AIDS by CDC
  • Isolation of Lymphadenopathy-Associated Virus
    (LAV) by Pasteur Institute (Luc Montagnier)
  • Isolation of Human T-Lymphotrophic Virus , Type
    III (HTLV-III) by NCI/NIH (Robert Gallo)
  • Recommendation of the name Human Immunodeficiency
    Virus (HIV) by an international subcommittee on
    virus taxonomy

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HUMAN IMMUNODEFICIENCY VIRUSES (HIV)
  • Classification
  • Retroviridae (family)
  • Lentivirus (genus)
  • Characteristics
  • 100 nm in diameter
  • Genome of 2 single strands of RNA
  • Nine genes
  • Reverse transcriptase
  • RNA-dependent DNA polymerase
  • Transcribes RNA into DNA

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GENOME OF HIV
  • Contains 6 regulatory genes
  • Contains 3 structural genes
  • Env (Envelope glycoproteins)
  • gp120 and gp41
  • Gag (Core and matrix proteins)
  • p55, p40 and p24
  • Pol (Enzymes)
  • Reverse transcriptase (p66, p51)
  • Protease (p11)
  • Integrase (p32)

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HUMAN RETROVIRIDAE (EXOGENOUS RETROVIRUSES)
  • Seven genera
  • Alpha, Beta, Gamma, Delta, Epsilon, Lenti and
    Spuma
  • Deltavirus
  • Human T-lymphotropic virus, type I (HTLV-1)
  • Human T-lymphotropic virus, type II (HTLV-II)
  • Lentivirus
  • Human immunodeficiency virus, type 1 (HIV-1)
  • Human immunodeficiency virus, type 2 (HIV-2)

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CLASSIFICATION OF THE HUMAN IMMUNODEFICIENCY
VIRUSES (HIV)
  • Types
  • Human immunodeficiency virus, type 1 (HIV-1)
  • Human immunodeficiency virus, type 2 (HIV-2)
  • HIV-1 is divided into groups
  • M (Major)
  • N (New)
  • O (Outlier)
  • Group M is divided into
  • Subtypes (Clades)
  • Circulating recombinant forms (CRF)

15
CLASSIFICATION OF HIV
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ORIGIN OF HUMAN IMMUNODEFICIENCY VIRUSES
  • Existed as monkey virus in equatorial Africa
  • HIV-1
  • Chimpanzee (Pan troglodytes troglodytes)
  • HIV-2
  • Sooty Mangabey (Cercocebus atys)
  • Transition from monkeys to humans
  • When - Circa 1908
  • Molecular phylogenetics
  • How Hunter theory

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MECHANISM OF PATHOGENICITY OF HIV
  • Envelope protein (gp120) of HIV binds with CD-4
    receptor on surface of
  • T-lymphocytes
  • Macrophages
  • Dendritic cells
  • Microglial cells
  • Coreceptors for attachment of HIV
  • CCR5 (T-cells, macrophages, dendritic cells,
    microglial
  • cells)
  • CXCR4 (T-cells)

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MECHANISM OF PATHOGENICITY OF HIV
  • Early infection
  • CCR5 coreceptor is used (R5 strains)
  • Growth equal in monocytes and lymphocytes
  • Non syncytium-inducing (NSI)
  • Late infection
  • CXCR4 coreceptor is used (X4 strains)
  • Growth in T cells
  • Syncytium-inducing (SI)
  • Emergence of X4 strains associated with
    accelerated decline in CD4 T cells
  • Cause or consequence?

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MECHANISM OF PATHOGENICITY OF HIV
  • Following attachment, virus enters cells and
    removes protein coat
  • Viral RNA is transcribed into DNA by
  • Reverse transcriptase
  • Viral DNA then integrated into host cell DNA
  • Integrase
  • Integrated viral DNA
  • Referred to as provirus
  • Production of active infection

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EPIDEMIOLOGY OF HIV INFECTION AND AIDS
  • Since 1981, 65 million people worldwide have
    contracted HIV
  • gt 25 million deaths
  • 87 of HIV cases in developing nations
  • 64 in sub-Saharan Africa
  • 23 in southern and Southeast Asia
  • Since 1981, 1.5 million people in the U.S. have
    contracted HIV
  • Approximately 576,000 deaths
  • In 2009, 56K new cases in the U.S.

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TRANSMISSION OF HIV INFECTION AND AIDS
  • Sexual intercourse with infected person
  • Homosexual (MSM)
  • Heterosexual
  • Bisexual
  • Children born to infected mothers
  • Perinatal
  • IV drug addicts sharing contaminated
    syringes/needles
  • Transfusion of blood and blood products
  • Transfusion recipients
  • Hemophiliacs
  • Occupational exposure in health-care setting

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CDC CLASSIFICATION OF HIV INFECTION AND DISEASE
IN ADULTS AND ADOLESCENTS
  • Latest revision in 1993
  • Clinical Categories
  • A
  • B
  • C
  • CD4 T Cell Categories (Absolute number or )
  • gt 500/uL or gt 29 of total lymphocytes
  • 200 499/uL or 14-28 of total lymphocytes
  • lt 200/uL or lt 14 of total lymphocytes

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CDC CLASSIFICATION SYSTEM
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CDC CLASSIFICATION SYSTEM(CLINICAL CATEGORY A)
  • Following initial infection
  • Asymptomatic
  • Acute Retroviral Syndrome
  • Infectious mononucleosis-like or flu-like illness
  • 2 days to 4 weeks following infection
  • Clinical manifestations
  • Fever, headache, lethargy, pharyngitis, myalgias,
    photophobia, lymphadenopathy and a faint
    maculopapular rash
  • Resolution within 30 days
  • Persistent generalized lymphadenopathy (PGL)

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CDC CLASSIFICATION SYSTEM (CLINICAL CATEGORY B)
  • Symptomatic conditions not meeting conditions of
    clinical categories A or C
  • Herpes zoster (shingles)
  • Oropharyngeal Candidiasis (thrush)
  • Candida albicans
  • Vulvovaginal candidiasis
  • Bacillary angiomatosis
  • Bartonella henselae
  • Peripheral neuropathy
  • Idiopathic thrombocytopenic purpura (ITP)
  • Hairy leukoplakia (oral)

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CDC CLASSIFICATION SYSTEM (CLINICAL CATEGORY C)
  • Acquired Immunodeficiency Syndrome (AIDS)
    Defining Conditions
  • Esophageal Candidiasis
  • Cryptosporidiosis
  • Pneumocystis jiroveci (carinii) pneumonia
  • Tuberculosis (pulmonary or extrapulmonary)
  • Disseminated Mycobacterium avium complex (MAC)
    disease
  • Histoplasmosis (disseminated or extrapulmonary)

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HIV INFECTION IN ADULTS (CLINICAL CATEGORY C)
  • Acquired Immunodeficiency Syndrome (AIDS)
    Defining Conditions
  • HIV wasting syndrome
  • Cryptococcal meningitis
  • Cytomegalovirus retinitis
  • Cerebral Toxoplasmosis
  • Progressive multifocal leukoencephalopathy (PML)
  • JC virus
  • Kaposis sarcoma
  • Human herpesvirus type 8 (HHV-8)

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PROGNOSIS AND MONITORING OF HIV TREATMENT AND
DISEASE
  • CD4 T cell count (Immunological response)
  • Absolute number
  • Best indicator for patients with counts lt 200
    cells/uL
  • Percent
  • Best indicator for patients with counts gt 200
    cells/uL
  • HIV-1 RNA (Viral load) (Virological response)
  • Discordant immunological and virological
    responses exist

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TREATMENT OF HIV INFECTION AND DISEASE
  • Anti-retroviral drugs do not cure HIV infection
    or disease
  • Suppression of virus to undetectable levels
  • Suppression of virus
  • Drugs must be taken continuously
  • Patients remain infectious
  • Mutation rate in HIV is high and resistance
    develops
  • Recommendation for combination therapy
  • Combination of drugs from two or more classes
  • Highly Active Anti-Retroviral Therapy (HAART)

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TREATMENT OF HIV INECTION AND DISEASE
  • Classes of anti-retroviral drugs
  • Reverse Transcriptase Inhibitors (RTIs)
  • Nucleoside
  • Nucleotide
  • Non-nucleoside
  • Protease Inhibitors (PIs)
  • Fusion or Entry Inhibitors
  • Act on gp41 or CCR5 coreceptor
  • Integrase Inhibitors
  • Fixed dose combinations
  • Drugs from two or more classes into a single
    product

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TREATMENT OF HIV INECTION AND DISEASE
  • Reverse transcriptase inhibitors
  • Nucleoside analog (NARTI, NRTI)
  • Converted into nucleotide
  • Incorporated into and stops viral DNA synthesis
  • Zidovudine (Retrovir)
  • Nucleotide analog (NtARTI, NtRTI)
  • Incorporated into and stops viral DNA synthesis
  • Tenofir (Viread)
  • Non-nucleoside (NNRTI)
  • Not incorporated into viral DNA
  • Binds to enzyme and inhibits function
  • Nevirapine (Viramune)

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TREATMENT OF HIV INECTION AND DISEASE
  • Goals of HAART
  • Suppression of HIV
  • Decrease viral load
  • Reduce potential for resistance to anti-viral
    agents
  • Immune system reconstitution
  • Restore CD4 T cell population
  • Immune system reconstitution
  • Most successful with high baseline CD4 count at
    HAART initiation
  • Increase of 50 to 150 cells per year

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TREATMENT OF HIV INECTION AND DISEASE
  • HAART negatives
  • High cost, medication fatigue, adherence to
    complicated drug regimens, adverse events, names
    for anti-retroviral drugs
  • HAART Interruption
  • Minimize negatives using structured treatment
    interruption (STI)
  • 6 months of IL-2 without HAART
  • Safety (unclear) and efficacy (inferior)
  • HAART associated with
  • Immune reconstitution syndrome

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IMMUNE RECONSTITUTION SYNDROME (IRS)
  • Immune reconstitution inflammatory syndrome
    (IRIS)
  • Strong response by recovering immune system to
    latent or active infections
  • Risk factors for IRIS following HAART
  • CD4 percent of lt 15
  • CD4 count of lt 100 cell/uL
  • High rate of increase of CD 4 count
  • Most commonly associated with
  • Pneumocystis pneumonia
  • Cytomegalovirus disease
  • Herpes zoster
  • Mycobacterium avium complex (MAC) disease
  • Tuberculosis

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IMMUNE RECONSTITUTION SYNDROME
  • Important to distinguish between IRIS and
    clinical failure
  • Clinical failure
  • Disease progression with development of OI or
    malignancy when drugs given for sufficient time
  • IRIS
  • Seen within first several weeks of therapy when a
    latent or active infection is present

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IMMUNE RECONSTITUTION SYNDROME
  • Management options
  • Inflammatory reaction treated with
  • Steroids
  • Non-steroidal anti-inflammatory drugs (NSAIDS)
  • Antimicrobial agents directed at the infectious
    agent
  • Antiretroviral therapy
  • Withhold or continue (?)

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NAMING ANTI-RETROVIRAL DRUGS
  • Anti-retroviral drugs have at least 3 names
  • Abbreviation
  • Research or chemical name
  • Generic name
  • Generic name
  • Trade name
  • Example
  • Abbreviation (Research/Chemical) AZT
  • Abbreviation (Generic name) ZDV
  • Generic
    Zidovudine
  • Trade
    Retrovir

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MARAVORIC (MVC / SELZENTRY)
  • First in new class anti-retroviral drug
  • CCR5 co-receptor antagonist (entry inhibitor)
  • Indicated for CCR5 tropic HIV-1 showing
    resistance to multiple anti-retroviral drugs
  • Black box warning
  • Hepatotoxicity
  • Systemic allergic reaction
  • Pruritic rash, eosinophilia, elevated IgE
  • FDA approval on August 8, 2007
  • Requires tropism testing

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HIV CO-RECEPTOR TROPISM ASSAY
  • Trofile (Monogram Bioscience)
  • FDA approval on August 6, 2007
  • In vitro diagnostic assay
  • Determines tropism of patients HIV
  • CCR5
  • CXCR4
  • D/M (dual / mixed)
  • Trofile assay
  • Specimen is EDTA plasma
  • Viral load of 1,000 copies/mL
  • TAT of 14 days
  • Cost

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LABORATORY DIAGNOSIS OF HIV INFECTION
  • Standard algorithm consists of using two tests
    for the detection of antibody to HIV-1/2
  • Screening
  • Enzyme immunoassay (EIA) or
  • Enzyme-linked Immunosorbent Assay (ELISA)
  • High sensitivity
  • Confirmation
  • Western blot (WB)
  • High specificity
  • Sensitivity is positivity in disease
  • Specificity is negativity in disease

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LABORATORY DIAGNOSIS OF HIV INFECTION (STANDARD
ALGORITHM)
  • Specimens initially reactive by EIA / ELISA are
    retested in duplicate
  • One or both repeat tests positive, specimens are
    considered repeatedly reactive for antibody
  • Specimens repeatedly reactive by EIA / ELISA
    then tested by Western Blot (WB) assay
  • Specimens reactive for both EIA / ELISA and WB
    are considered positive for HIV infection
  • Seroconversion
  • From infection to antibody

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LABORATORY DIAGNOSIS OF HIV INFECTION
  • Rapid detection of HIV-1/2 antibody
  • OraQuick ADVANCE Rapid HIV-1/2 Antibody
  • OraSure Technologies, Inc., PA
  • Immunochromatographic assay (ICA)
  • Analytical time of 25 minutes
  • Sensitivity of 99.5 and specificity of 99.9
  • Specimens of Choice
  • Whole blood
  • Fingerstick
  • Venipuncture (EDTA)
  • EDTA plasma
  • Oral fluid (Oral mucosal transudate)

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CLINICAL USE OF ORAQUICK RAPID HIV-1/2 ASSAY
  • Rapid screening
  • HCW with potential HIV exposure
  • Pregnant females with unknown HIV status at time
    of delivery
  • New HIV clinic patients
  • Same day screening
  • All other patients
  • Reporting of Results
  • Negative for HIV-1/2 Antibodies
  • Preliminary Positive for HIV-1/2 Antibodies.
    Confirmation by Western Blot testing to follow.

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LABORATORY DIAGNOSIS OF HIV INFECTION
  • Detection of HIV Core Antigen (p24)
  • Serum or CSF
  • Methods
  • EIA or ELISA (Non-ICD)
  • EIA or ELISA (immune complex dissociation)
  • Positives confirmed by neutralization
  • Clinical Use
  • Early diagnosis before antibody response
  • Monitor effectiveness of therapy
  • Marker of disease progression

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LABORATORY DIAGNOSIS OF HIV INFECTION
  • Detection of proviral DNA
  • EDTA whole blood
  • Method
  • Polymerase chain reaction (PCR)
  • Clinical Use
  • Diagnosis of infection in neonates of HIV
    positive mothers
  • Early diagnosis before antibody response

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LABORATORY PROGNOSIS OF HIV INFECTION
  • Quantitation of HIV-1 RNA (Viral load)
  • EDTA plasma
  • Methods
  • Reverse Transcriptase PCR (RT-PCR)
  • Branched chain DNA (bDNA)
  • Clinical Use
  • Determination of amount of free virus (Viral
    load)
  • Predicting progression and outcome of infection
  • Assessing efficacy of antiviral therapy

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LABORATORY DIAGNOSIS OF HIV INFECTION BY ORAL
FLUID TESTING
  • OraQuick ADVANCE Rapid HIV-1/2 Antibody Test
  • Pad on test device used to swab between upper and
    lower outer gums and cheek
  • Pad is stored in preservative vial and sent for
    ICA testing
  • Advantages
  • Reduces occupational exposure
  • Patient appeal

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LABORATORY DIAGNOSIS OF HIV INFECTION BY URINE
TESTING
  • Calypte HIV-1 Urine EIA (Calypte Biomedical,
    Berkeley, CA)
  • FDA approval for EIA (1996) and Western Blot
    (1998)
  • Sensitivity and specificity
  • Lower compared to blood and oral fluid
  • Question
  • IgG in urine
  • Calypte Aware HIV-1/2 Urine Rapid Test
  • Available outside US
  • Advantages
  • Reduces occupational exposure
  • Patient appeal

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THE IMMUNOLOGY OF HIV INFECTION
  • Interactions between HIV and human immune system
    are extremely complex
  • HIV subverts immune system by
  • Infecting CD4 T cells and inducing quantitative
    and qualitative dysfunction
  • Hyperactivating B cells with resulting
    hypergammaglobulinemia
  • Inducing cytokine system to own replicative
    advantage
  • There are no known correlates of protective
    immunity

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MECHANISMS OF CD4 T-CELL DEPLETION
  • Direct killing of infected T cells
  • Increased rate of apoptosis in infected T cells
  • Molecule associated with apoptosis (PD-1) is
    over-expressed in chronic viremia
  • Syncytia formation
  • Fusion of infected and non-infected T cells
  • Killing of infected CD4 cells by CD8 cells

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KILLING OF INFECTED CD4 CELLS BY CD8 CELLS
ALTERNATIVE VIEW
  • Mechanism that keeps HIV in check in long term
    non-progressors (LTNPs)
  • Long term non-progressors (LTNPs)
  • Carry the virus but do not get AIDS
  • Have 20 times more CD8 T cells than progressors
  • Function of CD8 T cell surplus
  • Up-regulate production (2X rate of progressors)
    of 2 killer proteins
  • Perforin
  • Granzyme B

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IMMUNE DYSFUNCTION DURING HIV INFECTION - SUMMARY
  • HIV infection is multifactorial process capable
    of disarming immune system by direct and indirect
    mechanisms
  • Certain chemokine receptors function as necessary
    coreceptors for entry of HIV into cells
  • Central Paradox
  • Progression of HIV disease in setting of vigorous
    immune response
  • Lack of correlates of protective immunity are
    major obstacle to immunotherapy and vaccine
    development

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