3.7 about 32 minDeep Learning viewL3 p.47–55L1 p.46–48

HIV, complement disorders and amyloidosis

Three ways the immune system fails beyond the inherited lymphocyte defects: a virus that destroys the CD4 cells everything else depends on; missing complement components or regulators; and chronic immune activity that leaves misfolded protein in the tissues.

HIV: genes, transmission, entry and drug targets

L3 p.48–50

HIV is a retrovirus: an enveloped particle carrying two copies of single-stranded RNA plus the enzymes that will copy it into DNA and insert it into the host genome. Three structural genes build it:

  • env

    Proteins
    gp120 (surface) and gp41 (transmembrane), cut from gp160
    Role
    gp120 attaches to CD4 and the coreceptor; gp41 fuses the membranes
    Clinical use
    Antibodies to gp120/gp41 in screening tests; fusion and attachment inhibitors

  • gag

    Proteins
    p24 (capsid), p17 (matrix), nucleocapsid
    Role
    Core structure
    Clinical use
    p24 antigen appears early, before antibodies

  • pol

    Proteins
    Reverse transcriptase, integrase, protease
    Role
    Copy RNA to DNA; insert it; cut polyproteins during maturation
    Clinical use
    Targets of most antiretroviral drugs

Virus is present in blood, semen, vaginal secretions and breast milk, so it spreads by sexual contact, shared needles and transfusion, and from mother to child during pregnancy, delivery or breastfeeding.

  1. Attachment. gp120 binds CD4 on helper T cells, macrophages and dendritic cells.
  2. Coreceptor binding. gp120 then binds a chemokine receptor: CCR5 (on macrophages and memory T cells; the strains that transmit infection) or CXCR4 (on T cells; strains that often emerge late and predict faster decline). People homozygous for a CCR5 deletion are largely resistant; heterozygotes progress more slowly.
  3. Fusion. gp41 unfolds, inserts into the host membrane and pulls the two membranes together; the core enters the cytoplasm.
  4. Reverse transcription. RT copies the RNA into double-stranded DNA (error-prone, so resistance mutations arise quickly).
  5. Integration. Integrase inserts the DNA into the host genome as a provirus, which can stay silent (latency).
  6. Transcription. When the cell is activated (for example by another infection), host NF-κB switches on the provirus along with the cell's own cytokine genes.
  7. Assembly, budding and maturation. New cores assemble at the membrane and bud off; viral protease then cuts the Gag and Gag-Pol polyproteins so the particle becomes infectious.
L3 p.49–50

Teaching schematic

  1. 1Attachment

    gp120 binds CD4

    ⊣ Attachment inhibitor (binds gp120); anti-CD4 antibody

  2. 2Coreceptor

    gp120 binds CCR5 or CXCR4

    ⊣ CCR5 antagonist (maraviroc)

  3. 3Fusion

    gp41 joins the membranes

    ⊣ Fusion inhibitor (enfuvirtide)

  4. 4Reverse transcription

    RNA → dsDNA (RT)

    ⊣ NRTIs, NNRTIs

  5. 5Integration

    Integrase inserts provirus

    ⊣ Integrase inhibitors

  6. 6Transcription

    Host NF-κB activates the provirus

  7. 7Assembly and budding

    Gag, Gag-Pol, RNA at membrane

  8. 8Maturation

    Protease cuts Gag and Gag-Pol

    ⊣ Protease inhibitors

The life cycle with the drug class that blocks each step.L3 p.50

Lecture slide

Diagram of the HIV life cycle from attachment through budding and maturation, with blocking points for fusion inhibitors, CCR5 inhibitors, reverse transcriptase inhibitors, integrase inhibitors and protease inhibitors, and host restriction factors.
The lecture's life-cycle diagram. Note where protease inhibitors act: on the budded particle, at maturation.L3 p.50

Why CD4 cells disappear, and where the virus hides

L3 p.49

Losing CD4 helper cells removes the conductor of almost every adaptive response: B cells lose help, CD8 cells lose IL-2, and macrophages lose IFN-γ activation. Several processes kill CD4 cells:

  • Direct cytopathic effect: productive infection, with budding and accumulation of viral products, kills the cell (the lecture: HIV is cytotoxic to CD4 T cells).
  • Pyroptosis of bystander cells: in lymphoid tissue many resting CD4 cells are infected abortively; incomplete viral DNA is sensed in the cytosol and caspase-1 kills the cell in an inflammatory way (3.1). This explains why far more cells die than are productively infected.
  • CD8 killing of infected cells, and chronic immune activation that drives activated cells to die.
  • Loss of replacement: infection of thymic and lymph-node structures reduces production. In acute infection a large share of memory CD4 cells in the gut mucosa is lost within weeks.
L3 p.49

Reservoirs keep the virus out of reach of drugs and immunity. Macrophages and dendritic cells contain large numbers of particles but resist the cytolytic effect, carry virus to lymph nodes, spleen and brain, and keep producing it. Latently infected resting memory CD4 cells carry silent provirus for years; treatment suppresses replication but does not eliminate them, which is why stopping therapy lets the virus return.

Core activity · The Missing Arrow

The Missing Arrow

Complete the causal chain. Place the missing step by dragging a card onto a gap, or tap a card and then tap the gap. Some gaps need an event; others need the mechanism that links one event to the next.

Follow HIV from the first contact with a CD4 T cell to the infections of AIDS.

Two gaps ask for a mechanism: how the virus gets in, and how cells die. Don't put an event there.

  1. gp120 binds CD4 on a helper T cell
  5. CD4 count falls over years; viral load rises
  6. B cells, CD8 cells and macrophages lose their help (IL-2, IFN-γ, CD40L)

Cards

Tap or drag a card. Placing a used card moves it.

Stages, tests, opportunistic infections and tumors

L3 p.51–52

Teaching schematic

Untreated HIV: viral load peaks in acute infection then rises again late; CD4 count falls over years; antibody appears after a few weeksCD4 500CD4 200Acute (weeks)Clinical latency (years)AIDSviral load peakset pointCD4 countanti-HIV antibodywindow: RNA, then p24, then antibodytime →
Viral load (relative, log) CD4 count Antibody
Untreated course: viremia peaks in the acute phase and falls to a set point; CD4 cells dip, partly recover, then decline over years; antibodies appear after a window of a few weeks.L3 p.51

Stages of untreated infectionL3 p.51

  • Acute HIV

    CD4 count (cells/mm³)
    Transient dip
    What happens
    1–6 weeks (usually 2–3) after infection: fever, malaise, pharyngitis, generalized rash, myalgia and arthralgia, painful lymphadenopathy; resolves in 1–2 weeks. Viral load very high; antibody tests may still be negative

  • Asymptomatic (clinical latency)

    CD4 count (cells/mm³)
    > 500
    What happens
    2–10 years. Replication continues in lymphoid tissue; CD4 count falls steadily

  • Early symptomatic

    CD4 count (cells/mm³)
    200–500
    What happens
    Generalized lymphadenopathy; non–AIDS-defining infections: oral candidiasis (thrush), oral hairy leukoplakia (EBV), zoster

  • AIDS

    CD4 count (cells/mm³)
    ≤ 200, or an AIDS-defining condition
    What happens
    Opportunistic infections and AIDS-defining tumors

What each laboratory measure tells youL3 p.51

  • Antigen/antibody immunoassay (4th generation)

    Measures
    p24 antigen plus antibodies to HIV (including anti-gp120, anti-gp41)
    Used for
    Screening; positive about 2–3 weeks after infection

  • HIV-1/HIV-2 differentiation immunoassay; nucleic-acid test (NAT)

    Measures
    Antibody type; viral RNA
    Used for
    Confirmation. NAT is positive earliest (about 10 days) and settles indeterminate results

  • Viral load (HIV RNA)

    Measures
    How much virus is replicating
    Used for
    Diagnosis of acute infection, response to therapy, transmission risk

  • CD4 count

    Measures
    How much immune capacity remains
    Used for
    Staging, risk of opportunistic infection, when to start prophylaxis

Opportunistic infections and tumors by CD4 countL3 p.51–52

  • Any count (risk rises as CD4 falls)

    Infections
    Tuberculosis, bacterial pneumonia
    Tumors
    Kaposi sarcoma (HHV-8)

  • < 500

    Infections
    Oral thrush, oral hairy leukoplakia (EBV), zoster: oral and skin findings, not AIDS-defining
    Tumors
    —

  • < 200

    Infections
    Pneumocystis jirovecii pneumonia** (AIDS-defining)
    Tumors
    Invasive cervical carcinoma (HPV), aggressive B-cell lymphomas such as Burkitt (EBV)

  • < 100

    Infections
    Toxoplasma encephalitis, cryptococcal meningitis, esophageal or systemic candidiasis (AIDS-defining)
    Tumors
    —

  • < 50

    Infections
    Disseminated CMV (retinitis, colitis), disseminated **Mycobacterium avium complex**: common causes of death
    Tumors
    Primary CNS lymphoma (EBV)

Lecture image

Six images: purple-red nodular skin lesions; a chest x-ray with diffuse bilateral interstitial opacities; a resected cervix with an ulcerated tumor; a young man with a massive neck mass; and a CT and MRI showing a frontal brain mass.
AIDS-defining conditions from the lecture: Kaposi sarcoma (violaceous nodules); diffuse bilateral infiltrates of **Pneumocystis pneumonia; invasive cervical carcinoma; a bulky lymphoma of the neck; and primary CNS lymphoma**.L3 p.52

Complement deficiencies: early, central, terminal and regulators

L3 p.54

Complement has three jobs: opsonization (C3b on a microbe lets phagocytes eat it), inflammation (C3a and C5a), and lysis (C5b–C9, the membrane attack complex). It also clears immune complexes and apoptotic debris. Which component is missing decides which job fails, and so which disease follows.

Teaching schematic

Classical

C1q binds IgM/IgG on antigen → C1r, C1s → C4, C2✕ C1q, C2, C4poor complex clearance → SLE; C2: pneumococcus✕ C1-INH (regulator)kallikrein unchecked → bradykinin → HAE

Lectin

Mannose-binding lectin on microbial sugars → MASPs → C4, C2

Alternative

Spontaneous C3 activation on microbial surfaces; factors B, D, properdin

C3 convertase → C3a (inflammation) + C3b (opsonin, clears complexes)

✕ C3severe pyogenic infections; GN

C5 convertase → C5a (chemotaxis) + C5b–C9 = membrane attack complex (lysis)

✕ C5–C9recurrent Neisseria✕ DAF (CD55) + CD59 lost (PNH)own red cells lysed: hemoglobinuria, thrombosis
Three activating pathways meet at C3. Each deficiency is placed where it breaks the cascade, with its typical disease; regulators that normally restrain complement are shown in red.

Deficiency → what fails → diseaseL3 p.54

  • Early classical (C1q, C2, C4)

    Job that fails
    Clearance of immune complexes and apoptotic cells; some opsonization
    Disease
    SLE-like disease; C2 (the most common deficiency) also pneumococcal septicemia

  • C3

    Job that fails
    Opsonization and everything downstream
    Disease
    Severe recurrent pyogenic infections with encapsulated bacteria from infancy; immune-complex glomerulonephritis

  • Terminal (C5–C9)

    Job that fails
    Membrane attack complex
    Disease
    Recurrent, disseminated *Neisseria meningitidis and N. gonorrhoeae* infections (thin-walled organisms killed best by lysis); the same risk follows drugs that block C5

  • C1 esterase inhibitor (regulator)

    Job that fails
    Control of C1 and of kallikrein
    Disease
    Hereditary angioedema (bradykinin; next topic)

  • DAF (CD55) and CD59 (regulators on cell membranes)

    Job that fails
    Protection of our own cells from complement
    Disease
    Paroxysmal nocturnal hemoglobinuria: an acquired PIGA mutation in a stem cell removes the GPI anchor that holds DAF and CD59, so red cells are lysed by complement (hemoglobinuria, thrombosis; diagnosed by flow cytometry)

Angioedema: bradykinin or histamine?

L3 p.54–55Ch. III cases p.9, 13

Angioedema is swelling of the deep dermis, subcutaneous tissue or submucosa: lips, eyelids, tongue, larynx, bowel wall. Two different mediators cause it, and they are treated differently, so the first question is always which mediator.

Lecture image

Young woman photographed from the front and in profile with marked swelling of the lips and lower face.
Angioedema of the lips and lower face (lecture image). The photograph alone cannot tell you the mediator: look for itching and hives, a drug history and a family history.L3 p.55
  • Hereditary angioedema (autosomal dominant). C1 esterase inhibitor normally restrains C1 and also kallikrein, the enzyme that releases bradykinin from kininogen. When it is deficient, kallikrein runs free, bradykinin accumulates and opens endothelial junctions. Attacks of nonpitting, non-itchy swelling of the face, limbs, upper airway and gut (abdominal pain, vomiting, diarrhea) come on over hours and resolve in 2–3 days; laryngeal swelling can kill. Trauma, dental work and estrogens trigger attacks; onset is usually in childhood or adolescence. There are no hives, and antihistamines and corticosteroids do not work. Because C1 is uncontrolled, C4 is low even between attacks, the best screening test; C1-INH level or function confirms. Treatment: C1-INH concentrate or a bradykinin B2-receptor antagonist.
  • ACE-inhibitor angioedema. ACE is the enzyme that degrades bradykinin (kininase II). Block it and bradykinin accumulates: the same swelling of lips, tongue, face, airway or bowel, without itching or hives, in someone recently started on (or long taking) an ACE inhibitor. C4 and C1-INH are normal. Stop the drug.
  • Mast-cell (histamine) angioedema. IgE-mediated allergy (foods, stings, drugs) or direct mast-cell activation releases histamine: swelling with itch and urticaria, sometimes wheeze and hypotension (anaphylaxis, 3.3). Raised tryptase; responds to antihistamines, corticosteroids and epinephrine.
L3 p.54Ch. III cases p.9, 13

Core activity · Almost Twins

Almost Twins

Two look-alikes side by side. Decide what they share, then pick the clue that separates them and say why it works.

Look-alike A

Hereditary angioedema

Bradykinin: swelling without wheals or itchC1-INH ↓ (or ACE blocked) → bradykininsmooth skin, no itch
Lip and skin during an attack (schematic).
  • Nonpitting swelling of lips, face, larynx
  • No itch, no hives; mediator is bradykinin (C1 inhibitor deficient)
  • Abdominal attacks; family history (autosomal dominant)
  • Low C4; antihistamines and steroids do not help

Step 1 · What they share

What do the two share?

Select every feature that both show.

Core activity · One Fact Changes

One Fact Changes

Answer a case and name the decisive clue. Then exactly one fact changes. Decide whether the answer moves, and why.

1 · The original case

A 72-year-old man has sudden swelling of his lips and tongue with abdominal pain and diarrhea. There is no itching and no rash anywhere on his skin. Three weeks ago he started lisinopril for hypertension.

Which mediator is responsible?

Which fact decided it?

Amyloidosis from the immune system: AA and AL

L1 p.46–48Syllabus

Amyloid is protein that misfolds into β-pleated sheets and aggregates outside cells, staining with Congo red and showing apple-green birefringence under polarized light. Chapter 1 holds the full account (amyloid and amyloid types). Two of the systemic forms are products of the immune system:

Chronic inflammation to AA amyloid

  1. Chronic inflammation (rheumatoid arthritis, IBD, tuberculosis, bronchiectasis, osteomyelitis, familial Mediterranean fever)
  2. Macrophages release IL-1, IL-6, TNF
  3. Liver makes serum amyloid A (acute-phase protein) for years
  4. Incomplete breakdown → AA fragments misfold
  5. AA amyloid in kidney (nephrotic syndrome), liver, spleen, adrenals
L1 p.47
  • AA amyloid follows years of raised SAA. Familial Mediterranean fever is an inherited inflammasome disorder (3.1): untreated attacks keep SAA high, and colchicine prevents the amyloid.
  • AL amyloid comes from immunoglobulin light chains (λ more than κ) secreted by a monoclonal plasma cell clone, in multiple myeloma or a smaller plasma-cell dyscrasia. Heart (restrictive cardiomyopathy), kidney, nerves (carpal tunnel), tongue (macroglossia).
  • Aβ₂M amyloid is β₂-microglobulin, the light chain of MHC class I (3.2), which dialysis membranes do not clear: joints and carpal tunnel.
  • Localized forms stay in one organ: Aβ in Alzheimer disease, calcitonin in medullary thyroid carcinoma, amylin in type 2 diabetes islets.
L1 p.46–48

Knowledge check · 3.7

Answer, read why, and try again whenever you like. Answers are kept in both study modes.

0 of 7 correct
  1. Q1HIV entry: gp120 attachmentL3 p.48–50Ch. III cases p.2

    Investigators mix HIV-infected and uninfected CD4⁺ T-cell lines with a synthetic peptide triazole complex. The complex binds gp120 with high affinity and irreversibly inhibits its function, reducing infection of the CD4⁺ T cells.

    Which step of HIV infection does this experimental drug most likely inhibit?

  2. Q2ACE-inhibitor angioedemaL3 p.54Ch. III cases p.9

    A 72-year-old man recently diagnosed with heart disease has sudden abdominal pain, diarrhea and vomiting, with painful swelling of his face, lips and mouth. He denies itching. His physician recently started drugs to control his blood pressure and cholesterol. He sometimes gets a rash after antibiotics and has 'hives' every spring.

    Accumulation of which substance most likely causes his symptoms?

  3. Q3Hereditary angioedemaL3 p.54Ch. III cases p.13

    A 23-year-old woman with past episodes of facial swelling attributed to 'allergies' arrives with marked difficulty breathing, abdominal pain and swelling of the face, neck and limbs, and is intubated. Her father has had similar attacks and was prescribed antihistamines.

    Which laboratory finding is most likely?

  4. Q4HIV window period and testsL3 p.51Ref.

    Twelve days after a condomless sexual exposure to a partner with untreated HIV, a 24-year-old man has fever, sore throat, a diffuse rash and tender lymph nodes. A 4th-generation antigen/antibody test is negative.

    Which test is most likely to establish acute HIV infection now?

  5. Q5Terminal complement deficiencyL3 p.54

    A 19-year-old college student has his second episode of meningococcal meningitis; his older brother had disseminated gonococcal infection. Total hemolytic complement (CH50) is undetectable.

    Which deficiency best explains this pattern?

  6. Q6AA amyloid from chronic inflammationL1 p.47

    A 61-year-old woman has had poorly controlled rheumatoid arthritis for 20 years. She now has heavy proteinuria and edema. A renal biopsy shows amorphous eosinophilic material in the glomeruli that is apple-green under polarized light after Congo red staining.

    What is the precursor of the deposited protein?

  7. Q7Image: Kaposi sarcomaL3 p.51–52

    A 38-year-old man with untreated HIV has the purple-red nodular skin lesions shown in the top-left panel and a CD4 count of 140 cells/mm³.

    Lecture image

    Six images: purple-red nodular skin lesions; chest x-ray with bilateral interstitial opacities; cervical tumor; massive neck mass; CT and MRI of a frontal brain mass.

    Which statement about the skin lesions is correct?

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