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Immunity, Types of Immunity, Complement System, and AIDS

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1. Definition of Immunity

Robbins, Cotran & Kumar Pathologic Basis of Disease

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2. Types of Immunity

A. Innate Immunity (Natural / Native Immunity)

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B. Adaptive Immunity (Acquired / Specific Immunity)

• Specificity - targets a precise antigen
• Memory - rapid and stronger response upon re-exposure
• Self-limitation - response winds down after antigen is cleared
• Self-tolerance - does not attack the host's own tissues

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C. Other Classifications

• Active immunity - generated by the individual's own immune response (natural infection or vaccination); long-lasting
• Passive immunity - conferred by transfer of antibodies (e.g., maternal IgG across placenta, immunoglobulin therapy); immediate but short-lived
• Herd immunity - indirect protection of unimmunized individuals when a sufficient proportion of the population is immune

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3. The Complement System

Definition

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Activation Pathways

1. Classical Pathway

• Trigger: Fixation of C1 to antibody (IgM or IgG) that has combined with antigen
• Leads to sequential binding of C2 and C4
• Culminates in formation of a multiprotein enzyme (C3 convertase) that cleaves C3
• This pathway links adaptive immunity (antibodies) to complement

2. Alternative Pathway

• Trigger: Microbial surface molecules such as endotoxin (LPS), complex polysaccharides, cobra venom - in the absence of antibody
• Spontaneous cleavage of C3 is amplified and stabilized on microbes
• This pathway operates as part of innate immunity

3. Lectin Pathway (Mannose-Binding Lectin Pathway)

• Trigger: Plasma mannose-binding lectin (MBL) binds to carbohydrates (mannose residues) on microbes
• Activates a protease homologous to C1; subsequent steps identical to the classical pathway
• Also functions in innate immunity (no antibody required)

• C3a (released into plasma)
• C3b (covalently attached to the microbial surface)

• C5a (released - potent inflammatory mediator)
• C5b (remains on cell surface)

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Functions of the Complement System

1. Inflammation (Anaphylatoxins)

• C5a, C3a, and C4a are cleavage products that stimulate:
  • Histamine release from mast cells -> increased vascular permeability and vasodilation
  • Recruitment and chemotaxis of neutrophils, monocytes, eosinophils, and basophils (especially C5a)
  • Activation of the lipoxygenase pathway in neutrophils -> further inflammatory mediators
• Called anaphylatoxins because they mimic mast cell mediators involved in anaphylaxis

2. Opsonization and Phagocytosis

• C3b and iC3b (inactive C3b), when fixed to a microbial cell wall, act as opsonins
• Neutrophils and macrophages bear cell surface receptors for these complement fragments (CR1, CR3)
• This promotes efficient phagocytosis of the coated microbes

3. Cell Lysis (Membrane Attack Complex - MAC)

• MAC is composed of C5b + C6 + C7 + C8 + multiple C9 molecules
• Deposition of MAC on cell membranes creates holes/pores in the membrane
• This allows intracellular water and ions to leak out -> osmotic lysis
• Particularly important for killing microbes with thin cell walls (e.g., Neisseria bacteria)
• Deficiency of terminal complement components (C5-C9) predisposes to Neisseria infections

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Regulation of Complement

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Complement in Disease

• In autoimmune diseases, antibodies against self antigens activate complement via the classical pathway -> tissue injury
• Inherited deficiencies of early complement proteins (C1, C4, C2) increase susceptibility to infections and SLE-like disorders
• Inhibitors of C5 (e.g., eculizumab) and C3 are now approved therapies for complement-mediated diseases like PNH and aHUS

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4. Note on AIDS (Acquired Immunodeficiency Syndrome)

Etiology

Pathogenesis - How HIV Destroys Immunity

1. gp120 (viral envelope glycoprotein) binds to CD4 molecules on helper T cells
2. Interaction with co-receptors - mainly CCR5 (C-C chemokine receptor 5), and CXCR4
3. gp41 anchors the virus into the T-cell membrane, allowing fusion
4. Viral RNA (with reverse transcriptase) is injected into the T-cell cytoplasm
5. Reverse transcriptase converts viral RNA into double-stranded DNA
6. Viral DNA enters the nucleus and is integrated into the host genome (becoming a provirus) via integrase
7. The provirus drives production of new viral particles, which bud out and infect more CD4+ T cells

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Clinical Staging (CDC Classification)

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AIDS-Defining Opportunistic Illnesses (CDC Stage 3 / AIDS)

• Infections: Pneumocystis jirovecii pneumonia (PCP), Toxoplasmosis of the brain, CMV retinitis, Cryptococcosis, Mycobacterium avium complex (MAC), Histoplasmosis, Cryptosporidiosis, Esophageal/pulmonary Candidiasis, TB, Herpes simplex (chronic)
• Malignancies: Kaposi's sarcoma, Burkitt's lymphoma, Immunoblastic lymphoma, Primary CNS lymphoma, Invasive cervical cancer
• Other: HIV encephalopathy, Wasting syndrome, Progressive multifocal leukoencephalopathy (PML)

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Treatment - Antiretroviral Therapy (ART)

• AZT (azidothymidine) was the first drug used, an inhibitor of reverse transcriptase
• Currently, the most effective treatment is multidrug ART (combination therapy):
  • NRTIs (nucleoside reverse transcriptase inhibitors) + one of the following:
  • NNRTIs (non-nucleoside reverse transcriptase inhibitors)
  • Protease inhibitors (block viral protease)
  • Integrase strand transfer inhibitors (INSTIs) (prevent viral DNA integration)
• ART offers synergistic effects, reduced side effects, and reduced drug resistance compared to monotherapy
• ART effectively raises CD4+ counts, prevents AIDS, and improves longevity, but does not cure HIV infection
• No vaccine is currently available

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Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease; Histology: A Text and Atlas (Eroschenko); Harrison's Principles of Internal Medicine 22E

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IMMUNITY - Detailed Study Notes

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PART 1: DEFINITION OF IMMUNITY

• Host defense against infections (bacteria, viruses, fungi, parasites)
• Tumor immunity (defense against cancer cells)
• Transplant rejection (immune reactions against foreign tissue)
• Autoimmunity (immune reactions against self antigens)

Robbins, Cotran & Kumar Pathologic Basis of Disease

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PART 2: TYPES OF IMMUNITY

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2.1 INNATE IMMUNITY (Natural / Native Immunity)

Key Features

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A. Recognition Strategy - PAMPs, DAMPs, and PRRs

• PAMPs (Pathogen-Associated Molecular Patterns) - microbial structures that are essential for infectivity (and therefore cannot be easily mutated), e.g., LPS (Gram-negative bacteria), peptidoglycan (Gram-positive), flagellin, viral RNA/DNA, mannans (fungi)
• DAMPs (Damage-Associated Molecular Patterns) - molecules released by injured and necrotic cells, e.g., uric acid, ATP, heat shock proteins, HMGB1, cytosolic DNA
• PRRs (Pattern Recognition Receptors) - cellular receptors that recognize PAMPs and DAMPs; located in all cellular compartments where microbes may be found

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B. Classes of Pattern Recognition Receptors

• Family of 10 receptors in mammals; present on plasma membranes and endosomal vesicles
• Each TLR recognizes a different set of microbial molecules
• Signaling: All TLRs signal via a common pathway activating two transcription factors:
  • NF-kB - stimulates synthesis of cytokines and adhesion molecules critical for leukocyte recruitment
  • IRFs (Interferon Regulatory Factors) - stimulate production of antiviral type I interferons (IFN-α, IFN-β)
• Examples: TLR4 recognizes LPS; TLR3 recognizes dsRNA; TLR9 recognizes CpG DNA
• Loss-of-function TLR mutations cause rare but serious immunodeficiency syndromes

• Cytosolic receptors (named after founding member NOD-2)
• Recognize products of necrotic/damaged cells (uric acid, ATP, K+ loss) and some microbial products
• Several NLRs signal via the inflammasome - a cytosolic multiprotein complex that activates caspase-1, which cleaves pro-IL-1β into biologically active IL-1
• IL-1 promotes fever and acute phase response
• Example: NLRP3 inflammasome detects cholesterol crystals (atherosclerosis) and uric acid crystals (gout)

• Located in the cytosol; detect viral RNA of viruses replicating in the cytosol
• Stimulate production of type I interferon (IFN)

• Detect microbial (and aberrant self) DNA in the cytosol
• Activate the STING (Stimulator of Interferon Genes) pathway -> type I IFN
• Excessive STING activation causes systemic interferonopathies

• On plasma membrane of macrophages and DCs
• Recognize fungal glycans and elicit inflammatory responses to fungi

• Recognize terminal mannose residues on microbial glycoproteins (unlike mammalian glycoproteins)
• Induce phagocytosis of microbes

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C. Cellular Components of Innate Immunity

• Skin, GI tract, and respiratory tract epithelium block physical entry of microbes
• Produce antimicrobial molecules: defensins, lysozyme, collectins
• Intraepithelial lymphocytes combat microbes at these sites
• Mucus trapping and mucociliary clearance in the respiratory tract

• Neutrophils (PMNs): first cells recruited to sites of infection; kill bacteria by oxidative burst (ROS), lysosomal enzymes (myeloperoxidase), and neutrophil extracellular traps (NETs)
• Macrophages: tissue-resident (Kupffer cells in liver, microglia in brain, alveolar macrophages in lung) or recruited from circulating monocytes; phagocytose and destroy microbes; produce pro-inflammatory cytokines (TNF, IL-1, IL-6, IL-12); act as APCs to initiate adaptive immunity
• Both cell types carry surface receptors for PAMPs and for complement fragments (opsonins)

• Specialized sentinels present in epithelia, lymphoid organs, and most tissues
• Capture protein antigens and present them to T lymphocytes (antigen-presenting function)
• Rich collection of PRRs; secrete cytokines critical for inflammation and antiviral defense
• Bridge innate and adaptive immunity - upon activation, DCs mature and migrate to lymph nodes to initiate T-cell responses

• Large granular lymphocytes making up 5-10% of peripheral blood lymphocytes
• Recognize and kill virus-infected cells and tumor cells without prior sensitization
• Mechanism of regulation (missing-self hypothesis):
  • Carry activating receptors that recognize stress-induced ligands on infected/tumor cells
  • Carry inhibitory receptors that recognize MHC class I molecules on healthy cells
  • Virus infection -> upregulates activating ligands + downregulates MHC class I -> NK cell activation and killing
• Express CD16 (FcγRIII) - binds Fc tail of IgG -> antibody-dependent cellular cytotoxicity (ADCC)
• Kill by releasing perforins and granzymes

• Tissue-resident lymphocytes lacking antigen receptors
• Activated by cytokines from sites of tissue damage
• Classified into ILC1, ILC2, ILC3 based on cytokines produced (mirroring Th1, Th2, Th17 T cell subsets)
• Sources of early inflammatory cytokines (IFN-γ, IL-5, IL-17)

• Contain granules rich in histamine, heparin, and inflammatory mediators
• Activated by IgE (in allergic reactions) and by PAMPs; release preformed and newly synthesized mediators

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D. Soluble Effector Molecules of Innate Immunity

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2.2 ADAPTIVE IMMUNITY (Acquired / Specific Immunity)

Key Features Compared to Innate Immunity

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A. Two Arms of Adaptive Immunity

• Mediated by B lymphocytes and their secreted products: antibodies (immunoglobulins)
• Protects against extracellular microbes and their toxins
• Antibody functions: neutralization, opsonization (enhanced phagocytosis), complement activation, ADCC, neonatal immunity (IgG crosses placenta; IgA in breast milk)

• Mediated by T lymphocytes
• Responsible for defense against intracellular microbes (viruses, mycobacteria) and cancer cells
• Also mediates delayed-type hypersensitivity and transplant rejection

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B. Lymphocytes - The Key Cells of Adaptive Immunity

• Naive: Mature lymphocytes that have never encountered their antigen; circulate among blood, lymphoid organs, and tissues
• Effector: Activated lymphocytes that perform immune functions (killing, antibody production)
• Memory: Long-lived cells that survive after infection is cleared; respond faster and more vigorously upon re-exposure (basis of vaccination)

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C. T Lymphocytes

• MHC Class I molecules (HLA-A, HLA-B, HLA-C): expressed on all nucleated cells and platelets; present peptides from cytosolic (intracellular) proteins (viruses, tumor antigens) to CD8+ CTLs
• MHC Class II molecules (HLA-DP, HLA-DQ, HLA-DR): expressed on professional APCs only (DCs, macrophages, B cells); present peptides from exogenous (endocytosed) antigens to CD4+ T cells
• The HLA system is highly polymorphic (thousands of alleles in humans), making it a major barrier to organ transplantation

1. Signal 1 - TCR binds MHC-peptide complex on APC
2. Signal 2 - Costimulatory molecules: CD28 on T cell binds B7 (CD80/CD86) on APC

• Without Signal 2 -> anergy (tolerance, not activation)
• Activated T cells produce IL-2 (autocrine growth factor) and express IL-2R -> clonal expansion

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D. B Lymphocytes and Humoral Immunity

• B cells (bone marrow-derived) express membrane-bound immunoglobulins as their antigen receptors (BCR)
• BCR can recognize native antigens (proteins, polysaccharides, lipids, nucleic acids) directly - no MHC presentation required
• When activated, B cells:
  1. Proliferate
  2. Differentiate into plasma cells (secrete antibodies) and memory B cells
  3. Undergo somatic hypermutation (in germinal centers) -> affinity maturation
  4. Undergo class switching (IgM -> IgG, IgA, IgE) under cytokine influence from Th cells

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2.3 OTHER CLASSIFICATIONS OF IMMUNITY

• Generated by the individual's own immune response
• Natural active: result of infection
• Artificial active: result of vaccination
• Characterized by immunologic memory; long-lasting (years to lifetime)

• Conferred by transfer of preformed antibodies
• Natural passive: maternal IgG across the placenta; IgA via breast milk
• Artificial passive: injection of immunoglobulins (e.g., anti-tetanus, anti-rabies)
• No memory generated; immediate but short-lived (weeks to months)

• When a sufficient proportion of a population is immune, unimmunized individuals are indirectly protected because the chain of transmission is broken

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PART 3: THE COMPLEMENT SYSTEM - IN DETAIL

3.1 Definition and Overview

• Alternative and lectin pathways function in innate immunity (no antibody needed)
• Classical pathway links adaptive immunity (antibodies) to complement

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3.2 The Three Activation Pathways

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PATHWAY 1: CLASSICAL PATHWAY

1. C1 (a complex of C1q, C1r, C1s) binds via C1q to the Fc region of antibody-antigen complexes
2. C1q binding activates C1r, which activates C1s (a protease)
3. C1s cleaves C4 into C4a (released) and C4b (covalently binds surface)
4. C4b binds C2; C1s cleaves C2 into C2a and C2b
5. C4b2a = Classical C3 convertase (cleaves C3)
6. C4b2a3b = Classical C5 convertase (cleaves C5)

• Requires preformed antibody -> bridges adaptive and innate immunity
• IgM is the most efficient complement activator (one molecule); IgG requires multiple molecules

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PATHWAY 2: ALTERNATIVE PATHWAY

1. C3 undergoes slow spontaneous hydrolysis in plasma (C3 "tick-over") generating C3(H2O)
2. C3(H2O) binds Factor B; Factor D (circulating protease) cleaves Factor B into Ba and Bb
3. C3(H2O)Bb = initial C3 convertase, cleaves C3 into C3a and C3b
4. C3b is deposited on microbial surfaces; binds Factor B; Factor D cleaves to form C3bBb = Alternative C3 convertase
5. Properdin (Factor P) stabilizes C3bBb (extends its half-life)
6. C3bBbC3b = Alternative C5 convertase

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PATHWAY 3: LECTIN PATHWAY (Mannose-Binding Lectin Pathway)

1. MBL binds microbial mannose residues; MBL is associated with MASPs (MBL-Associated Serine Proteases) - MASP-1 and MASP-2
2. MASP-2 (homologous to C1s) cleaves C4 and C2
3. Subsequent steps identical to classical pathway
4. C4b2a = Lectin pathway C3 convertase

• Antibody-independent innate immune pathway
• MBL is an acute-phase protein; levels rise during infection

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Common Convergence Point

• C3a (released into plasma - anaphylatoxin)
• C3b (covalently deposited on the activating surface - opsonin)

• C5a (released - most potent anaphylatoxin and chemotactic factor)
• C5b (stays on surface - nucleates MAC formation)

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3.3 Terminal Pathway - Membrane Attack Complex (MAC)

1. C5b binds C6, then C7 (C5b-7 complex inserts into lipid bilayer)
2. C8 binds C5b-7
3. Multiple C9 molecules polymerize around C5b-8 to form the MAC (C5b-6789n)

• MAC creates a transmembrane pore (10 nm diameter) in the cell membrane
• Allows free flow of water and ions into the cell -> osmotic lysis
• Effective against microbes with thin cell walls, especially Neisseria (gonorrhea, meningitis)

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3.4 Functions of the Complement System

Function 1 - Inflammation (Anaphylatoxins)

• Histamine release from mast cells and basophils -> vasodilation and increased vascular permeability
• Chemotaxis: C5a is a powerful chemotactic agent for neutrophils, monocytes, eosinophils, and basophils; recruits them to sites of infection
• Leukocyte activation: C5a activates the lipoxygenase pathway in neutrophils/monocytes -> further release of inflammatory mediators (leukotrienes)
• Called "anaphylatoxins" because their effects resemble those of mast cell mediators in anaphylaxis

Function 2 - Opsonization and Phagocytosis

• C3b and its cleavage product iC3b (inactive C3b), when fixed to microbial cell walls, act as opsonins
• Phagocytes (neutrophils and macrophages) express surface receptors for complement fragments:
  • CR1 (CD35) - binds C3b and C4b
  • CR3 (CD11b/CD18) - binds iC3b
• Opsonized microbes are recognized and efficiently phagocytosed
• This function is especially important for encapsulated bacteria (S. pneumoniae, H. influenzae) that resist phagocytosis otherwise

Function 3 - Cell Lysis via MAC

• As described above, the MAC creates pores in cell membranes -> osmotic lysis
• Critical against thin-walled microbes especially Neisseria meningitidis and N. gonorrhoeae
• Deficiency of terminal complement components (C5-C9) -> recurrent Neisseria infections

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3.5 Regulation of Complement Activation

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3.6 Complement in Disease

• Eculizumab (anti-C5 monoclonal antibody) - approved for PNH and aHUS
• Ravulizumab (longer-acting anti-C5) - PNH
• Pegcetacoplan (C3 inhibitor) - PNH
• Avacopan (C5a receptor antagonist) - ANCA vasculitis

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PART 4: AIDS - A DETAILED NOTE

4.1 Introduction and Epidemiology

• An estimated 88.4 million people have become infected with HIV since the start of the pandemic
• In 2023, 1.3 million new infections occurred worldwide (including 120,000 children <15 years)
• 30.7 million people (77% of all HIV-positive individuals) are currently on antiretroviral therapy (ART)
• Sub-Saharan Africa (WHO Eastern and Southern Africa region) is most severely affected: >5.7% adult prevalence, >50% of worldwide HIV burden

• HIV-1: Responsible for most infections worldwide; divided into groups M, N, O, P; Group M has subtypes A-K; Subtype C is most prevalent globally (~50% of infections); Subtype B predominates in Western countries
• HIV-2: Less virulent; lower transmissibility; mainly in West Africa; lacks the vpu gene (has vpx instead)

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4.2 Structure of HIV

• Envelope glycoproteins: gp120 (surface unit - binds CD4) and gp41 (transmembrane unit - mediates membrane fusion)
• Core (capsid): p24 protein
• Matrix: p17/p18 proteins (inner membrane lining)
• Genome: Two copies of single-stranded (+) RNA with reverse transcriptase, integrase, and protease
• Key genes:
  • gag - encodes core structural proteins (p24, p17)
  • pol - encodes reverse transcriptase, integrase, protease
  • env - encodes envelope glycoproteins (gp120, gp41)
  • tat, rev - regulatory genes
  • nef, vif, vpr, vpu - accessory genes that enhance viral replication and pathogenesis
  • LTRs (Long Terminal Repeats) - flank the genome; contain regulatory elements for gene expression

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4.3 Transmission

1. Sexual contact (most common globally) - both heterosexual and male-to-male; mucosal trauma facilitates entry
2. Blood and blood products - transfusions, needle sharing among injection drug users
3. Vertical (mother-to-child) transmission:
   • Intrapartum (during delivery) - most common
   • Perinatally (in utero) - less common
   • Via breast milk (postnatal)
4. Occupational exposure - needlestick injuries in healthcare workers

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4.4 Pathogenesis of HIV Disease

Step 1 - Entry into CD4+ T Cells

1. gp120 on the HIV envelope binds the CD4 receptor on helper T cells with high affinity
2. This binding induces a conformational change, exposing a co-receptor binding site on gp120
3. gp120 then binds a co-receptor:
   • CCR5 (C-C chemokine receptor 5) - used by R5-tropic (macrophage-tropic) viruses, predominantly during early/transmitted infection
   • CXCR4 (CXC chemokine receptor 4) - used by X4-tropic (T-cell-tropic) viruses, emerging in later disease stages
4. Co-receptor binding exposes gp41, which anchors the virus into the T-cell membrane and mediates fusion of viral and cellular membranes
5. Viral RNA with reverse transcriptase is injected into the T-cell cytoplasm

Step 2 - Reverse Transcription and Integration

1. Reverse transcriptase converts viral ssRNA into double-stranded viral DNA (error-prone, ~1 error per genome per cycle - source of HIV's extraordinary genetic diversity and drug resistance)
2. The newly synthesized viral DNA (with the viral integrase enzyme) is transported into the nucleus
3. Integrase inserts the viral DNA into the host cell genome -> provirus
4. The provirus can remain latent for years (in resting CD4+ T cells) - this forms the latent reservoir, the primary barrier to cure

Step 3 - Viral Replication and Spread

1. Activation of the infected T cell (e.g., by another infection or antigen) triggers transcription of the provirus
2. New viral RNA is transcribed, translated, and viral proteins are assembled
3. New virus particles bud from the T-cell surface, acquiring their lipid envelope in the process
4. Viral protease cleaves polyproteins into mature viral proteins during or after budding (essential for infectivity)
5. New virions infect other CD4+ T cells, macrophages, and dendritic cells

Step 4 - Acute HIV Infection

• Occurs 2-4 weeks after initial infection in ~50% of individuals
• Characterized by high-level plasma viremia (millions of copies/mL)
• Acute mononucleosis-like syndrome: fever, lymphadenopathy, pharyngitis, rash, myalgias, headache
• Massive viral replication in gut-associated lymphoid tissue (GALT) depletes CD4+ T cells from the intestinal mucosa
• Immune response (CD8+ CTLs, antibodies) partially controls viremia -> viral set point is established
• The viral set point (after ~1 year) correlates with the rate of long-term disease progression

Step 5 - Chronic HIV Infection and CD4+ T-Cell Depletion

1. Direct cytopathic effects of viral replication in CD4+ T cells (most important)
2. CD8+ CTL killing of HIV-infected CD4+ T cells
3. Pyroptosis - inflammatory caspase-1-dependent cell death; HIV replication in GALT triggers IL-1β and IL-18 release -> bystander killing of uninfected CD4+ T cells
4. Depletion in GALT of IL-17-producing T cells -> impaired defense against extracellular bacteria and fungi at mucosal surfaces
5. Microbial translocation: HIV damages gut mucosal barrier -> bacterial LPS enters circulation -> chronic systemic immune activation -> drives HIV replication (vicious cycle) and contributes to non-AIDS comorbidities

Step 6 - Persistent Immune Activation

• HIV replication is persistent and drives chronic immune activation throughout the course of untreated disease
• HIV replicates most efficiently in activated CD4+ T cells - chronic activation fuels further viral replication
• Even in patients on ART with suppressed viremia (<20 copies/mL), low-level immune activation persists due to:
  • Residual low-level viral replication
  • Transcription from defective integrated proviruses
  • Microbial translocation
• Chronic immune activation contributes to non-AIDS comorbidities:
  • Accelerated cardiovascular disease
  • Metabolic disorders (diabetes, dyslipidemia)
  • Bone fragility
  • Non-AIDS cancers
  • Neurocognitive dysfunction
  • Accelerated aging syndrome

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4.5 Clinical Stages of HIV/AIDS

Stage A - Acute and Early Infection

• Primary HIV infection (acute retroviral syndrome, if symptomatic)
• Asymptomatic infection - may last years (average ~10 years without treatment)
• Persistent Generalized Lymphadenopathy (PGL) - lymph node enlargement >1 cm in 2 or more non-contiguous sites for >3 months
• CD4+ count: typically >500 cells/µL

Stage B - Symptomatic, Non-AIDS

• CD4+ count: 200-499 cells/µL
• Conditions attributable to HIV-related immunodeficiency but not AIDS-defining:
  • Oral thrush (oropharyngeal candidiasis)
  • Recurrent vaginal candidiasis
  • Oral hairy leukoplakia (EBV)
  • Herpes zoster (shingles)
  • Constitutional symptoms (fever, night sweats, weight loss)
  • Peripheral neuropathy

Stage C - AIDS (Advanced HIV Disease)

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4.6 Laboratory Monitoring

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4.7 Antiretroviral Therapy (ART)

• 2 NRTIs + 1 INSTI (e.g., Tenofovir-Emtricitabine + Dolutegravir or Bictegravir)
• ART is now recommended for all HIV-infected individuals regardless of CD4+ count
• ART also prevents transmission: U=U (Undetectable = Untransmittable) - individuals with sustained undetectable viral load cannot sexually transmit HIV

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4.8 Prevention

• Pre-Exposure Prophylaxis (PrEP): Daily tenofovir-emtricitabine (or cabotegravir long-acting injectable) for HIV-negative high-risk individuals; >99% effective when taken correctly
• Post-Exposure Prophylaxis (PEP): 28-day ART course started within 72 hours of exposure
• Condom use, harm reduction programs, needle exchange programs
• No licensed HIV vaccine currently exists, though research continues

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4.9 Summary Table - AIDS

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Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease 11th ed.; Cellular and Molecular Immunology (Abbas, Lichtman & Pillai); Histology: A Text and Atlas (Eroschenko); Harrison's Principles of Internal Medicine 22nd Edition (2025)