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Immunology - Path > HIV infections > Flashcards

HIV infections Flashcards

1
Q

What is HIV-1? How does it work to infect humans?

A
  • HIV-1 is a retrovirus
  • Genes composed of RNA molecules.
  • Replicates inside cells using an enzyme called Reverse Transcriptase (RT) to convert RNA into DNA which can be integrated into host cell’s genes.
  • Primarily infects immune system cells causing immunodeficiency and AIDS.
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2
Q

Describe the organisation of the HIV-1 virion

  • Type of virus
  • Shape
  • Genome
  • Genes
  • Proteins
A
  • Retrovirus with CD4+ T helper cells (& CD4+ MO) as preferred host targets.
  • Icosahedral (20-faced tr).
  • Slow developing disease (up to 10 years before major symptoms seen).
  • Genome is diploid, Plus (+) ssRNA genome.
  • 9 genes (e.g. env, gag, pol) (tat, rev, nef) (vif, vpr, vpu) encoding: 15 Structural, Regulatory & Auxiliary Proteins.
  • Proteins e.g. gp120 & gp41p17, p24,p9,p7; RT, IN, PR
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3
Q

What does HIV-1 do to the immune system?

A
  • HIV-1 targets the immune system
  • Infects cells of the immune system.
  • Uses the cells to replicate and move cell to cell.
  • In doing so changes the function of those cells.
  • Induces a selective loss of CD4+ T helper cells.
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4
Q

How does the immun system protect itself against HIV-1?

A

•Effective immunity requires antibodies (B cells) to prevent infection and neutralize virus, and sufficient CD8+ T cells (CTL) to eliminate (kill) latently infected cells.

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5
Q

What are the main targets for HIV-1 in the immune system?

Hint: why does the immune system fail to control a HIV-1 infection?

A

One reason that the immune system fails to control HIV-1 infection is that the CD4+ T helper cells are the target of the virus. Progressive decline in CD4 T-cell function & numbers: HIV-specific, Recall, Allo, and Mitogen (and even IL-2).

CD4+ T-lymphocytes and cells of the monocyte lineage are the principal targets of HIV-1 infection. Because CD4+ T cells play a critical role in the orchestration of normal immune responses, it is not surprising that many of the immune defects observed during HIV-1 disease are secondary to progressive decline in the number and function of CD4+ T cells.

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6
Q
  1. What is the receptor for HIV-1?
  2. What do infecting strains of HIV-1 also use?
  3. Are more or less receptors needed for HIV-1 entry and infection?
A
  1. CD4 molecule/Ag is the Receptor for HIV-1.
  2. Most infecting strains of HIV-1 use co-receptor molecules (CCR5 and CXCR4) in addition to CD4 to enter target cells.
  3. More appears to be necessary for entry: A chemokine receptor on the surface of MO and activated T helper CD4+ cells was targeted by researchers as co-receptor for HIV because of its known binding to three chemokines that block infection.
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7
Q

How can HIV be transmitted?

A
  • Sexually. The virus enters through mucosal surfaces. Increased by factors which damage such surfaces. Infects CD4+ cells, but also DC in the mucosa may bind to and carry the virus from the site of infection to the LNs where other immune cells become infected.
  • Infected blood - transfusion, sharing needles, blood products.
  • Mother to child before or during birth or via breast milk.
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8
Q

Describe the action of the immune system in response to an infection?

A

Mobilised within hours of infection and involves:

  • Inflammation.
  • Non-specific activation of macrophages.
  • Non-specific activation of NK cells and complement.
  • Release of cytokines and chemokines.
  • Stimulation of pDCs via toll-like receptors.
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9
Q

Describe the action of antibody and B cells/acquired immunity on HIV infection

A

Specific humoral responses where neutralising antibodies are produced.

Anti-gp120 and anti-gp41 (Nt) antibodies are thought to be important in protective immunity.

Non-neutralising anti-p24 gag IgG also produced.

HIV remains infectious even when coated with antibodies.

Humoral Immune Responses; Important: Binding Abs that mediate ADCC. Fc-related antibody activities, such as antibody-dependent cellular cytotoxicity (ADCC), or more broadly, antibody-mediated cellular viral inhibition (ADCVI). ADCVI/ADCC-inducing responses are rapidly generated following acute HIV-1 infection; peak at approximately 6 months postinfection. *Functionally coordinated antibodies in HIV control.

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10
Q
  1. What are the actions of CD4 + T cells
  2. How are they affected in HIV infection?
A

1.

  • White blood cells that orchestrate the immune response, signalling other cells in the immune system to perform their special functions.
  • Recognise processed antigen - especially Gag p24 (peptides) - in the context of class II HLA molecules.
  • Required for the long-term maintenance of CD8+ T-cell response.

2.

  • Also known as T helper (Th) cells, these cells are infected, killed or disabled during HIV-1 infection.
  • Selective loss of CD4+ T cells.
  • In acute infection there is a massive loss of CD4+ T cells in the gut.
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11
Q

What is the function of CD8 + T cells?

A
  • White blood cells that kill cells infected with HIV or other viruses, or transformed by cancer (CTL). Also able to suppress viral replication.
  • Secrete soluble molecules (cytokines and chemokines such as MIP-1a, MIP-1b, and RANTES) which are able to prevent infection by blocking entry of virus into CD4+ T cells.
  • Recognise processed antigen - (peptides) - in the context of class I HLA molecules.
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12
Q

Describe the key points where HIV-1 can interefre with an immune response

A

Activated infected CD4+ helper T cells die and are lost

Infected CD4+ T cells are also disabled (ANERGISED) by the virus

  • MO/DC are not activated by the CD4+ T cells and can not prime naïve CD8+ CTL
  • CD8+ T cell and B cell responses are diminished without help
  • CD4+ T cell memory is lost

Infected MO/DC are killed by virus or CTL

  • Defect in antigen presentation
  • Failure to activate memory CTL
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13
Q

Variation and mutation

  1. Replication of the retroviral genome depends on 2 steps, describe them
  2. What does this mean for HIV?
A
  1. 2 steps - 1) Reverse Transcriptase lacks the proof reading mechanisms associated with cellular DNA polymerases and therefore genomes of retroviruses are copied into DNA with low fidelity. Transcription of DNA into RNA copies is also of low fidelity. 2)RNA polymerase II.
  2. Therefore HIV can accumulate many mutations and numerous variants or quasispecies.
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14
Q

What is the benefit of HIV virions being able to mutate into numerous variants?

A
  • Escape from neutralising antibodies.
  • Escape from HIV-1-specific T cells.
  • Resistance and escape from antiretroviral drugs.
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15
Q

Describe the life cycle of HIV/Viral replication (7 steps)

A
  1. Attachment/Entry
  2. Reverse Transcription & DNA Synthesis
  3. Integration
  4. Viral Transcription
  5. Viral Protein Synthesis
  6. Assembly of Virus & Release of Virus
  7. Maturation
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16
Q

Name the different therapies for HIV-1 infection and how they act.

A
  • Attachment inhibitors - affects the docking process
  • Fusion inhibitors
  • INI -integrase inhibitors
  • RTI - Nucleoside analogues and non-nucleoside analogues interrupt transcription of viral RNA into viral DNA
  • Protease inhibitors - prevents maturation
17
Q

Describe the steps of the HIV-1 infection cycle and the drugs that affect it at each stage

A
  • Attachment getting in to the cell
    • Prevented by attachment inhibitors and fusion inhibitors
  • Reverse transcriptase from viral RNA to cDNA
    • Inhibited by reverse transcriptase inhibitors
  • Integration and transcription a) viral DNA joins host DNA b) making multiple viral RNAs
    • Inhibited by integrase inhibitors
  • Translation, to produce the viral protein
  • Viral protease cleaving viral proteins
    • Inhibited by Protease inhibitors
  • Assembly and budding - HIV replicates leaving the cell
18
Q

What is the median time from infection with HIV to development into AIDS?

A

8-10 years

19
Q

What is the viral burden in HIV?

A

Viral burden is the set point and can be used to predict disease progression

20
Q

Describe the disease progression of HIV and what happens to CD8 lymphocytes, CD4 lymphocytes and plasma viral load.

A
  • Primary infection - 12 weeks approx
    • Plasma viral load increases dramatically in the first few weeks of infection
    • CD8 lymphocytes increase dramatically in the first few weeks of infection
    • CD4 lymphocytes decreases in the first few weeks of infection
  • Asymptomatic phase - 1-10 years
    • CD8 lymphocytes decreases and plateaus
    • CD4 lymphocytes increase and peak during mid asymptomatic phase
    • Plasma viral loads decreases dramatically and plataeus
  • AIDS:
    • As the asymptomatic period ends, and AIDS defining illnesses begin to develop, viral load increases
    • At the same time, CD8 and CD4 lymphocyte count decreases
21
Q
  1. What effects CD4 count?
  2. What does CD4 count relate to?
A

1.

  • CD4 T cell count is decreased by HIV infection
  • CD4 T cell count increases with treatment
  1. CD4 T cell count relates to the risk of disease, raising it increases the protection from disease
22
Q

What is the CD4 count in AIDS?

A

HIV causes AIDS, CD4 T cell count <200cells/ul. Plus development of AIDS defining illnesses

23
Q

What are the AIDS defining illnesses?

A
  • Candidiasis of the esophagus, bronchi, trachea, or lungs [(but NOT the mouth (thrush)]
  • Cervical cancer, invasive
  • Coccidioidomycosis, disseminated or extrapulmonary
  • Cryptococcosis, extrapulmonary
  • Cryptosporidiosis, chronic intestinal (greater than one month’s duration)
  • Cytomegalovirus disease (other than liver, spleen, or nodes)
  • Cytomegalovirus retinitis (with loss of vision)
  • Encephalopathy, HIV related
  • Herpes simplex: chronic ulcer(s) (more than 1 month in duration); or bronchitis, pneumonitis, or esophagitis
  • Histoplasmosis, disseminated or extrapulmonary
  • Isosporiasis, chronic intestinal (more than 1 month in duration)
  • Kaposi sarcoma
  • Lymphoma, Burkitt’s (or equivalent term)
  • Lymphoma, immunoblastic (or equivalent term)
  • Lymphoma, primary, of brain
  • Mycobacterium avium complex or M kansasii, disseminated or extrapulmonary
  • Mycobacterium tuberculosis, any site (pulmonary or extrapulmonary)
  • Mycobacterium, other species or unidentified species, disseminated or extrapulmonary
  • Pneumocystis jiroveci pneumonia
  • Pneumonia, recurrent
  • Progressive multifocal leukoencephalopathy
  • Salmonella septicemia, recurrent
  • Toxoplasmosis of brain
  • Wasting syndrome due to HIV
24
Q

Describe the patterns of HIV diseae progression. (3 types)

A
25
Q

Describe the 5% that are long-term non-progressors and their disease progression

A
  • > 8 years
  • >500 cells/ul
  • <50 copies/ml
  • No symptoms
  • No history of Anti-retroviral therapy
26
Q

What are the possible mechanisms of long-term nonprogression with HIV infection

  1. Host genetic factors
  2. Host immune response factors
  3. Virologic factors
A
  1. Host genetic factors
  • Slow progressor HLA profile - HLA B27 & HLA B57
  • Innate immunity receptors; KIR3DSL (regulatory NK cell receptor)
  • Heterozygosity for 32-bp deletion in chemokine receptor CCR5
  • Mannose binding lectin alleles
  • Tumor necrosis factor c2 microsatellite alleles
  • Gc vitamin D-binding factor alleles
  • Host proteins e.g. alpha1 antitrypsin - contains a peptide shown to inhibit viral attachment
  1. Host imune response factors:
  • Effective CTL & HTL responses
  • Secretion of CD8 antiviral factor
  • Secretion of chemokines that block HIV entry co-receptors CCR5 (e.g., MIP-1a, MIP-1b, and RANTES) and CXCR4 (e.g., SDF-1)
  • Secretion of IL-16
  • Effective humoral immune response
  • Maintenance of functional lymphoid tissue architecture
  • Less immune hyperactivation
  1. Virologic factors
    * Infection with attenuated strains of HIV
27
Q

How is HIV-1 detected?

A
  • HIV is found in all cases of AIDS.
  • In the infected patient, it can be detected by the presence of anti-HIV antibodies (ELISA) or by the presence of the virus itself (viral load) using polymerase chain reaction (PCR) which detects viral RNA. The latter is very sensitive and can show HIV in situations in which it is not detectable immunologically.
  • The HIV antibody ELISA is a screening test and the HIV antibody Western blot is a confirmatory test.
  • The initial baseline plasma viral load (that is when the patient is first monitored for virus number) is a good predictor of the time it will take for disease to appear.
28
Q

How is CD4 T cell levels assessed?

A

Flow cytometry

The onset of AIDS correlates with the diminution of the number of CD4 T cells

29
Q

Describe the 2 established assays for measuring resistance to antiviral drugs

A
  • Phenotypic: Viral replication is measured in cell cultures under selective pressure of increasing concentrations of antiretroviral drugs – compared to wild-type
  • Genotypic: Mutations determined by direct sequencing of the amplified HIV genome (so far limited to sequencing of RT and P)
30
Q

Describe the action of Highly Active antiretroviral therapy (HAART)

A
  • Substantial control of viral replication - Suppresses viral load
  • Increase in CD4 T cell counts
  • Improvement in their host defences (dramatic decline in opportunistic infections (AIDS-related disease) & deaths (mortality))
31
Q

Describe the basic HAART regimen

A

Combination of 3 or more drugs

Two drug backbone + one or more Binding agents

Commonly: 2NRTIs (Nucleoside reverse transcriptase inhibitors) + 1 NNRTIs (Non-NRTI) or boosted Protease inhibitor

32
Q

What are the limitations and complications of HAART regimens?

A
  • Effective HAART does not eradicate latent HIV-1 in the host
  • Fails to restore HIV-specific T-cell responses
  • Is dogged by the threat of drug resistance
  • Significant Toxicities
  • High pill burden
  • Adherence problems
  • Quality of life issues
  • Cost (>40%)
33
Q

What are the different drug classes that can be part of the HAART regimen?

A
  • Nucleoside reverse transcriptase inhibtors
  • Nucleotide reverse transcriptase inhibitors
  • Non-nucleoside reverse transcriptase inhibitors
  • Protease inhibitors
  • Integrase inhibitors
  • Attachment inhibitors
  • Fusion inhibitors

Immunology - Path (9 decks)

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