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    Summary of HIV/AIDS

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    bibiMh
    1. HIV is a retrovirus that infects CD4+ T cells and causes AIDS. It has an outer envelope with inner core containing two copies of RNA and three key enzymes. 2. HIV is transmitted through unprotected sex, blood transfusions, needle sharing, and from mother to child during birth or breastfeeding. It binds and enters target cells through interaction with CD4 and CXCR4/CCR5 coreceptors. 3. Untreated HIV progresses from primary infection to asymptomatic infection and eventually AIDS, defined by a CD4 count below 200 or opportunistic infections. Antiretroviral therapy can suppress the virus and prolong the asymptomatic stage.

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    Summary of HIV/AIDS

    Uploaded by

    bibiMh
    323 views5 pages
    1. HIV is a retrovirus that infects CD4+ T cells and causes AIDS. It has an outer envelope with inner core containing two copies of RNA and three key enzymes. 2. HIV is transmitted through unprotected sex, blood transfusions, needle sharing, and from mother to child during birth or breastfeeding. It binds and enters target cells through interaction with CD4 and CXCR4/CCR5 coreceptors. 3. Untreated HIV progresses from primary infection to asymptomatic infection and eventually AIDS, defined by a CD4 count below 200 or opportunistic infections. Antiretroviral therapy can suppress the virus and prolong the asymptomatic stage.

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    contains information on the HIV, course of disease, pathophysiology and treatment <3

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    1. HIV is a retrovirus that infects CD4+ T cells and causes AIDS. It has an outer envelope with inner core containing two copies of RNA and three key enzymes. 2. HIV is transmitted through unprotected sex, blood transfusions, needle sharing, and from mother to child during birth or breastfeeding. It binds and enters target cells through interaction with CD4 and CXCR4/CCR5 coreceptors. 3. Untreated HIV progresses from primary infection to asymptomatic infection and eventually AIDS, defined by a CD4 count below 200 or opportunistic infections. Antiretroviral therapy can suppress the virus and prolong the asymptomatic stage.

    Copyright:

    © All Rights Reserved
    Download as PDF, TXT or read online from Scribd
    Download as pdf or txt
    323 views5 pages

    Summary of HIV/AIDS

    Uploaded by

    bibiMh
    1. HIV is a retrovirus that infects CD4+ T cells and causes AIDS. It has an outer envelope with inner core containing two copies of RNA and three key enzymes. 2. HIV is transmitted through unprotected sex, blood transfusions, needle sharing, and from mother to child during birth or breastfeeding. It binds and enters target cells through interaction with CD4 and CXCR4/CCR5 coreceptors. 3. Untreated HIV progresses from primary infection to asymptomatic infection and eventually AIDS, defined by a CD4 count below 200 or opportunistic infections. Antiretroviral therapy can suppress the virus and prolong the asymptomatic stage.

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    U2P8G2 1

    Scribe: Salsabeel M

    Case No. 8: Infection by HIV


    Human Immunodeficiency Virus (HIV)

    1. Structure

    Belongs to the Lentivirus subfamily of


    Retrovirus.( Lentivirus cause slow
    degenerative disease)
    Two copies of the ss(+)RNA
    Long incubation period
    Spherical in shape
    Enveloped with 3 layers namely;
    i.
    Innermost genome layer
    ii.
    Middle nucleocapsid consisting of
    3 enzymes; reverse transcriptase,
    integrase and protease
    iii.
    Outer membrane of glycoprotein surrounded by lipoprotein envelope
    Contains 3 major genes namely gag,pol and env encoding for the structural proteins.
    genes
    products
    STRUCTURAL GENES

    Function

    Gag

    Group-specific antigens
    p24
    p7p9
    p17
    pol
    Reverse transcriptase
    integrase
    protease
    Env
    Gp120
    Gp41
    REGULATORY GENES

    Structural proteins
    Capsid protein
    Core nucleocapsid protein
    Matrix protein
    Produces dsDNA provirus
    Viral DNA integration into host cell DNA
    Cleaves viral protein
    Surface protein that binds to CD4 and coreceptors
    Transmembrane protein for viral fusion to host cell

    LTR
    Tat
    Rev

    DNA, long terminal repeats


    Regulatory protein
    Regulatory proteins

    Nef

    Regulatory proteins

    Integration and viral gene expression


    Facilitate viral gene transcription
    Transport of mRNA from nucleus into the
    cytoplasm
    Suppresses MHC class I proteins

    2. Mode of transmission
    i.
    ii.
    iii.
    iv.
    v.

    Sexual transmission
    Perinatal transmission
    Intravenous drug use
    Blood transfusion
    Occupational exposure
    1

    U2P8G2 2
    Scribe: Salsabeel M

    3. Pathogenesis (Life Cycle)


    1) Transmission of HIV can occur across intact mucosal surface but abrasions increase
    the risk of infection.
    In stratified epithelium for e.g. vagina, exocervix, tonsils, anus and prepuce,
    infection is mediated by dentritic cells.
    In simple epithelium for e.g. rectum, endocervix, infection is mediated by
    dendritic cells or M cells.

    Primary cell target of HIV-1:

    Receptors
    CD4 for T cells and DC
    Lectin and proteoglycans for
    DC
    Lipid receptor for genital and
    intestinal epithelial cells

    Coreceptors
    CXCR4 on T cells
    CCR5 on epithelial cells,
    macrophage, DC and T cells

    2) Attachment, Binding and Entry


    Attachment: Env interact with DC-SIGN
    Gp120 binds to CD4 conformational change bind to CCR5 on macrophage
    or DC and CXCR4 on T cells activates gp41 fusion of viral and host
    membrane forms bundle span
    3) Reverse transcription
    Nucleocapsid uncoats in cytoplasm reverse transcription of viral RNA
    yields a dsDNA out of 2 RNA molecules contain in the virion.
    4) Nuclear transport
    dsDNA in PIC actively transported to the nucleus along microtubules PIC
    cross nuclear envelop through nuclear pore complex which comprises of
    multiple nucleoporins).
    5) Proviral DNA integration
    After entry into the nucleus, PIC gains access to chromatin viral DNA is
    integrated into host chromosome with the help of viral integrase.
    6) Transcription
    Transcription of viral DNA into messenger RNA (mRNA)
    7) Translation
    mRNA translated into viral proteins (rev,tat,nef, envelope proteins,vpr,RT)
    The new viral RNA forms the genetic material of the next generation of
    viruses.
    8) Viral Assembly and Budding
    The viral proteins are assembled at the cell surface the virus buds from the
    cell surface released to infect another cell.

    U2P8G2 3
    Scribe: Salsabeel M

    4. Course of HIV-1 infection


    Acquisition of infection
    i.

    Eclipse phase (approx. 10days following infection) : T cells and DC affected at the
    site of infection

    ii.

    End of eclipse phase: virus to draining lymph nodes meet activated CD4+ and
    CCR5+ T cells (targets for further infection) virus replicate rapidly spread to
    GALT where activated T cells are present in high numbers recruitment of
    additional T cells to site.
    In GALT, 20% T cells infected and 60% uninfected T cells are activated and die
    by apoptosis release of microparticles suppress immune system

    Primary HIV infection

    Dissemination of virus burst of HIV viremia Primary infection in peripheral


    blood decrease CD4+ level in blood due to HIV mediated cell killing or to cell
    retrafficking to lymphoid tissues.

    Asymptomatic HIV infection

    Time between infection and onset of clinically apparent disease= approx. 10yrs

    However HIV is not uniformly expressed in all individuals.


    Few HIV infected develop AIDS and die within month of primary infection (rapid
    progression)
    About 5% of HIV infected individuals remain assymptomatic even after 12years
    or more.

    Early symptomatic infection

    Skin rash, fatigue, slight weight loss, mouth ulcers, fungal skin and nail infection

    Hairy leukoplakia

    Late symptomatic infection

    Chronic oral and vaginal thrush, recurrent herpes blisters on mouth or genitals,
    ongoing fever, persistent diarrhoea, significant weight loss

    Advanced HIV disease

    Opportunistic infection; some of the common opportunistic infections include


    pneumocystis carinii pneumonia, mycobacterium avium complex disease,
    cytomegalovirus, toxoplasmosis, candidiasis

    An AIDS diagnosis can be given to an HIV positive person who has a CD4 count
    of less than 200/mm3 or a history of an AIDS defining illness( such as one of the
    opportunistic infection mentioned above).

    U2P8G2 4
    Scribe: Salsabeel M

    5. Mechanism of CD4+ T cell depletion


    1) Killing of infected CD4+ T cells
    2) Killing of bystander CD4+ T cells- when bystander CD4+ T cells come in contact
    with HIV infected CD4+ T cells, they get killed by FasL-Fas-induced apoptosis.
    3) The Gut hypothesis- HIV replicates massively in CD4+ T cells from GIT mucosa
    suggesting that the gut is the site where all CD4+ T cells are killed.

    6. HIV latency

    At the level of individual T cells


    Rare but appear to arise when activated CD4+ T cells become infected and survive
    long enough to revert back to a resting memory state which is non permissive for
    viral gene expression( cannot replicate).
    As it resides in memory T cells, it persists indefinitely even in patients on potent
    antiretroviral therapy.
    Molecular mechanisms for HIV latency:
    i.
    Absence of host transcription factor(NFkB or NFAT) in nucleus of resting
    CD4+ T cells
    ii.
    Absence of tat and associated host factors that promote efficient
    transcriptional elongation
    iii.
    Transcriptional interference (displace transcription factor or decrease in
    expression of transcription factor)
    iv.
    Epigenetic changes inhibiting HIV gene expression ( chromatin
    configuration or methylation)

    7. Immune Response
    A. Innate Immunity
    1. TLR : PAMPS generated by HIV infection are recognised by TLR leading to
    expression of antiviral and inflammatory gene products
    2. DCs: HIV does not induce maturation of DCs leading to bystander DCs.
    3. NK cells: decreased intracellular stores of perforin and granzyme A and
    incomplete activation of NK cells due to chronic stimulation.
    4. Macrophages : escape killing and act as reservoir for viral replication
    B. Adaptive Immunity
    1. B cells responses
    HIV induced B cell hyperactivity leading to hypergammaglobulinemia,
    increased polyclonal B cell activation, increased differentiation into
    plasmablasts, increase production of autoantibodies, increase frequency
    of B cell malignancies (e.g Non-Hodgins lymphoma)
    B cell exhaustion leading to increased level of inhibitory receptors such
    as programmed cell death
    2. Cytotoxic CD8+ T cell- control HIV replication
    3. Inactivation of Helper CD4+ T cells

    U2P8G2 5
    Scribe: Salsabeel M

    8. Diagnostic Test- cannot detect HIV in eclipse phase.


    Purpose
    Initial screening

    Test
    Rapid test

    confirmation

    Western blot

    Detection of virus in blood (evaluate


    viral load)
    Detect HIV infection in newborns of
    HIV+ mother (provirus)
    Early marker of infection

    RT-PCR

    Evaluate progression of disease

    CD4;CD8 T cell ratio

    PCR
    p24 antigen

    NOTE: RT-PCR tests for circulating viral RNA and is used to monitor the efficacy of treatment while
    PCR detects integrated virus (provirus). Viral load has been demonstrated to be the best prognostic
    indicator during infection.

    9. Treatment
    Antiretroviral drugs against HIV-(start at CD4 < 500)
    1. Reverse transcriptase inhibitor
    i.
    ii.
    iii.

    Interact with catalytic


    Nucleoside reverse transcriptase inhibitors (NRTIs)
    site of the enzyme RT
    Nucleotide reverse transcriptase inhibitors (NtRTIS)
    Non-Nucleoside reverse transcriptase inhibitors (NNRTIS)- interact with an
    allosteric site located at a short distance from catalytic site

    2. Protease inhibitor (e.g Ritonavir)


    Inhibit maturation of viral proteins
    3. Fusion inhibitor (e.g. enfuvirtide)
    Block fusion of viral particle with outer cell membrane
    4. Co receptor inhibitor (e.g. moraviroc)
    Interact with the co-receptor CCR5 or CXCR4
    5. Integrase strand transfer inhibitor (e.g.Raltegravir)
    Inhibit the final step in integration of strand transfer of the viral DNA into
    host DNA.
    ANTI-HIV DRUG COMBINATION

    HAART: 2NRTIs

    + a protease inhibitor or a non-nucleoside RTI or an integrase

    inhibitor
    Advantages:
    i.
    ii.
    iii.

    Obtain synergism between different compounds


    To lower individual drug dosage to reduce their toxic side effects
    To diminish the likelihood of development of drug resistance

    Higher efficacy
    and low side
    effects profile

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